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Adenosine in the Central Nervous System: Effects on Neurotransmission and Neuroprotection

August 2007
Immunology Endocrine & Metabolic Agents - Medicinal Chemistry 7(4):304-321

August 2007
7(4):304-321

DOI:10.2174/187152207781369832

Authors:

Felicita Pedata

University of Florence

Anna Maria Pugliese

University of Florence

Elisabetta Coppi

University of Florence

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Adenosine is one of the principal neuromodulators in the brain and acts on four specific receptor subtypes: the A1, A2A, A2B and A3 receptors. Adenosine concentrations normally reached in the extracellular space are in the nanomolar range and may stimulate the high affinity A1 and A2A receptors. Inhibitory effects on neurotransmission are mediated mainly by A1 receptors while excitatory effects are mediated by A2A receptors. Adenosine has an overall net inhibitory effect on neurotransmission. Under normoxic conditions, A3 receptors do not exert a significant effect on neurotransmission and no data are available concerning the effect of A2B receptors. Given its ability to modulate neurotransmission, adenosine plays several physiological roles in the brain. It controls motility, acts as an endogenous anticonvulsant, and affects pain control, sleep, cognition and memory. It is also likely to be involved in the tonic modulation of affective states and consequently in social interaction and aggressive behaviour. Under pathological conditions, adenosine plays an important role in neuroprotective mechanisms interacting with A1 and A2A receptors and more recently there is evidence that A3 receptors are also involved. It has been demonstrated that A2A antagonists may be useful for control of symptoms and potentially for neuroprotection in Parkinson's disease. One possible approach in cerebral ischaemia is that of agents increasing locally the extracellular concentration of adenosine and of using A2A antagonists. Recent data support the putative utility of A2A receptor ligands in Huntington's disease.

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Immun., Endoc. & Metab. Agents in Med. Chem., 2007, 7, 000-000 1

Adenosine in the Central Nervous System: Effects on Neurotransmission

and Neuroprotection

F. Pedataa,*, A.M. Pugliesea, E. Coppia, P. Popolib, M. Morellic, M. A. Schwarzschildd and

A. Melania

aDepartment of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy, bDepartment of Drug

Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy, cDepartment of Toxicology, University of Cagliari,

Cagliari, Italy and dMassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard

Medical School, Charlestown, MA, USA

Abstract: Adenosine is one of the principal neuromodulators in the brain and acts on four specific receptor subtypes: the

A1, A2A, A2B and A3 receptors. Adenosine concentrations normally reached in the extracellular space are in the nanomolar

range and may stimulate the high affinity A1 and A2A receptors. Inhibitory effects on neurotransmission are mediated

mainly by A1 receptors while excitatory effects are mediated by A2A receptors. Adenosine has an overall net inhibitory ef-

fect on neurotransmission. Under normoxic conditions, A3 receptors do not exert a significant effect on neurotransmission

and no data are available concerning the effect of A2B receptors. Given its ability to modulate neurotransmission, adeno-

sine plays several physiological roles in the brain. It controls motility, acts as an endogenous anticonvulsant, and affects

pain control, sleep, cognition and memory. It is also likely to be involved in the tonic modulation of affective states and

consequently in social interaction and aggressive behaviour.

Under pathological conditions, adenosine plays an important role in neuroprotective mechanisms interacting with A1 and

A2A receptors and more recently there is evid ence that A3 receptors are also involved. It has been demonstrated that A2A

antagonists may be useful for control of symptoms and potentially for neuroprotection in Parkinson’s disease. One possi-

ble approach in cerebral ischaemia is th at of agents increasing locally the ex tracellular concentration of ad enosine and of

using A2A antagonists. Recent data support the putative utility of A2A receptor ligands in Huntington’s disease.

Key Words: Adenosine, adenosine receptors, neurotransmission, neuroprotection, ischaemia, parkinson’s disease, huntington’s

disease, alzheimer’s disease.

INTRODUCTION

It is well established that adenosine plays a crucial role in

the central nervous system (CNS), as a modulator of neuro-

transmission and in neurodegeneration.

Adenosine is physiologically present in the extracellular

brain fluid in nanomolar concentrations [1] and mediates

specific actions through membrane receptors which have

been cloned and classified as A1, A2A, A2B and A3 receptors

[2].

The activation of different receptor subtypes causes en-

dogenous adenosine to have different effects. Inhibitory ac-

tions of adenosine on excitatory neurotransmission are prin-

cipally ascribed to A1 receptor activation [3,4], whereas exci-

tatory actions of adenosine on neurones have been observed

after A2A receptor stimulation [5,6]. However, the net effect

of adenosine is as an inhibitory tonus on neurotransmission.

The neuroprotective role of adenosine has been demon-

strated in a variety of in vitro and in vivo physio-pathological

models and is principally ascribed to A1 receptor stimulation

[7,8,9]. Most recent data show a neuroprotective role of A2A

*Address correspondence to this author at the Department of Preclinical and

Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139

Florence, Italy; Tel: + 39 055 4271.262; Fax: + 39 055 4271.280;

E-mail: felicita.pedata@unifi.it

receptor antagonists in different in vivo models of Parkin-

son’s disease [10] and cerebral ischaemia [11,12]. Several

lines of evidence indicate that adenosine A2A receptors can

be regarded as promising targets for Huntington’s disease

[13-15].

Little information is available at the moment on the spe-

cific effects of A2B receptors in the CNS, and controversial

effects have been ascribed to A3 adenosine receptor under

ischaemic conditions [16].

The purpose of this review is to summarise the physio-

logical role of adenosine on neurotransmission and to em-

phasise the important implications of adenosine in neurode-

generative diseases that recent studies have brought to light.

1. ADENOSINE RECEPTORS AND DISTRIBUTION

IN THE CNS

In the CNS, adenosine may be formed intracellularly

from degradation of adenosine monophosphate (AMP) or

extracellularly by the metabolism of released nucleotides [1]

(see Fig. 1). The contribution of adenosine triphosphate

(ATP) metabolism to the extracellular concentrations of

adenosine under physiological and pathological conditions is

still under study [17,18].

All adenosine actions are mediated by specific activation

of four different receptors, known as P1 receptors, from the

2 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

P1 (adenosine selective)/P2 (ATP selective) nomenclature

[19], located on cell membranes and belonging to the family

of G protein-coupled receptors: A1, A2A, A2B and A3 (Table

1). Definitive evidence for the existence of each type of

adenosine receptor has been established by molecular clon-

ing and expression studies [2]. It has long been known that

A1 and A3 receptors are coupled to Gi/o proteins which inhibit

adenylate cyclase and that A2A and A2B receptors are coupled

to Gs protein which stimulates adenylate cyclase. However,

adenosine receptors, by coupling to other G-protein sub-

types, have also been reported to modulate other second

messenger systems (see Table 1). In addition to their inhibi-

tory effects on adenylate cyclase and, contrary to adenosine

A2A receptors, adenosine A1, A2B and A3 receptors ar e also

characterized by their stimulatory effect on phospholipase C

[20,21]. A1 and A3 receptors can also activate phospholipase

D [2]. Several types of Ca++ and K++ channels are also acti-

vated (directly or by second messengers) after adenosine

receptors stimulation. If expressed in chinese hamster ovary

(CHO) cells, all adenosine receptors are able to induce phos-

phorylation of the mitogen-activated protein kinase (MAPK)

ERK1/2 (extracellular-regulated kinase 1/2) [22]. All these

cellular events might contribute to a fine-tuning of neuronal

function.

Fig. (1). Sites of action of putative neuroprotective adenosinergic

drugs. A1: adenosine A1 receptor; A2A: adenosin e A2A receptor; A3:

adenosine A3 receptor; ADA: adenosin e deaminase; ADO: adeno-

sine; AKA: adenosine kinase; AMP: adenosine monophosphate;

ATP: adenosine triphosphate; 5’-N: ecto-5’-nucleotidase; NT: neu-

rotransmitter; T: bidirectional nucleoside transporter. During cere-

bral ischaemia, extracellular ADO concentration increases. In the

extracellular space, ADO acting on several receptor subtypes, both

at a pre- and at a postsynaptic level, plays different roles. Different

therapeutic strategies for ischaemic events which are under study

include: (1) ADA inhibitors; (2) AKA inhibitors; (3) T inhibitors;

(4) A1 agonists (5) A2A antagonists (6) A3 agonists or antagonists

about which, contradictory data are available.

Adenosine receptors are subdivided into high affinity

receptors (A1 and A2A) and low affinity receptors (A2B and

A3) on the basis of their affinity for adenosine [2]. Extracel-

lular adenosine concentrations are estimated to be in the

range 30 to 200 nM (see:[1]). These levels are able to acti-

vate high affinity receptors: A1 and A2A subtypes. The affin-

ity value of A2B and A3 receptors for adenosine in binding

experiments is higher than 1 M [2]. Thus, activation of

these adenosine receptor subtypes requires a higher concen-

tration of adenosine than that necessary to activate A1 and

A2A receptor subtypes. During hypoxic/ischemic conditions

in vivo [11] and in vitro [23] high extracellular adenosine

concentrations are reached which may activate all adenosine

receptor subtypes. Adenosine effects on A1, A2A and A2B

receptors are antagonised by methylxanthines such as caf-

feine and theophylline, whereas the adenosine A3 receptor

subtype is relatively xanthine-insensitive [24,25].

Adenosine A1 receptors have been well characterised [26-

28] thanks to the availability of radiolabeled agonists and

antagonists. Recently using [18F]8-cyclopentyl-3-(3-fluoro-

propyl)-1-propylxanthine ([18F]CPFPX) and PET imaging A1

receptors were quantified in the human brain [29]. The high-

est expression of A1 receptors has been found in the cortex,

hippocampus, cerebellum and dorsal horn of the spinal cord;

intermed iate levels in basal ganglia structures including the

striatum, globus pallidus, subthalamic nucleus and thalamus

[2,30]. An abundant expression of the adenosine A1 receptor

protein also occurs in the trigeminal ganglia, which supports

a role of this receptor in analgesia [31]. The mRNA encod-

ing A1 receptors is present in large striatal cholinergic in-

terneurones [30]. Neuronal A1 receptors are localized both

pre- and postsynaptically [32]. In the hippocampus, a brain

area in which A1 receptors are abundant, subcellular frac-

tionation of nerve terminals revealed that A1 receptor im-

munoreactivity is strategically located in the active zone of

presynaptic nerve terminals, as expected on the basis of the

efficiency of A1 receptors to depress neurotransmitter re-

lease. However A1 receptors are also present in nerve termi-

nals outside the active zone in accordance with the existence

of a presynaptic A1 receptor reserve [33]. It has also been

demonstr ated that A1 receptor immunoreactivity is evident at

postsynaptic sites together with N-methyl-D-aspartate

(NMDA) receptor subunits 1, 2A and 2B and with N-and

P/Q-type calcium channel immunoreactivity, emphasizing

the importance of A1 receptors in the control of dendritic

integration [33]. A1 receptors can be found also extrasynapti-

cally on dendrites [34] and on the axonal fibers of the hippo-

campus [35]. Activation of A1 receptors at axonal level may

be a powerful mechanism by which adenosine alters axonal

transmission to inhibit neurotransmitter release [35].

2A receptors are located in the striatum, principally in

the caudate-putamen, nucleus accumbens and olfactory tu-

bercle [36,37]. In particular, this receptor subtype is ex-

pressed on striatopallidal -amino-butyric acid (GABA)

ergic-enkephalin neurones, where co-localises with dopa-

mine D2 receptors, but not on GABAergic-dynorphin striatal

neurones [38-40] (see Fig. 2). The prominent A2A-dependent

signalling in the brain is therefore integrated with the dopa-

mine D2 signal and it was reported that the heterodimeriza-

tion between A2A and D2 receptor subtypes inhibits D2 recep-

tor function [41]. In the striatum the A2A receptor gene is

Adenosine in the Central Nervous System Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 3

found to a lesser extent also in large striatal cholinergic in-

terneurones [30]. Although molecular biology studies have

revealed a single A2A receptor population, pharmacological

studies differentiated subpopulations of A2A receptors. In

particular the main expressed A2A striatal receptor (the proto-

typical A2A receptor) has a higher affinity for selective A2A

agonists in comparison to a less extensively expressed stri-

atal A2A receptor and to the cortical and hippocampal A2A

receptor [42-45].

Sensitive techniques have permitted the identification of

A2A receptor mRNA not only in the striatum but also in other

brain areas: hippocampus and cortex [30,46]. Besides post-

synaptically, A2A receptors are also located presynaptically

on different GABAergic, cholinergic, glutamatergic neurone

types, although to a lesser extent [47,48].

Both A1 and A2A receptors are expressed not only on neu-

rones but they are also located on microglial cells [49], as-

trocytes [50,51] and blood cells and vasculature [52]. Both

A1 and A2A receptors undergo desensitisation [53,54].

The adenosine A3 receptor is the most recently discov-

ered [55]. The expression level of this receptor in the brain is

lower than that of other subtypes [56] and is highly species-

dependent [2,57]. A3 receptors are found in both neuronal

and non-neuronal elements, i.e. astrocytes, microglia, and

vasculature of the cer ebral tissue with widespread distribu-

tion. Both human and rat A3 receptors are quickly desensi-

tised within a few minutes after agonist exposure [58-62].

2B receptors are ubiquitously distributed in the brain and

mRNA has been detected in all rat cerebral areas studied

[30,63]. Up to now it has been difficult to relate A2B recep-

tors to specific physiological responses in the brain because

of the paucity of A2B selective agonists or antagonists.

2. ADENOSINE EFFECTS ON NEUROTRANSMIS-

SION

Under physiological conditions adenosine exerts a tonic

influence on neuronal activity as demonstrated in several

brain regions such as the hippocampus, striatum and olfac-

tory cortex. It is known that the A1 receptor subtype tonically

inhibits synaptic transmission both in vitro or in vivo [63,1].

The inhibitory effect of adenosine A1 receptor stimula-

tion has a pre- and postsynaptic component. These mecha-

nisms were studied in brain regions with a high concentra-

tion of A1 receptors, such as the hippocampus. Activation of

the presynaptic A1 receptors reduces Ca2+ influx through the

preferential inhibition of N-type and, probably, Q-type chan-

nels [64-66]. Inhibition of presynaptic calcium currents de-

creases transmitter release [67] and adenosine, by stimula-

tion of A1 receptors, has been found to inhibit the release of

virtually all classical neurotransmitters e.g., glutamate, ace-

tylcholine, dopamine, noradrenaline, serotonin (see in [68]).

In particular a powerful suppression of glutamate release

from presynaptic terminals in the hippocampus [69,70] has

been described. A Ca2+-independent component of adeno-

sine-mediated depression of neurotransmitter release has also

been observed [71].

The postsynaptic effects on A1 receptors consist in direct

hyperpolarisation of neurones via activation of G-protein

coupled to inward rectifying potassium (GIRK) channels at

the postsynaptic site [72,73]. In slices taken from homozy-

gous A1 receptor knockout mice, no evidence was found of

endogenous inhibitory modulatory action of adenosine in the

Schaffer collateral pathway in the CA1 region of the hippo-

campus or at the mossy fiber synapses in the CA3 region

[74]. In addition, no inhibition of synaptic transmission was

Table 1. Characteristics and Distribution of Adenosine Receptor Subtypes in the CNS

Receptor

subtypes

G-protein G-protein coupli ng

effect Adenosine affinity* Distribution

 cAMP

 PLC, IP3/DAG

Arachidonato,PLA2

Gi1/2/3

 PLD

3-30 nM High levels in cortex, hippocampus, cerebellum and

intermediate levels in striatum, thalamus

Gs  cAMP

Golf  cAMP

A2A

G15/16  IP3

1-20 nM High levels in: caudate-putamen, nucleus accumbens,

olfactory tubercle Low levels in: cortex ,

hippocampus

Gs  cAMP A2B

Gq/11  PLC, IP3/DAG,

 PLD

5-20 M Low levels

Gi2/3  cAMP A3

Gq/11  PLC, IP3/DAG

 PLD

>1 M Low levels

cAMP, cyclic AMP; DAG, diacylglycerol; PLA2, , phospholipase A2; PLC, phospholipase C; PLD, phospholipase D. From: [2] and [16].

4 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

elicited by exogenous adenosine [75]. Similarly, the targeted

deletion of A1 receptors from CA3 neurones abolished the

inhibi-tory response to adenosine, but deletion of A1 recep-

tors from CA1 neurones had no effect, demonstrating a pre-

synaptic site of adenosine action [76].

The concerted action of these pre- and post-synaptic

mechanisms resu lts in control of excitatory neurotransmis-

sion under physiological and pathological conditions. In rela-

tion to the control of excitatory neurotransmission mediated

by A1 receptors, endogenous adenosine regulates the degree

of long-term potentiation (LTP) [77] and long-term depres-

sion (LTD) magnitude [78] in hippocampal slices.

2A receptor activation has been shown to mediate

adenosine excitatory actions in the nervous system [6]. Elec-

trophysiological investigations into the role of A2A receptors

in synaptic functions under physiological conditions have

shown that they increase synaptic neurotransmission [79,46].

In the hippocampus in vitro A2A receptor stimulation results

in a calcium-dependent release of acetylcholine [80] and 2-

p-(2 - carboxyethyl)phenethylamino - 5' - N - ethylcarboxamido -

adenosine hydrochloride (CGS 21680), a selective A2A re-

ceptor agonist, decreases the ability of A1 receptor agonists

to inhibit excitatory neurotransmission [46,81]. The mecha-

nisms by which A2A receptors increase synaptic transmission

are not fully understood but it has been proposed that A2A

receptor stimulation brings about A1 receptor desensitization

[82,17]. It is suggested that the net excitatory synaptic activ-

ity in the hippocampus is the result of adenosine A1- and

A2A-mediated effects [23,44,83]. Electrophysiological stud-

ies showing a positive involvement of A2A receptors in the

induction or facilitation of LTP in the hippocampus [84,85]

and nucleus accumbens [86] are consistent with excitatory

effects mediated by A2A receptors. It was proposed that only

when A2A receptors undergo a protracted stimulation does

their effect on synaptic transmission become evident [44]. In

agreement, hippocampal activation of A2A receptors under

oxygen-glucose deprivation may reduce the effects mediated

by A1 receptors and a beneficial effect of A2A selective an-

tagonists may be related to the relief of tonic inhibition upon

A1 receptors [44]. Cross-talk between A1 and A2A receptors

has also been described in the cerebral cortex [87].

Selective stimulation of A2A receptors increases excita-

tory amino acid release in the striatum [88-90]. In addition,

the discovery of co-expression, co-localisation [91] and

functional relationships [92,93] between A2A and dopamine

D2 receptors in neurones expressing enkephalin and dopa-

mine D2 receptors in the basal ganglia, has added new insight

into the role of this receptor subtyp e in controlling move-

ment. A2A receptors have been found to decrease the affinity

of D2 receptors for agonists and to tonically inhibit D2-

dependent effects in the striatum [94] (see Fig. 2). Formation

of heterodimers between the A2A and D2 receptors [95,96]

possibly accounts for the observation that in dopamine D2

receptor knockout mice, functional uncoupling of adenosine

A2A receptors and reduced response to caffeine was found

[97]. However, much evidence ind icates that A2A receptor

activation by endogenous adenosine may exert an influence

on striatopallidal neurons also by a D2 receptor-independen t

mechanism. Adenosine A2A receptor selective agonists re-

duce spontaneous and amphetamine induced locomotion in

D2 receptor knockout-mice [98] and A2A receptor antagonism

rescues behavioural and cellular parameters altered in D2

receptor knockout-mice [98,99] and in striatal dopamine–

depleted rats [100]. More recently, striatal A2A receptors

have been demonstrated to interact with metabotropic gluta-

mate 5 receptors (mGluR5s) in the control of striatal func-

tions under physiological and pathological conditions. The

stimulatory effect of (RS)-2-chloro-5-hydroxyphenylglycine

(CHPG), an agonist of mGluR5s, on glutamate release was

prevented by a selective A2A receptor antagonist in a mi-

crodialysis study [101]. Evidence for the existence of

A2A/mGluR5s complexes in striatal membrane preparations

has been reported [102].

Most evidence indicates that in the rat hippocampus,

where A3 receptors are located at the presynaptic level [103],

activation of adenosine A3 receptors has an excitatory effect

on synaptic transmission. It attenuates LTD and allows in-

duction of LTP elicited by a subliminal weak-burst protocol

[104]. In the same brain area, activation of A3 receptors, by a

selective adenosine A3 agonist, antagonises the adenosine A1

receptor-mediated inhibition of excitatory neurotransmission

[105]. However, recently, by using binding and electro-

physiological studies, no significant interactions between A1

and A3 receptors were discovered [106]. Furthermore, in the

hippocampus in vitro, A3 receptors stimulation always at-

tenuated the presynaptic inhibition caused by metabotropic

glutamate receptors, by a protein kinase C (PKC)-dependent

mechanism [107]. In CA3 hippocampal pyramidal neurones,

through recording in whole-cell configuration, activation of

adenosine A3 receptors results in significant potentiation of a

high threshold hippocampal Ca++ current in a protein kinase

A (PKA)-dependent manner [108]. Contrary to the previous

results, Brand et al. [109] demonstrates that in rat cortical

neurones, the selective activation of A3 adenosine receptors

is involved in the inhibition of excitatory neurotransmission,

indicating that A3 receptors may sustain the inhibitory action

of adenosine brought about by A1 receptor.

Despite results obtained by A3 receptor stimulation, ev i-

dence that selective block of A3 receptors does not affect

neurotransmission in the CA1 region of the hippocampus,

indicates that endogenous adenosine at physiological con-

centration does not exert tonic activation of A3 receptors

[105,110]. On the contrary, during hypoxic/ischemic condi-

tions in vivo and in vitro, high adenosine extracellular con-

centrations are reached that may activate adenosine A3 re-

ceptors, contributing to cell death signalling when a thresh-

old has been reached [63,110].

3. ROLES OF ADENOSINE IN THE CNS

Because of the important role played by adenosine in

controlling neurotransmission under physiological condi-

tions, it is mainly considered a neuromodulator in the CNS,

primarily because of its effect on A1 and A2A receptors. Its

primary roles include control of motility and it acts as an

endogenous anticonvulsant but it also affects pain, sleep,

cognition and memory. Furthermore, adenosine has an im-

portant tonic modulation of the affective state [111] thus

influencing social interaction and aggressive behavior. A

recent rev iew paper analyzed the role of adenosine, taking

into account the recent insights from studies using adeno-

sine-receptor knockout mice [112].

Adenosine in the Central Nervous System Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 5

Fig. (2). Diagram of the proposed mechanism of antiparkinsonian activity of A2A antagonists acting on potentially heteromeric A2A receptors

in the striatum. As depicted in a simplified basal ganglia diagram of the normal state (A), the inhibitory influence of the striatonigral ‘direct’

pathway on basal ganglia output, from the substantia nigra pars reticulata (SNr)/internal globus pallidus (GPi) complex, is counterbalanced by

the disinhibitory influence of the striato/globus pallidus pars externa (GPe) ‘indirect’ pathway to this complex. Enk: enkephalin neurones;

6 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

(Legend Fig. 2 ) contd….

Dyn: dinorphin neurones. Striatal dopamine, acting on D1 receptors, facilitates transmission along the direct pathway and inhibits transmis-

sion along the indirect pathway through D2 receptors. Adenosine excites striatopallidal neurones via postsynaptic adenosine A2A receptors in

the striatum and presynaptic receptors in GPe, and perhaps also indirectly via presynaptic A2A receptors on corticostriatal glutamatergic (exci-

tatory) nerve terminals (see panel D). The loss of striatal dopamine in Parkinson’s disease (PD) (B) uninhibits striatal spiny projection neu-

rones of the indirect pathway, which leads to suppressed activity of the GPe and therefore uninhibition of the subthalamic nucleus (STN).

Depletion of dopamine leads also to decreased activation of striatal spiny neurones in the direct pathway. The resulting imbalance between

activity in the direct and indirect pathways engenders increased inhibitory output from the GPi and SNr with excess inhibition of thalamocor-

tical neurones, resulting in the characteristic reduced movement of PD patients. A2A receptor blockade in PD (C) should result in recovery of

GPe activity. This in turn would relieve excessiv e excitatory drive from the STN to the GPi-SNr complex, thereby restoring some balance

between the direct and the indirect pathways. Note, however, that the reduced activity in the direct pathway would not be normalised by

blocking adenosine A2A receptors. Consequently, overactivity of GPi-SNr output neurones (and the resultant motor deficits) in PD may be

only partially reversed by A2A antagonists alone. These schematics are adapted from Albin et al. (1989). See also Kase et al. (2003). Hetero-

meric interactions of A2A receptors (D) may also contribute to A2A antagonist effects on motor function. Within the striatum functional het-

eromeric G protein-coupled receptors complexes comprising A2A receptors and antagonistic D2 receptors and/or cooperative mGlu5 receptors

may reside presynaptically on corticostriatal neurones and postsynaptically on striatopallidal neurones. See text for further citations.

3.1. Anticonvulsant Effect

As an inhibitory modulator of neuronal activity, adeno-

sine has been proposed to be a major endogenous anticon-

vulsant. Local release of adenosine by encapsulated fibro-

blasts implanted near an epileptic focus led to transient de-

creased seizure susceptibility [113]. Moreover recent data

indicate that overexpression of adenosine kinase in discrete

parts of the epileptic hippocampus may contribute to the

development and progress of seizure activity [114,115]. A

prolonged increase in seizure resistance was obtained when

myoblasts, engineered to release adenosine by genetic inac-

tivation of adenosine kinase, were grafted into the lateral

brain ventricles of epileptic rats [116]. The importance of A1

receptors in the control of epileptic activity is strongly sup-

ported by the observation that the selective block of adeno-

sine A1 receptors diminished the anticonvulsive effects of the

most common antiepileptic drugs: diazepam, phenobarbital,

valproate and gabapentin against seizures evoked by the mi-

tochondrial toxin, 3-nitropropionic acid (3-NPA) in mice

[117].

3.2. Nociception

The first indication of the role of purines on spinal cord

processing of nociceptive information was described by

Sawynok and Sweeney [118]. The role of adenosine recep-

tors in nociception is complex and may involve different

mechanisms in the CNS and in peripheral tissues. Adenosine

has dual activity on nociception. It acts centrally within th e

spinal cord to suppress nociceptive signaling, presumably

through the activation of A1 receptors [119,75]. In the pe-

riphery adenosine has algogenic activity, which is probably

due to A2A receptors [120-122]. Caffeine, a nonselective A1,

A2A, and A2B adenosine receptor antagonist, exhibits antino-

ciceptive effects and shows adjuvant analgesic properties in

combination with opioid and non-opioid analgesics, for ex-

ample paracetamol [123,124]. In an animal model of acute

nociception, th e hot-plate test, several A2B-selective com-

pounds have antinociceptive effects [125].

3.3. Sleep

Adenosine is proposed to be an endogenous sleep-pro-

moting substance [126] since it is thought to serve as a ho-

meostatic regulator of brain energy during sleep [127,128]. It

is believed that adenosine's sleep-promoting effects result

from its signaling to cease behavioral activity in order to

prevent excessive activity-related changes, and thus allow

other restorative sleep-related processes to take over [129].

Both in humans and rodents, caffeine is shown to reduce

sleep and increase sleep fragmentation [130]. Microdialysis

measurements in freely behaving cats demonstrate that ex-

tracellular concentrations of adenosine in the brain progres-

sively increase during wakefulness and decline slowly during

recovery sleep [131,132]. Many studies have implicated A1

and A2A receptors in both sleep and decreased arousal [133].

The cholinergic basal forebrain is an important area of the

brain for mediating somnogenic effects. The role of A1 re-

ceptors is supported by the observation that A1 receptor an-

tisense oligonucleotide in the basal forebrain increases wake-

fulness [134]. However, it was found that A1 receptor

knockout mice do not have modified sleep pattern [135].

2A receptors are also thought to play a role in sleep,

since several studies have shown that the intracerebroven-

tricular infusion of the A2A receptor agonist CGS 21680

promotes sleep [136-139]. The largest increase in sleep oc-

curred when CGS 21680 was administered to the subarach-

noid space underlying the rostral basal forebrain (SS-rBF),

the sleep prostaglandin D2-sensitive sleep-promoting zone

[140,137]. Recently, the observation that caffeine, adminis-

tered at differen t doses, increases wakefulness in both wild-

type mice and A1 receptor knockout mice, but not in A2A

receptor knockout mice, indicates a primary involvement of

A2A receptor subtype in the control of sleep and wakefulness

[141].

3.4. Cognition and Memory

The role of adenosine in learning and synaptic plasticity

was recently reviewed by Stone et al. [17]. It is known that

LTP, a form of synaptic plasticity associated with memory,

is inhibited by A1 receptor activation [78,77] and enhanced

by A2A [85] receptor activation. A2A knockout mice show

reduced LTP in the nucleus accumbens [86]. Recent data

further support the involvement of adenosine A1 receptors in

memory mechanisms. LTP is impaired in slices from the

temporal hippocampus that show spontaneous sharp wave

(SPW) activity [142]. http://jp.physoc.org/cgi/content/full/-

558/3/953 - B17#B17SPWs are a spontaneous EEG pattern

intrinsically generated in the hippocampus and are character-

istic of the hippocampal EEG during certain behaviors

Adenosine in the Central Nervous System Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 7

(awake immobility, slow-wave sleep) [143]. It was sug-

gested that SPWs constitute a neural mechanism for forget-

ting [143-145]. A stable LTP was obtained, despite the pres-

ence of SPWs, in hippocampal slices treated with an adeno-

sine A1 receptor antagonist, suggesting that adenosine acti-

vating A1 receptor disrupts the cellular events that stabilize

potentiation [143]. Furthermore, in middle aged rats where

LTP is impaired, brief applications of A1 receptor antago-

nists, immediately after theta stimulation, fully restored LTP

[146].

3.5. Affects

The anxiogenic actions of adenosine antagonists, such as

caffeine, in animals and humans have generally been attrib-

uted to blockade of A1 sites [130,147]. Selective stimulation

and antagonism of A1 receptors is associated with anxiolytic

and anxiogenic actions, respectively [148,111]. In contrast,

in two animal models of anxiety, the social interaction test

and elevated plus maze, a selective A1 antagonist which is

orally active and highly brain penetrable, showed specific

anxiolytic activity without significantly influencing general

behavior [149].

There is evidence that A2A receptors in the hippocampus

facilitate release of GABA in vitro [150] and 5-HT in vivo

[151]. These effects may be related to the observation that

A2A receptor knockout mice display higher anxiety and ex-

hibit reduced exploratory behavior [121]. An A2A receptor

involvement in relief from anxiety is also suggested by Je-

gou et al. [152] who demonstrated that adenosine A2A recep-

tor knockout mice show a significant increase in alpha-

melanocyte-stimulating hormone (alpha-MSH) content in the

amygdala and cerebral cortex. Alpha-MSH is known to in-

crease anxiety and aggressiveness. In humans, individuals

with polymorphisms in A2A receptors are reported to have a

higher level of anxiety after caffeine administration [153].

As for possible A3 receptor involvement in anxiety, Fe-

dorova et al. [154] demonstrate that A3 receptor-deleted mice

show an increased level of anxiety.

There is little experimental evidence regarding the role of

adenosine in stress-related conditions. Caffeine potentiates

stress-related effects in animals [155] as well as in humans

[156] whereas activation of central adenosine receptors can

protect animals against stress-induced ulcer formation [157].

Stress can cause consistent increases in the number of

adenosine A1 receptors specifically in the hypothalamus

[158] as well as trigger adenosine release. After acute stress,

adenosine levels are increased in the hippocampus [159] and

ATPase, adenosine diphosphate (ADPase) and 5’-nucleo-

tidase activities in the blood serum are increased [160]. Fur-

thermore, restrained stress increases adenosine concentration

in the anterior pituitary, suggesting its possible role in hor-

monal stress response [161].

The administration of caffeine exacerbates schizophrenic

symptoms [162] and psychosis can be produced by intoxica-

tion with both caffeine and theophylline [163]. Adenosine

analogues have shown an antipsychotic-like profile in animal

models with predictive validity for antipsychotics [164,165]

and A2A receptors appear mainly involved in this mecha-

nism. The adenosine A2A receptor agonist CGS 21680 exhib-

its antipsychotic-like activity in Cebus apella monkeys

[166]. Reduced prepulse inhibition (PPI) and startle habitua-

tion were found by Wang et al. [167] in A2A receptor knock-

out mice. Both PPI and startle habituation are disrupted in

patients with schizophrenia [168]. A role of A2A receptors in

this mental disturbance is supported by the observation that

A2A knockout mice do not show behavioral sensitization to

repeated psychostimulant exposure [169]. Such behavior

may underlie some features of human psychosis. Although

data suggest an adenosine A2A receptor involvement in psy-

chosis, it was also considered that there is a limited evidence

from preclinical and clinical studies that A2A receptor an-

tagonists exert antipsychotic effects [170].

Evidence that adenosine is involved in depression was

suggested by early reports that antidepressants were capable

of potentiating suppression of neuronal firing by adenosine

[171]. Plasma concentrations of adenosine and serotonin are

increased in depressive patients after acute and chronic ad-

ministration of citalopram, a selective serotonin reuptake

inhibitor used in the treatment of depression [172]. Recent

investigations have shown that citalopram reduces the re-

lease of excitatory amino acid neurotransmitters in the rat

brain by involvement of adenosine [173]. In agreement, the

atypical antidepressant trazodone is an inhibitor of adenosine

deaminase [174]. An antidepressant-like effect of adenosine

was recently demonstrated in mice and it might involve the

interaction of both A1 and A2A receptors [175].

4. ROLES OF AD ENOS INE I N NEUR OD EGEN ERA-

TIVE DISEASES

4.1. Parkinson’s Disease

Adenosine A2A Receptor Antagonists: Symptomatic Effects

Parkinson’s disease (PD) is a neurodegenerative disease

that affects dopaminergic nigrostriatal neurones and pro-

duces progressive motor deficits such as bradykinesia and

rigidity. Current therapies of PD, either by increasing dopa-

mine levels or directly stimulating dopamine receptors, pro-

vide substantial relief from motor deficits. However, as the

dopaminergic treatment progresses neuroadaptive modifica-

tions that cause “on/off” responses and involuntary move-

ments such as dyskinesia take place. Therefore, the devel-

opment of non-dopaminergic therapies for the treatment of

PD has attracted much interest in recent years and, of the

new classes of drugs proposed, adenosine A2A receptor an-

tagonism is emerging as one of the best candidates [176,10].

Adenosine A2A receptors are selectively located in dopa-

mine-rich areas such as the striatum, nucleus accumbens and

olfactory tubercle [37]. Adenosine A2A and dopamine D2

receptors are co-localised in striatopallidal neurones [38,39],

where they negatively interact at the receptor and second

messenger level, at which A2A and D2 receptors stimulate

and inhibit cAMP formation respectively [177,96]. The co-

localisation of adenosine A2A and dopamine D2 receptors in

the striatopallidal neurones, provides the anatomical basis for

the existence of functional antagonistic interactions between

these receptors. Furthermore, indirect interactions between

D1 receptors located in striatonigral neurones [178] and A2A

receptors, play a major role in mediating motor behaviour.

In unilaterally 6-hydroxydopamine (6-OHDA) lesioned

rats, the most commonly used model of PD, adenosine A2A

8 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

receptor mRNA levels are increased in the striatum [179]

and A2A receptor agonists effectively reduce the contralateral

turning behaviour induced by dopamine receptor agonists

[180], suggesting that this receptor has a negative role on

motor behaviour. In contrast, blockade of adenosine A2A

receptors markedly increases the number of contralateral

rotations induced by L-dihydroxyphenylalanine (L-DOPA)

or by stimulation of dopamine D1 and D2 receptors, as well

as the expression of Fos-like immunoreactivity in the dorsal

striatum and globus pallidus [181-185]. In line with these

results, the A2A receptor antagonist 5-amino-7-(2-phenyl-

ethyl)-2-(2 - furyl) - pyrazolo[4,3-e] - 1,2,4 - triazolo[1,5 - c]pyri -

midine (SCH 58261) relieves muscle rigidity in reserpine-

treated rats [186]. Furthermore, in 1-methyl-4-phenyl-1,2,3,

6-tetrahydropyridine (MPTP)-treated primates, A2A receptor

antagonists improve motor deficits and enhance antiparkin-

son’s effects of low doses of L-DOPA, suggesting a potential

use of A2A antagonists as symptomatic therapy for PD [187,

188].

According to current models of basal ganglia organisa-

tion [189], inhibition of the striatopallidal pathway or stimu-

lation of the striatonigral pathway is associated with in-

creased motor activity. Therefore, adenosine A2A receptor

antagonists, when administered with L-DOPA that elevates

extracellular dopamine levels and thus stimulates both D1

and D2 receptors, would directly facilitate the inhibitory cel-

lular action of D2 receptors on striatopallidal neurones and in

turn, through the basal ganglia circuitry, would indirectly

favour the activation of the striatonigral pathway stimulated

by D1 receptors (Fig. 2).

Similarly to what has been described for acute admini-

stration, beneficial effects on motor behaviour have been

observed after chronic administration of A2A receptor an-

tagonists. In 6-OHDA lesioned rats, chronic-intermittent L-

DOPA induces a progressive increase of the turning behav-

ioural response (sensitization) which has been correlated

with the dyskinetic potential of this drug [190]. The chronic-

intermittent treatment with SCH 58261 plus L-DOPA, re-

sults in a stable turning behavioral response and prolongation

of the L-DOPA effect duration, indicating that this drug

combination has a low dyskinetic potential and reverses the

shortening in motor response [187,191-193]. Accordingly,

the genetic inactivation of A2A receptors prevents the sensiti-

sation of contralateral turning induced by chronic L-DOPA

treatment in unilaterally 6-OHDA-lesioned mice [194]. One

study, however, did not show prevention of abnormal

movements [195]. Results in rodent models of dyskinesia are

consistent with studies showing that the A2A receptor an-

tagonist (E)-1,3-diethyl-8(3,4-dimethoxystyryl)-7-methyl-

3,7-dihydro-1H-purine-2,6-dione (KW-6002) did not permit

or exacerbate dyskinesia in primates chronically and inter-

mittently treated with L-DOPA or dopaminergic agonists

[187,188,193].

An increase in the expression of striatal enkephalin and

glutamic acid decarboxylase (GAD67) mRNAs and a ten-

dency toward a decrease in dynorphin mRNA have been

reported to correlate with motor impairment in PD models

[178,196,197], whereas after chronic L-DOPA administra-

tion an increase in the striatal levels of GAD67 and dynor-

phin mRNAs has been observed [197,198]. It is of interest

that in animals treated with SCH 58261 plus L-DOPA, no or

only a minimal increase in GAD67 and dynorphin is ob-

served in the striatum, showing that neuroadaptive changes

in striatal efferent neurones after this drug pairing are not as

marked as after L-DOPA administration alone [198].

Dopamine denervation causes an incr ease in cholinergic

transmission which in turn produces another cardinal symp-

tom of PD, the resting tremor. The acetylcholinesterase in-

hibitor tacrine is a reliab le model of PD tremor in rats since

it induces tremulous jaw movements having many character-

istics of parkinsonian tremor, such as a frequency of 3-7 Hz

[199]. In agreement with a recent clinical trial indicating that

the combination of KW-6002 and a threshold dose of L-

DOPA counteracts resting tremor [200], recent studies dem-

onstrate that A2A receptor antagonists effectively counteract

tacrine-or haloperidol-induced jaw movements in rats

[201,202].

Preliminary clinical trials show th at a low dose of L-

DOPA plus KW-6002 produces symptomatic relief no dif-

ferent from that produced by an optimal dose of L-DOPA

alone, whereas dyskinesias and “off” periods can be reduced

[203-205]. In addition to the favourable safety profile dem-

onstrated by KW-6002, these clinical results are very en-

couraging for the future therapy of PD.

Adenosine A2A Receptor Antagonists: Neuroprotective Po-

tential

Recent epidemiological and laboratory data have con-

verged to suggest that A2A receptor blockade by caffeine, a

nonselective adenosine receptor antagonist, may protect

against the underlying neurodegeneration of PD. Drinking

caffeinated beverages (coffee and to a lesser extent tea) has

emerged as the dietary factor most consistently linked to an

altered (reduced) risk of developing PD [206]. After multiple

case-control studies in the 1990s suggested an inverse rela-

tionship between coffee or tea drinking and the risk of later

developing PD, several well-designed prospective studies

confirmed the association [207-209]. Thirty years after 8,000

Japanese-American men enrolled in the Honolulu Heart Pro-

gram and filled out a dietary questionnaire including ques-

tions on their consumption of coffee and other caffeinated

beverages, 102 of them were found to have developed PD.

Higher coffee intake at the outset of the study was associated

with a lower incidence of PD with a 2-fold risk reduction

observed in those who drank a single (6 oz) cup per day

compared to non-drinkers, and a 5-fold reduction in PD risk

in those who drank over four cups per day [207]. In a larger,

multi-ethnic male population that was followed for two dec-

ades in the Harvard Health Professionals’ Follow-Up Study,

[209] similarly found that consumption of caffeinated bever-

ages (coffee, tea or others) or total caffeine consumption was

inversely correlated with the incidence of subsequent PD in a

dose-dependent manner. However, drinking decaffeinated

coffee was not associated with an altered risk of PD, clearly

implicating caffeine as the component of coffee and tea that

accounts for the reduced risk.

Interestingly, the caffeine-PD link observed in men ap-

peared to be absent or more complex in women. Benedetti et

al. [208] reported that amongst men the relative risk of PD

could to be >10-fold higher in those who “never” drank cof-

fee (compared to ever drinkers), whereas among women the

relative risk was ~1.0. Studying a larger number of women

Adenosine in the Central Nervous System Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 9

whose caffeine intake was more rigorously assessed,

Ascherio et al. [209] also found that in contrast to men,

women in the Nurses Health Study showed no overall asso-

ciation between caffeine use and PD. However in subsequent

analyses of this cohort and an independent prospectively

followed cohort (of the Cancer Prevention II Study), stratifi-

cation of the women by their history of estrogen exposure

revealed a remarkable interaction between estrogen and cof-

fee/caffeine exposures in modifying the risk of PD [210,

211]. In women who reported never using postmenopausal

estrogen -- just as in men -- the consumption of caffeine or

coffee was reproducibly associated with a significant reduc-

tion in PD risk. On the other hand, women who reported

having used postmenopausal estrogen showed no such in-

verse association. These data suggest a hormonal basis for

the gender difference in caffeine’s association with PD risk,

and encourage consideration of estrogen status as a potential

confounding factor in any neuroprotection trial of caffeine or

more specific A2A antagonists for PD [210].

Neuroprotection by Caffeine and More Specific A2A An-

tagonists

Despite their considerable strengths, these epidemiologi-

cal investigations cannot directly distinguish between alter-

native, plausible explanations for the inverse association

between caffeine and PD risk:

1. caffeine may help prevent PD, or

2. an early determinant or feature of PD may reduce one’s

propensity for caffeine.

Although the question of causality is difficult to address

in humans (short of controlled clinical trials), animal models

can provide valuable clues. The former hypothesis that caf-

feine protects humans from dopaminergic neurone degenera-

tion has been strengthened by laboratory research demon-

strating that caffeine and other more specific means of inac-

tivating the A2A receptor protect against dopaminergic neu-

rone toxicity in rodent models of PD.

Caffeine, at doses in mice that correspond to those of

typical human ingestion, dose-dependently attenuates the

loss of striatal dopamine measured one week after systemic

exposure to the dopaminergic neurone toxin MPTP [212].

Caffeine also prevented 6-OHDA- as well as MPTP-induced

loss of dopaminergic nerve terminals in the striatum, and

dopaminergic cell bodies in the substantia nigra [212-214].

Of note, in contrast to caffeine’s motor stimulant effects,

which show characteristic tolerance after repeated drug ex-

posure, its neuroprotective effect in the MPTP model re-

mained undiminished after repeated caffeine administration

[215]. These persistent neuroprotective effects of caffeine in

rodent models of PD support (but do not prove) a causal ba-

sis for the inverse relationship in humans between caffeine

consumption and the risk of later developing PD.

Further animal studies have implicated the blockade of

the A2A subtype of adenosine receptor as the likely initial

mechanism of caffeine’s neuroprotective effects in models of

PD. MPTP- and 6-OHDA-induced nigrostriatal lesions have

been lessened by numerous A2A (but not A1) antagonists,

including KW-6002 [212,216,217] and SCH 58261 [212]. In

addition, A2A receptor knockout mice lacking functional A2A

receptors were assessed for their susceptibility to dopa-

minergic neurone toxins. MPTP- (but not 6-OHDA-) in-

duced losses of striatal dopamine and dopamine transporter

were attenuated in A2A knockout mice compared to their

wild-type littermates [212,194]. Thus, complimentary phar-

macological and genetic methodologies demonstrate that A2A

receptor inactivation, like caffeine itself, can protect dopa-

minergic nigrostriatal neurones.

How A2A receptor blockade protects neurones remains

unclear. Numerous hypotheses (reviewed in detail by Xu et

al. [10]) have been proposed, including the logical possibil-

ity that blockade of A2A receptors where they are so densely

expressed on GABAergic striatopallidal neurones may indi-

rectly protect dopaminergic neurones through the circuitry of

the basal ganglia (e.g., via the subthalamic nucleus). Alterna-

tively, blocking the stimulation of the sparser but functional

A2A receptors expressed on glutamatergic nerve terminals or

on glial cells may offer a generalised anti-excitotoxic or anti-

inflammatory influence of A2A antagonists in the substantia

nigra and striatum, as well as elsewhere in the brain.

4.2. Cerebral Ischaemia

Ischaemic stroke represents the third leading cause of

death in major industrialised countries, with a mortality rate

of around 30%, and the major cause of long-lasting disabili-

ties. It results from a transient or permanent reduction in

cerebral blood flow which is, in most cases, caused by the

occlusion of a major brain artery, either by an embolus or by

local thrombosis. Yet there is not a good therapy for this

pathology, in fact neuroprotective drugs that have been de-

veloped and have achieved positive results in animal stroke

models, have failed to be efficacious during clinical trials

[218].

Since the extracellular adenosine concentration increases

dramatically during ischaemia [219-225,12], numerous

authors have indicated adenosine and its receptors as a target

for therapeutic implementation in the treatmen t of stroke (see

Fig.1). Adenosine-potentiating agents which elevate endoge-

nous adenosine levels by either inhibiting its metabolism by

adenosine deaminase or kinase [226-232] or preventing its

transport [220,229,233-239] offered protection against

ischaemic neuronal damage in different in vivo ischaemia

models. Moreover, adenosine infusion into the ischaemic

striatum during medial cerebral artery (MCA) occlusion

proved to significantly ameliorate the neurological outcome

and to reduce infarct volume after transient focal ischaemia

[240].

Adenosine by stimulation of A1 receptors exerts a protec-

tive role in ischaemia by reducing Ca2+ influx, thus counter-

acting the presynaptic release of excitatory neurotransmitters

[4,241,242]and in particular of glutamate which during

ischaemia exerts an excitotoxic role mainly by overstimula-

tion of NMDA receptors [243]. By directly increasing the K+

and Cl- ion conductances, adenosine stabilises the neuronal

membrane potentials, thus reducing neuronal excitability

[244]. Consequent reductions in cellular metabolism and

energy consumption [245] and moderate lowering of the

body/brain temperature [246] are protective in ischaemia.

1 receptor agonists are shown to attenuate ischaemic or

excitotoxic neuronal damage in both in vitro and in vi vo

models of cerebral ischaemia.

10 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

In in vitro hypoxia/ischaemia models, it was demon-

strated that both adenosine and selective A1 receptor agonists

reduce neuronal damage following hypoxia and/or glucose

deprivation in primary cortical or hippocampal cell cultures

[247,248,249] and brain slices [250-252]. Marcoli and co-

workers [253] demonstrate that the selective A1 receptor

antagonist, 1,3-dipropyl-8-cyclopentyla-denosine (DPCPX),

increases ischaemia-evoked aspartate and glutamate efflux in

rat cerebrocortical slices. In accordance, the oxygen-glucose

deprivation-induced depression of synaptic transmission,

mainly attributed to activation of A1 adenosine receptors, is

reversed by administration of selective A1 receptor antago-

nists to rat hippocampal slices [242,23,254].

Recent studies show that sublethal anoxic/ischaemic in-

sults may "precondition" and protect the brain from subse-

quent insults and adenosine, by stimulating A1 receptors,

plays a crucial role in this phenomenon. In fact, an A1 recep-

tor agonist, 2-chloroadenosine (CADO), markedly enhanced

[255] and A1 receptor antagonists completely prevented

[255,110,256] the protective effect of ischaemic precondi-

tioning in hippocampal slices. In accordance with data found

“in vitro” the selective A1 antagonist, DPCPX, attenuated the

neuroprotective effect of ischaemic preconditioning in mod-

els of global [257] and focal [258,259] cerebral ischaemia.

In in vivo animal models of global or focal cerebral

ischaemia, it has been demonstrated that local administratio n

of an adenosine analogue, CADO, and of a non-selective A1

receptor agonist, N6-(L-2-phenylisopropyl) adenosine (L-

PIA), attenuate the neuronal loss in the CA1 region of the rat

hippocampus [260,261] and that acute systemic or intracere-

broventricular injection of the A1 agonists cyclohexyladeno-

sine (CHA) and R-phenylisopropyl-adenosine (R-PIA) im-

proves neurological deficits [262-264], protects the CA1

region of the hippocampus [265] and prevents the reduction

of adenosine A1 receptors [266] in rats or gerbils subjected to

global forebrain ischaemia. Similarly, the A1 agonists N6-

cyclopentyladenosine (CPA) and 2-chloro-N(6)-cyclopentyl-

adenosine (CCPA) given acutely reduce mortality and the

loss of neurones in gerbils after global forebrain ischaemia

[267]. In accordance, adenosine A1 antagonists given acutely

exacerbate the changes induced by ischaemia in different

animal models of ischaemia. An unselective A1 recep tor an -

tagonist, theophylline, increased mortality [268] and ischae-

mic cell damage [269,270] in gerbils subjected to global

forebrain ischaemia. Similar effects were also observed after

acute administration of the selective A1 antagonists DPCPX

and 8-cyclopentyl-1,3-dimethylxanthine (CPT) in animal

models of global ischaemia [271,267,272]. Interestingly, a

reverse effect appeared after chronic administration of

adenosine receptor antagonists. Both caffeine and DPCPX

given chronically for some weeks before an ischaemic insult

reduced the neuronal injury assessed by magnetic resonance

and histopathological examination in rats and gerbils

[270,273,267]. It has been suggested that the beneficial ef-

fects seen after chronic administration of adenosine antago-

nists may be due to up-regulation of A1 receptors [274]. Un-

like acute treatment, chronic administration of A1 agonists

worsened survival and increased neuronal loss [274], a phe-

nomenon thought to depend on A1 receptor desensitisation.

Although data converge in demonstrating a neuroprotec-

tive effect of adenosine through A1 receptors during ischae-

mia, the use of selective A1 agonists is hampered by un-

wanted peripheral effects i.e. sedation, bradycardia, hypoten-

sion [164,275,276]. Von Lubitz and coworkers [277] have

reported that post-ischemic administration of the A1 receptor

agonist adenosine amine congener (ADAC), which induces

fewer undesirable effects, increases survival in gerbils.

Moreover we may consider that administration of agents

which elevate the local con centration of adenosine at injury

sites by inhibiting its metabolism to inosine, rephosphoryla-

tion to AMP or reuptake may have the advantage of restrict-

ing the effect of such inhibitors to areas of injury-induced

adenosine release [278].

More recently, the role of A2A receptors in ischaemic

neuroprotection has been studied. Gao and Phillis [279]

demonstrated for the first time that the non-selective A2A

receptor antagonist 9-chloro-2-(2-furanyl)-[1,2,4] triazolo

[1,5-c]quinazolin-5-amine (CGS 15943) reduces cerebral

ischaemic injury in the gerbil following global forebrain

ischaemia. Thereafter many reports have confirmed the neu-

roprotective role of A2A receptor antagonists in different

models of ischaemia. The selective A2A receptor antagonist

8-(3-chlorostyryl)caffeine (CSC), as well as the less selective

antagonists CGS 15943 and 4-amino [1, 2, 4] triazolo [4, 3a]

quinoxalines (CP 66713), were able to ameliorate hippocam-

pal cell injury during global forebrain ischaemia in gerbils

[272,280]. Similarly, the selective A2A receptor antagonist

SCH 58261 reduced ischaemic brain damage in a rat neona-

tal model of hypoxia/ischaemia [281] and adult rat model of

focal cerebral ischaemia [282,12]. The same antagonist, sub-

chronically administerd was protective against both brain

damage and neurological deficit [283,284]. Studies in ge-

netically manipulated mice confirmed the neuroprotective

role of A2A receptor antagonists on ischaemic brain damage

[285]. In fact, in A2A receptor knockout mice subjected to

focal cerebral ischaemia, the cerebral damage and neurologi-

cal deficits were attenuated [285].

The beneficial effects

evoked by A2A antagonists are mainly attributed to blockade

of A2A receptors located presynaptically on glutamatergic

terminals [47,48] thus reducing excitotoxicity [253,286].

Adenosine in fact, by A2A receptor stimulation, promotes

glutamate release under normoxic and ischaemic conditions

[287,288,88-90].

After ischaemia, excitotoxicity is an early event, during

which microglial cells initiate a rapid change in their pheno -

type that is referred to as microglial cell activation [289].

They start to proliferate and migrate toward the site of dam-

age [290,291] and by producing cytotoxic substances and

cytokines, may contribute to the inflammatory response that

follows ischaemic insult, hence aggravating brain damage

[292]. An increase of intracellular mediator involved in tran-

scription mechanisms that may be relevant to neurodegenera-

tion was described. In particular following focal cerebral

ischaemia in the rat, activation of both ERK and p38 MAPK

was reported up to 24 after ischaemia [293] and the A2A an-

tagonist SCH 58261 was able to reduce both p38MAPK ac-

tivation in microglial cells [284] and gene c-fos expression

in the isch aemic hemisphere in the rat model of focal cere-

bral ischaemia [294]. Besides neurones, adenosine A2A re-

ceptors are located in microglial cells [49] and astrocytes

[51] where they can modulate production of proinflamma-

tory and inflammation products [49,295,296]. Selective inac-

Adenosine in the Central Nervous System Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 11

tivation of A2A receptors on bone-marrow-derived cells

(wild-type mice transp lanted with A2A receptor knockout

bone marrow cells) attenuates infarct volumes and ischemia-

induced expression of several proinflammatory cytokines in

the brain [297]. Therefore, protective effects of A2A antago-

nists may also be attributed to inhibition of production of

inflammation products.

It should be considered however that in several studies,

A2A receptor agonists have been found protective in the

global ischaemia model in the gerbil [280,298]. Jones and

coworkers [299] show that peripheral administration of the

A2A receptor agonist, CGS 21680, protects the hippocampus

against k ainate-induced excitotoxicity. However, the direct

injection of CGS 21680 into the hippocampus failed to af-

ford protection [299] while when injected directly into the

hippocampus, the A2A antagonist 4-(2-[7-amino-2-(2-furyl)

[1,2,4]triazolo[2,3 - a][1,3,5]triazin - 5 - yl - amino] ethyl) phenol

(ZM 241385) reduced kainate-induced neuronal damage

[299]. These data suggest that the neuroprotective properties

of A2A agonists are mainly due to peripherally mediated ef-

fects rather than direct neuronal sites. Major mechanisms

that may account for A2A-mediated protection include inhibi-

tion of platelet aggregation and vasodilation [226,52] and

anti-inflammatory actions. A2A receptors on neutrophils may

account for inhibition of adhesion to endothelial cells and

ensuing production of free radicals [300,301].

At the moment a possible adenosinergic th erapeu tic strat-

egy worth consideration after ischaemia is that of increasing

adenosine concentrations at the ischaemic sites by adenosine

inhibitors of metabolism or reuptake in association with

adenosine A2A antagonists (see Fig. 1). When considering the

possible use of adenosine kinase inhibitors, it should be

taken into account that adenosine represents only a small

percentage of nucleotide content [302], therefore inhibition

of its rephosphorylation to ATP by adenosine kinase inhibi-

tors does not weigh upon the ATP content.

The few studies present in the literature concerning the

role of A3 receptors in the pathophysiology of cerebral

ischaemia are rather contradictory. The reported effects on

A3 receptor stimulation appear to depend on drug administra-

tion (acute versus chronic), dosage and timing of treatment

with respect to the onset of the ischaemic insult. In vi vo stud-

ies show that a selective agonist of A3 receptors, 1-deoxy-1-

[6-[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-N-methyl-

beta-D-ribofuranuronamide (IB-MECA), acutely adminis-

tered, impaired post-ischaemic blood flow, increased mortal-

ity and exacerbated the loss of hippocampal neurones in the

model of global forebrain ischaemia in the gerbil [303].

However, beneficial effects were reported when the A3 ago-

nist was administered chronically in the same ischaemia

model [303,304]. Treatment with IB-MECA administered

20 min after focal cerebral ischaemia decreases the infarct

volume, the intensity of reactive gliosis, and the microglial

infiltration, whereas administration 20 min prior to ischae-

mia results in an increase in infarct volume [305]. In a model

of in vitro ischaemic preconditioning it has been shown that

the selective A3 receptor antagonist, 5-propyl-2-ethyl-4-pro-

pyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate

(MRS 1523), facilitated the full recovery of CA1 hippocam-

pal neurotransmission after 7 min of oxygen-glucose depri-

vation (OGD) [110]. Moreover recent data demonstrate that

MRS 1523 prevents the irreversible failure of neurotransmis-

sion induced by 7 min OGD and the development of anoxic

depolarization [306]. Taking into account that A3 receptors

are stimulated by M concentrations of adenosine [2], we

may speculate that A3 mediated effects would become par-

ticularly important during ischaemia when high levels of

adenosine are reached extracellularly and detrimental effects

of A3 receptor activation may be due, at least in part, to the

attenuation of the beneficial effects of A1 receptors [105].

Contrary to the evidence reported, it has been shown that

the A3 receptor agonist, IB-MECA, reduced the amplitude of

the postsynaptic potentials in the rat cortex under normal

[109] and hypoxic [307] conditions. In agreement, A3 recep-

tor knockout mice showed more pronounced hippocampal

pyramidal neurone damage following repeated episodes of

hypoxia and a decline in cognitive function compared to

wild-type mice [154]. These histological and cognitive

changes were reproduced in wild-type mice by repeatedly

administering th e selective A3 receptor antagonist, MRS

1523 [154].

Few studies, due to the paucity of A2B selective agonists

and antagonists, indicate a possible role for A2B receptors

during brain ischemic damage. In the stratum radiatum of

CA1 hippocampal slices the number and immunostaining

density of immunoreactive cells for A2B receptors after

ischemic preconditioning were increased [308]. In human

astroglial cells N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-

2,6-dioxo-1,3-dipropyl-1H-purin-8-yl) phenoxy]acetamide

(MRS 1706), a selective A2B receptor antagonist, completely

prevents the elongation of astrocytic processes, a typical

morphological hallmark of in vivo reactive astrogliosis, in-

duced by selective stimulation of A2B receptors [309].

4.3. Alzh eimer’s Disea se

Alzheimer’ disease (AD) is a progressive neurodegenera-

tive disorder characterised by loss of memory and other cog-

nitive functions leading to dementia. Irrespective of the etio-

logic agent, AD is characterised by excessive deposition of

amyloid -peptide (A) in senile plaques, formation of neu-

rofibrillary tangles (NFTs) and loss of neurones and syn-

apses [310-312]. Few studies on the role of adenosine in AD

are availab le. A1 adenosine r eceptors are decreased in the

hippocampus [313-317] and striatum [318] of AD patients.

Moreover, a change in the pattern of expression and a redis-

tribution of adenosine receptors has been found in the hippo-

campus and cerebral cortex of necropsies of AD patients. A1

receptors accumulate in degenerating neurones with neurofi-

brillary tangles and in dystrophic neurites of senile plaques,

and A2A receptors appear in glial cells of the hippocampus

and cerebral cortex [319]. Limited evidence indicates that

propentofylline treatment is beneficial in AD patients [320-

323]. Protective effects of propentofylline are attributed to

block of adenosine uptake, inhibition of the enzyme phos-

phodiesterase, inhibition of the production of free radicals

and reduced activation of microglial cells [323]. Recently, in

a case-control study it was shown that chronic caffeine in-

take was associated with a significantly lower risk of AD

[324]. In accordance, Dall'Igna and coworkers [325] demon-

strated that coapplication of caffeine and the selective A2A

receptor antagonist ZM 241385 prevented neuronal cell

12 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

death caused by exposure to A peptide. These results indi-

cate that adenosine receptors are potential targets in AD.

4.4. Huntington’s Disease

Huntington’s disease (HD) is an inherited, dominant,

autosomal neurodegenerative disorder related to an abnormal

CAG triplet repeat expansion within the HD gene that en -

codes for a protein named huntingtin [326]. HD is a progres-

sive and fatal disorder characterised by motor, cognitive and

psychiatric symptoms [327]. From a neuropathological point

of view, the disease is characterised by a certain degree of

neuronal loss in the cerebral cortex and a marked degenera-

tion of the basal ganglia where spiny striatal GABA neu-

rones are preferentially and progressively lost in the course

of HD [328]. To date, no neuroprotective drugs are available

for HD, and the search for therapeutic approaches in this

illness is critical [329]

Although the pathogenetic mechanisms underlying HD

are not completely understood, it is thought that abnormal

aggregation of mutant huntingtin leads to a cascade of

pathogenetic mechanism associated with transcriptional dys-

function, oxidative stress, mitochondrial alterations, energy

deficits and subsequent excitoxicity and neuronal death

[330,331].

In the rat, the intrastriatal administration of the glutamate

receptor agonist, quinolinic acid, reproduces the neuropa-

thological features of HD [332]. As well, the HD-like neuro-

pathology is reproduced in animals treated with mitochon-

drial toxins [333]. Most recently lines of mice transgenic for

a fragment of the human HD gene have been generated [334]

and are a helpful model of the disease. In mutant mice mod-

els of HD, it was demonstrated that NMDA currents and

NMDA-mediated excitotoxic cell death is enhanced [335,

336] and most recently that striatal adenosine extracellular

concentrations are increased [337]. The adenosine increase is

probably secondary to decreased ATP synthesis caused by

mitochondrial dysfunctions [338].

This information led to the hypothesis that increased glu-

tamatergic excitoxicity plays a role in the etiology of the

disease and, given the ability of adenosine A1 and A2A recep-

tors to modulate glutamate transmission, that adenosinergic

compounds acting on both A1 and A2A receptors may be a

possible neuroprotective approach to HD (reviewed in [14]).

Moreover, although A1 receptors are widely expressed in the

CNS [339] the preferential striatal expression of adenosine

A2A receptors [36] supports their possible role in HD.

Adenosine, by activation of presynaptic A1 receptors, is

known to mediate depression of synaptic transmission while

activation of post-synaptic A1 receptors can induce hyperpo-

larization of the cell membrane and inhibit NMDA receptor

activation [4,340]. Both pre- and post-synaptic activation of

A1 receptors can lead to decreased neuronal activity, particu-

larly by negatively modulating glutamatergic neurotransmis-

sion as demonstrated in electrophy-siological experiments

[86,341-343]. Such neurophysiological effects should limit

neuronal calcium influx and lead to neuroprotection in cases

where glutamate-induced excitotoxicity is involved. Simi-

larly to what is proposed under ischaemia, an outflow of

adenosine under conditions of metabolic stress in HD may

maintain extracellu lar glutamate levels within the normal

range and control striatal excitotoxicity, at least in an inter-

mediate phase of the illness.

Interestingly, a recent study has shown that ADAC, an A1

receptor agonist devoid of deleterious cardiovascular effects,

induces neuroprotective effects in the chronic 3-NPA model

of HD [333]. In particular, the acute administration of

ADAC completely prevented the development of hindlimb

dystonia and reduced the size of the the striatal degeneration

in 3-NPA-lesioned rats [333]. It is worth noting, however,

that after subchronic (3 days) and chronic (13 days) admini-

stration schedules, ADAC was no longer neuroprotective

[343]. Such a phenomenon, which is likely to depend on

receptor desensitisation, might strictly limit the therapeutic

potential of A1 receptor agonists in this neurode-generative

disease.

The role of A2A receptors in HD has attracted much atten-

tion in the past few years and several lines of evidence indi-

cate that adenosine A2A receptors can be regarded as promis-

ing targets for HD [14,15]. In particular A2A antagonism

aimed at reducing glutamate outflow has been carefully con-

sidered. The observations that SCH 58261 reduces glutamate

outflow, motor disabilities, electroencephalographic changes

and striatal gliosis induced by the injection of QA into the

striatum [13] and that A2A receptor knock-out mice as well as

A2A antagonist-treated mice display significant striatal pro-

tection in the HD model induced by 3-NPA intoxication [15,

344], support the idea that A2A antagonism might have a pro-

tective effect in HD secondary to reduced glutamate outflow.

Actually the selective adenosine A2A antagonist SCH 58261,

directly administered in the striatum, significantly decreases

glutamate outflow in HD transgenic but not wild-type mice

[337]. Reduction of glutamate outflow by A2A antagonists is

attributable to antagonism of the A2A receptors located on

corticostriatal glutamatergic terminals [47] where, on the

contrary, selective agonists of adenosine A2A receptors

stimulate striatal glutamate outflow in vivo in naive rats

[88,345,89].

The observation that adenosine A2A antagonism reduces

glutamate and adenosine outflow in transgenic but not in

wild-type mice suggests that striatal glutamatergic and

adenosinergic transmission are targets of the HD mutation

and that glutamatergic and adenosinergic transmission may

be strictly related in regulating striatal excitoxicity in HD.

Although mechanisms directly linking the HD mutation

with glutamatergic dysfunctions have not been identified to

date, a defect in energy metabolism is thought to produce

striatal excitotoxicity and oxidative stress, thereby contribut-

ing to neuronal death in HD [346]. A recent report, however

does not correlate the ability of A2A receptor antagonists to

prevent quinolinic acid (QA)-induced lipid peroxidation with

the neuroprotective effects [347].

In spite of the above evidence, the true neuroprotective

potential of A2A receptor antagonists in HD is still rather

controversial and the mechanisms involved are still under

scrutiny [348,347]. While SCH 58261 significantly pre-

vented QA-induced glutamate outflow in microdialysis stud-

ies, it increased at the same time QA-induced intracellular

calcium levels in striatal neurones [13]. The effect of QA in

calcium levels is prevented by the NMDA receptor antago-

nist MK-801 [13]. The potentiating effect of SCH 58261 on

Adenosine in the Central Nervous System Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 13

NMDA-mediated Ca++ influx is in agreement with the obser-

vation that the selective A2A agonist CGS 21680 inhibits

NMDA currents in striatal neurones [349]. The fact that the

stimulation, rather than the blockade of A2A receptors, may

result neuroprotective was also suggested by the finding that

activation of a major signaling pathway of A2A receptors i.e.

the PKA, increases the survival of striatal neurones treated

with 3NP [344]. Indeed in a chronic 3-NPA intoxication

model, treatment with an A2A antagonist increases the vol-

ume of striatal damage [344]. Furthermore very recent data

demonstr ate that in transgenic HD mice, chronic administra-

tion of the selective A2A receptor agonist CGS 21680 amelio-

rates several important symptoms of HD, reduces the num-

ber of huntingtin aggregates and reduces the over activation

of 5’-AMP activated protein kinase [350]. In pheochromocy-

toma (PC) 12 cells expressing mutant huntingtin, CGS

21680 restores the reduced c-AMP-response element-

binding protein (CREB) and reverses the reduction of the

transcript levels of A2A receptors [351].

Hence both A2A antagonists and agonists have been

shown to have potential as protective drugs in different mod-

els of HD. To find an explanation for this we may consider

the possibility that A2A receptors located at presynaptic sites

are harmful because of their modulation of glutamate out-

flow, while those on postsynaptic sites are protective [90,

344]. The bulk of striatal adenosine A2A receptors are consti-

tuted by those located postsynaptically on GABA-enkephalin

neurones [352]. The fact, however, that the GABA spiny

neurones expressing A2A receptors are prone to degenerate in

HD may be important, when considering such receptors as

potential targets. Several studies now demonstrate that a

dramatic reduction in the expression of adenosine A2A recep-

tors occurs in the striatum of 9-12 week old transgenic

(R6/2) mice [353,350], in striatal cell lines overexpressing

mutant huntingtin [354], in PC 12 cells expressing mutant

huntingtin [351] and in peripheral blood cells of HD patients

[355]. However the ability of striatal cells of transgenic mice

to trigger cAMP signaling is unchanged [350] or is even

aberrantly amplified in striatal or peripheral mutant HD cells

[354,355]. Such an amplified cAMP system would allow A2A

receptors to respond to A2A agonists even when they are re-

duced in number as shown in transgenic mice and in human

basal ganglia of HD patients [356]. Therefore the timing of

the administration of drugs acting on adenosine A2A recep-

tors to induce neuroprotection in HD should be carefully

verified in further studies.

GENERAL CONCLUSIONS

This review summarises and discuses the evidence for

adenosine receptors subtypes involved in neurotransmission.

Strong evidence is that A1 receptor mediate inhibition and

A2A receptor mediate excitatory effects. A3 receptors do not

appear to exert a significant effect under physiological con-

ditions. The lack of effect does not appear to be attributable

to a low density of A3 receptors in the brain but rather to the

fact that adenosine concentrations reached under physiologi-

cal conditions are not sufficient to stimulate this receptor

subtype. Under physiological conditions the net effect of

adenosine on neurotransmission is inhibitory.

A major mechanism by which adenosine compounds are

neuroprotective under neurodegenerative processes is that of

regulating excitoxicity and th e subsequent cascade of events

which include production of further compounds toxic for

cells. Recently it was pointed out that ad enosine recep tors

may modify intracellular pathways involved in transcription

regulation. Such pathways may be important in accounting

for protective effects of adenosinergic drugs. Evidence that

adenosine A2A receptor antagonism is of importance in Park-

inson’s disease from the point of view of both correction of

symptoms and as a neuroprotective agent, is summarised.

When considering the undesirable side effect of A1 agonists

in ischaemia, A2A antagonism in association with agents

which locally increase adenosine concentrations may be a

promising therapeutic approach. The most recent data on

Huntington’s disease support the view that both A2A agonists

and antagonists must still be investigated at different times

during progression of the illness to arrive at convincing evi-

dence of putative protective effects of this drug category.

Evidence of a role of adenosine in Alzheimer’s disease is

still scarce.

ACKNOWLEDGEMENTS

This work was supported by grants from the Italian Min-

istry of Health, Italian Ministry of Education, the US Na-

tional Institutes of Health (ES10804) and from “Ente Cassa

di Risparmio” of Florence.

ABBREVIATIONS

A = Amyloid -peptide

AD = Alzheimer’ disease

ADA = Adenosine deaminase

ADAC = Adenosine amine congener

AKA = Adenosine kinase

-MSH = Alpha-melanocyte-stimulating hormone

AMP = Adenosine monophosphate

ATP = Adenosine triphosphate

cAMP = Cyclic AMP

CADO = 2-Chloroadenosine

CCPA = 2-Chloro-N(6)-cyclopentyladenosine

CGS 15943 = 9-Chloro-2-(2-furanyl)-[1,2,4] triazolo[1,5-

c]quinazolin-5-amine

CGS 21680 = 2-p-(2-Carboxyethyl)phenethylamino-5'-

N-ethylcarboxamidoadenosine hydrochlo-

ride

CHA = Cyclohexyladenosine

CHO = Chinese hamster ovary

CHPG = (RS)-2-Chloro-5-hydroxyphenylglycine

CNS = Central nervous system

CP 66713 = 4-Amino [1, 2, 4] triazolo [4, 3a] quinox-

alines

CPA = N6-Cyclopentyladenosine

CPT = 8-Cyclopentyl-1,3-dimethylxanthine

CSC = 8-(3-Chlorostyryl) caffeine

DAG = Diacylglycerol

DPCPX = 1,3-Dipropyl-8-cyclopentyladenosine

14 Immun., Endoc. & Metab. Agents in Med. Chem., 2007, Vol. 7, No. 4 Pedata et al.

ERK1/2 = Extracellular-regulated kinase 

[18F]CPFPX = [18F]8-Cyclopentyl-3-(3-fluoropropyl)-1-

propylxanthine

6-OHDA = 6-Hydroxydopamine

GABA = -Amino-butyric acid

GIRK = Inwardly rectifying potassium

GAD67 = Glutamic acid decarboxylase

GPCR = G protein-coupled receptors

GPe = Globus pallidus pars external

GPi = Globus pallidus pars internal

HD = Huntington’s disease

IB-MECA = 1-Deoxy-1-[6-[[(3-iodophenyl)-

methyl]amino]-9H-purin-9-yl]-N-methyl-

beta-D-ribofuranuronamide

KW 6002 = (E)-1,3-Diethyl-8(3,4-dimethoxystyryl)-7-

methyl-3,7-dihydro-1H-purine-2,6-dione

L-DOPA = L-Dihydroxyphenylalanine

L-PIA = N6-(L-2-Phenylisopropyl) adenosine

LTP = Long-term potentiation

LTD = Long-term depression

MAPK = Mitogen-activated protein kinase

MCA = Medial cerebral artery

mGluR5s = Metabotropic glutamate type 5 receptors

MPTP = 1-Methyl-4-phenyl-1,2,3,6-

tetrahydropyridine

MRS 1523 = 5-Propyl-2-ethyl-4-propyl-3-

(ethylsulfanylcarbonyl)-6-phenylpyridine-

5-carboxylate

MRS 1706 = N-(4-Acetylphenyl)-2-[4-(2,3,6,7-

tetrahydro-2,6-dioxo-1,3-dipropyl-1H-

purin-8-yl) phenoxy]acetamide

NFTs = Neurofibrillary tangles

NMDA = N-methyl-D-aspartate

3-NPA = 3-Nitropropionic acid

OGD = Oxygen-glucose deprivation

PC12 = Pheochromocytoma 12

PD = Parkinson’s disease

PKA = Protein kinase A

PKC = Protein kinase C

PLA2 = Phospholipase A2

PLC = Phospholipase C

PLD = Phospholipase D

POMC = Proopiomelanocortin

PPI = Prepulse inhibition

QA = Quinolinic acid

R-PIA = R-phenylisopropyl-adenosine

SCH 58261 = 5-Amino-7-(2-phenylethyl)-2-(2-furyl)-

pyrazolo[4,3-e]-1,2,4-triazolo[1,5-

c]pyrimidine

SNr = Substantia nigra pars reticulate

STN = Subthalamic nucleus

SS-rBF = Rostral basal forebrain

SPW = Spontaneous sharp waves

ZM 241385 = 4-(2-[7-Amino-2-(2-

furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-

yl-amino]ethyl)phenol

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Received: October 23, 2006 Accepted: December 21, 2006

The role of adenosine kinase in noise induced hearing loss

Thesis

Feb 2009

Nuwan Shyanaka Dharmawardana

Extracellular adenosine acting via adenosine receptors (A 1 , A 2A , A 2B and A 3) plays neuromodulatory role in many tissues. Adenosine kinase (AdK) is the most abundant nucleoside kinase that phosphorylates intracellular adenosine to AMP and is a key regulator of adenosine concentrations on both sides of the cell membrane. Here, we report the AdK distribution in the rat cochlea at mRNA and protein levels and provides evidence that AdK inhibition may be a pharmacological tool in mediating cochlear recovery from injury. Adult Wistar rats were exposed to broadband or narrow band noise for 24 hours at 90 dB, 100 dB and 110 dB sound pressure level (SPL) and tissues were collected after 1 hour or 3 days following noise exposure. They were compared to control tissues that were not exposed to noise (non-noise controls). Noise presented at 90 dB and 100 dB represents the model of transient hearing loss (temporary threshold shift), whilst exposure to 110 dB SPL induces permanent hearing loss. AdK transcript levels were determined in the noise-exposed cochleae and compared to controls. Only the cochleae exposed to 90 dB SPL demonstrated increased AdK levels after 1 hour of recovery, whilst AdK expression levels were unchanged in other cochleae. Semi-quantitative analysis of AdK protein levels was carried out on cryo-sectioned and immunolabelled cochlear tissues examined under the confocal microscope. The intensity of immunostaining was measured using average pixel intensity in discrete regions of the cochlea. Immunofluorescence analysis demonstrated initial increase in AdK in the cochleae of animals exposed to high level noise (110 dB SPL), but transient increase in AdK levels returned to basal levels after 3 days of post-noise recovery. Immunolabelling with caspase-3 and nitrotyrosine to demonstrated the extent of tissue damage and oxidative stress in the noise-exposed cochleae. In other studies, Wistar rats were exposed to 110 dB SPL noise at various frequency bands for different durations. Systemic intra-peritoneal administration of ABT-702 demonstrated partial recovery of hearing thresholds in animals exposed to noise for 4 hours, whilst that effect was lost in animals exposed to noise for 24 hours. Therefore, this study provides the first evidence that inhibition of AdK following intense noise exposure can be used a s an effective treatment strategy to ameliorate noise induced hearing loss.

Investigation of potential behavioral and physiological effects of caffeine on D. magna

Article

Full-text available

Jun 2022
ENVIRON SCI POLLUT R

With the ever-increasing consumption of pharmaceutical compounds, their presence in the environment is now an undisputable reality. The majority of these compounds are released into the wild after their therapeutic use, as biotransformation products or in their original form. The presence of this class of compounds in the environment, due to their biological properties, can exert effects on non-target organisms, with adverse consequences. In addition, some bioactive substances, such as stimulants of the central nervous system, are also used by humans as part of their diet. The adverse consequences posed by such chemicals may be permanent or transient, if the exposure to xenobiotics is halted; it is thus of the paramount importance to study effects that result from long-term exposure to toxicants, but also the recovery of organisms previously exposed to such substances, especially if such chemicals may cause some type of addiction. Caffeine (1,3,7-trimethylxanthine) is a naturally occurring alkaloid found in many plants, being one of the most common stimulant/pharmaceutical compounds found in the environment. In addition, it is addictive, and strongly consumed by humans, a factor that contributes also for its continuous presence in the aquatic environment. The aim of this study was to evaluate the effects of environmentally relevant concentrations (0.08; 0.4; 2; 10; and 50 μg/L) of caffeine on behavior and physiological parameters (that are proxies of metabolic traits, such as oxygen uptake and glycogen content), in individuals of the freshwater crustacean species Daphnia magna, of distinct ages, and with or without a recovery period in the absence of caffeine. Regarding behavior, the results indicated that caffeine exposure altered the moved distance of the test organisms, but not according to a coherent pattern; low concentrations of caffeine reduced the movement of exposed daphnids, while higher levels did not have any measurable effect on this parameter. In addition, it was possible to identify subtle withdrawal effects (animals exposed to caffeine during 21 days and kept in uncontaminated media for 2 days). Regarding the other two studied parameters, caffeine exposure did not result in any significant modification in oxygen uptake and glycogen stores/reserves of the test organisms, in animals continuously exposed, or in those subjected to a recovery period, suggesting that despite a behavioral stimulatory effect, this was not followed by any metabolic change, and no addictive effect was possible to infer. The results showed that the presence of caffeine in environmental concentrations can induce mild behavioral effects at low, albeit realistic levels, but not capable of establishing clear biochemical changes.

Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: a multicenter, randomized, double-blind, placebo-controlled trial

Article

Full-text available

Jul 2020
BMC NEUROL

Background: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. Methods: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. Results: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. Conclusions: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. Trial registration: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.

Purinergic signalling in brain ischemia

Article

Full-text available

Nov 2015

Once Upon a Time Adenosine and Its Receptors: Historical Survey and Perspectives as Potential Targets for Therapy in Human Diseases

Chapter

Mar 2023

Endogenous autacoid adenosine plays important physiological roles in various tissues and organs by acting through A1, A2A, A2B, and A3 receptors. Dysregulated extracellular adenosine concentrations can cause many disorders such as inflammation, neurodegeneration, pain, and cancer, thus suggesting adenosine receptors (ARs) as interesting therapeutic targets. Medicinal chemistry studies have generated a large number of AR ligands, which have been pharmacologically characterized and optimized. Improvement in AR structural biology stimulated new computer-aided drug design approaches for drug discovery. Some AR ligands have reached clinical trials, and a limited number of them are on the market. To achieve these results, great progress has been made since the first steps in the intriguing world of adenosine and its receptors. New knowledge has been achieved, many issues have been solved, and new important aspects, previously ignored or underestimated, have been highlighted. In particular, but not only, taking into account important factors such as binding kinetics and biased signaling of ARs can lead to a rational design of more effective and safer drugs. Multitarget-directed ligands that combine, in the same molecule, the ability to interact with AR(s) and other target(s) are getting much attention as innovative therapeutic agents for treating multifactorial disorders such as neurodegenerative diseases and cancer.

Efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke: A multicenter, randomized, double-blind, placebo-controlled trial

Preprint

Full-text available

Mar 2020

Background: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 hours of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. Methods: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. Results: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p=0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p=0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. Conclusions: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. Trial registration: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827. Retrospectively registered June 13, 2019.

Adenosine and Oxygen/Glucose Deprivation in the Brain

Chapter

Jul 2018

Extracellular adenosine concentrations in the brain increase dramatically during ischemia in concentrations that able to stimulate all (A1, A2A, A2B, and A3) receptors. Adenosine exerts a clear neuroprotective effect through A1 receptors during ischemia mainly by reducing precocious excitotoxic phenomena. Unfortunately, the use of selective A1 agonists is hampered by undesirable peripheral effects. Evidence indicates that A2A receptor antagonists administered early after ischemia provide protection centrally by reducing excitotoxicity. After ischemia, the primary damage due to the early massive increase of extracellular glutamate is followed by activation of resident immune cells, i.e., microglia, and production or activation of inflammation mediators and blood cell infiltration. Evidences are that agonists at A2A, A2B, and A3 receptors mainly acting on blood and vascular endothelial cells provide protection by controlling neuroinflammation, endothelial leaking, and massive blood cell infiltration in the hours and days after brain ischemia. Since ischemia is a multifactorial pathology characterized by different events evolving in the time and protracted neuroinflammation is recognized as the predominant mechanism of secondary brain injury progression, adenosinergic drugs aimed at dampening damage in the hours/days after ischemia appear promising.

Adenosine and Oxygen/Glucose Deprivation in the Brain

Chapter

Mar 2017

Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia, primary damage due to the early massive increase of extracellular glutamate is followed by activation of resident immune cells, i.e., microglia, and production or activation of inflammation mediators. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. Extracellular concentrations of adenosine in the brain increase dramatically during ischemia at levels able to stimulate all (A1, A2A, A2B and A3) receptors. Although adenosine exerts a clear neuroprotective effect through A1 receptors during ischemia, the use of selective A1 agonists is hampered by undesirable peripheral effects. Evidence up to now in the literature indicates that A2A receptor antagonists provide protection centrally by reducing excitotoxicity, while agonists at A2A (and possibly also A2B) and A3 receptors provide protection by controlling massive infiltration and neuroinflammation in the hours and days after brain ischemia.

Adenosine and Stroke

Article

Nov 2013

The concentration of adenosine in the brain increases dramatically during ischemia, and adenosine has long been known to act predominantly as a neuroprotectant during ischemia. In agreement, adenosine infusion into the ischemic striatum significantly ameliorates neurological outcome and reduces the infarct volume after transient focal cerebral ischemia. Despite the neuroprotective effect of adenosine through A1 receptors during ischemia, the use of selective A1 agonists is hampered by unwanted peripheral effects such as sedation, bradycardia, and hypotension. An alternative therapeutic approach may consist of using agents that elevate the local concentration of adenosine at areas of injury-induced adenosine release, thus minimizing undesirable peripheral and central effects mediated by A1 receptors. Adenosine-potentiating agents at injury sites may act by (1) inhibiting its metabolism by adenosine kinase or adenosine deaminase, (2) preventing its transport through equilibrative membrane transporters (ENTs), (3) enhancing hydrolysis of extracellular ATP by use of nucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5′-nucleotidase (e5′-NTs). The role of A2A receptors also is important for neuroprotection during ischemia. Evidence suggests that low doses of A2A antagonists (that do not modify hemodynamic parameters) provide protection via centrally mediated control of precocious excessive excitotoxicity, while A2A agonists provide protection by controlling massive cell infiltration in the hours after ischemia. Information suggests that A2A receptors are a potentially attractive therapeutic target in ischemia. In perspective of using adenosine A2A active drugs to protect against brain ischemia, attention should be given to the dose and administration time after injury. Although much is still to be learned about the function of the A3 receptor, at the present time it can be speculated that A3 receptor selective ligands may be useful in the treatment of ischemic conditions involving inflammation. © 2013 Springer Science+Business Media New York. All rights are reserved.

Adenosine Receptors in Cerebral Ischemia

Article

Sep 2014
INT REV NEUROBIOL

Ischemic stroke is a complex pathology characterized by a sequence of events that evolve over time and space. It is the second leading cause of death and the main cause of adult long-term disability in developed countries. At the moment, there is no promising pharmacotherapy for acute ischemic stroke. Adenosine receptors (A1, A2A, A2B, A3) are important targets for therapeutic implementation in the treatment of stroke because extracellular adenosine concentrations increase dramatically soon after ischemia. Adenosine receptors located both on central nervous system cells and on immune blood cells exert important roles during ischemia. The neuroprotective role of adenosine through A1 receptor subtype during ischemia is accepted, but the use of selective A1 agonists is hampered by undesirable side effects such as sedation, bradycardia, and hypotension. Recently, the A2A receptor subtype emerged as a potential therapeutic attractive target in ischemia. Evidence suggests that A2A receptor has dual role: in a first phase of ischemia, it potentiates excitotoxicity, while hours and days after ischemia, A2A receptors on immune blood cells potentiate cell adhesion mechanisms and infiltration in the ischemic parenchyma. Consistently, the use of A2A receptor agonists/antagonists (administered at doses that do not modify blood pressure and heart rate) should be carefully evaluated in function of time after ischemia. Although much is still to be known about the role of A2B and A3 receptor subtypes in brain ischemia, most consistent information indicates their role in regulation of immunosuppression and inflammation.

A causal role for amyloid in Alzheimer's disease: The end of the beginning 1993 American Academy of Neurology Presidential Address

Article

May 1993

Roger R. N. Rosenberg

Local Antinociceptive and Hyper algesic Effects in the Formalin Test after Peripheral Administration of Adenosine Analogues in Mice

Article

Jun 1992
Pharmacol Toxicol

: Adenosine administered to humans has been reported to induce pain after intravenous administration. On the other hand adenosine analogues have been shown to possess antinociceptive effects after peripheral and intrathecal administration in animals. The aim of the present study was to investigate the effect of peripheral administration of adenosine agonists with different affinities for the A1 and A2 adenosine receptors on a persistent pain stimulus using the formalin test. The drugs chosen were, R-phenylisopropyl-adenosine (R-PIA) with high affinity for the A1 receptor, N-ethylcarboxamide-adenosine (NECA) with almost equal affinity for the A1 and A2 receptor and 2-(2-aminoethylamino)-carbonylethylphenylethylamino-adenosine (APEC) with high affinity for the A2 receptor. The drugs were mixed with formalin and administered subcutaneously into the dorsal hind paw in mice to study the local effects. They were also injected separately from the formalin solution in different paws to evaluate the systemic effect. The total time of licking the injected paw during the first 5 min. was recorded. In high doses all compounds reduced the licking activity, but a low dose of APEC (1 μM) injected together with the formalin solution had an algesic effect. All effects were antagonized by theophylline. These results suggests that A1 adenosine receptors mediate a local peripheral antinociceptive effect and the involvement of local peripheral A2 receptors in the enhancement of the algesic response.

Block by N6-L-phenylisopropyl-adenosine of the electrophysiological and morphological correlates of hippocampal ischemic injury in the gerbil

Article

Dec 1995

The effects of the mixed A 1 and A 2 adenosine receptor agonist N ⁶ ‐L‐phenyl‐isopropyladenosine (L‐PIA) were tested on ischaemia‐induced hippocampal neuronal injury in gerbils subjected to 5‐min bilateral carotid occlusion. For comparison, the effects of the selective A 2 adenosine receptor agonist, CGS 21680 were tested. Five‐min bilateral carotid occlusion produced within 1 week an irreversible suppression of the CA1, but not of the dentate extracellular electrical somatic responses, in 30% of gerbil hippocampal slices with respect to controls. In addition, a significant reduction occurred in the density of CA1 hippocampal pyramidal neurones but not of dentate granule cells with respect to controls. Injection 1 h before or after bilateral carotid occlusion of L‐PIA (0.8‐1.5 mg kg ⁻¹ , i.p.) but not of CGS 21680 (5 mg kg ⁻¹ , i.p.), significantly prevented the irreversible disappearance of the CA1 extracellular electrical somatic responses with respect to controls. In addition, the CA1 pyramidal neuronal loss was also prevented. The results show that activation of A 1 adenosine receptors is able to prevent or block the electrophysiological and morphological correlates of hippocampal neuronal injury after global ischaemia in the gerbil, suggesting that adenosine receptor agonists might have a useful role in the treatment of neuronal functional and anatomical injury due to ischaemia.

Spontaneous, low frequency (∼2–3 Hz) field activity generated in rat ventral hippocampal slices perfused with normal medium

Article

Jan 2002
BRAIN RES BULL

This study demonstrates that transverse slices taken from the ventral hippocampus of adult rats perfused with a medium of normal ionic composition sustain spontaneous periodic field potentials due to the synchronous activity of a population of neurons. This ventral hippocampus spontaneous synchronous activity (VHSSA) in CA1 stratum pyramidale consisted of positive potentials (∼0.12 mV, 55 ms) occurring at a frequency of 2.8 ± 0.2 Hz for hours without interruption. VHSSA was most frequently observed in slices taken 1–3 mm from the ventral end of hippocampus, and was absent in slices taken from tissue more than 4.5 mm away from it. Stimulation of Schaffer collaterals primed the appearance of potentials, which were similar to VHSSA and clearly distinguishable from excitatory postsynaptic potentials. In view of the known relative proneness of ventral hippocampus to epilepsy, we perfused ventral slices with high-[K+]o medium (8 mM). Albeit reduced in amplitude, VHSSA persisted during the high-[K+]o induced interictal-like epileptiform activity. We could not document any temporal relationship between the two phenomena. Low concentrations of the antagonist of γ-amino-butyric acid receptors, type A, bicuculline (2–3 μM), which enhanced the high-[K+]o induced epileptiform activity, reversibly blocked the VHSSA. We conclude that under standard in vitro conditions small circuits in the ventral hippocampus are most often and for long periods of time engaged in synchronous quasi-rhythmic low-frequency activity, generated locally by mechanisms substantially differing from those supporting epileptiform discharges.

The Controversial Role of Adenosine A2A Receptor Antagonists as Neuro-protective Agents

Article

Mar 2004
Curr Med Chem Cent Nerv Syst Agents

Adenosine is an endogenous modulator that regulates many Central Nervous System functions, and whose effects are mediated by four G-protein coupled receptors (A1 , A2A , A2B , A3 ). Adenosine A2A receptors have been recently regarded as promising targets for the development of neuroprotective strategies. In particular, since an abnormal glutamate outflow is thought to play a crucial role in triggering the cellular events leading to excitotoxic neuronal death, and since A2A receptors positively modulate glutamate outflow, it has been supposed that their blockade could represent a suitable approach to the treatment of neurodegenerative diseases. In agreement with this hypothesis, both the genetic inactivation and the pharmacological blockade of A2A receptors proved effective in several models of brain injury. In some studies, the neuroprotective effects of A 2A receptor antagonists correlated well with their ability to prevent injury- or toxin- stimulated glutamate outflow. The beneficial effects of A2A receptor antagonists at the pre-synaptic sites (namely their ability to attenuate glutamate release), however, seem to occur only at very low doses and at certain time points after the insult is given. Moreover, A2A receptor antagonists seem unable to prevent the toxic effects elicited by direct stimulation of post-synaptic NMDA receptors. It is concluded that, although A2A antagonists show clear neuroprotective effects in models of brain injury, their actual therapeutic potential needs to be confirmed in a wider range of doses, at different stages of brain injury as well as in models of neurodegenerative diseases, in which pre- and post-synaptic effects play different relative roles.

Unexpected neuroprotection observed with the adenosine A2A receptor agonist CGS 21680

Article

Sep 1996
DRUG DEVELOP RES

The selective adenosine A2A receptor agonists 2-[p-(2-carboxethyl)phenylethylaminol-5′-N-ethylcarboxyamidoadenosine (CGS 21680), N-[2-(3,5-dimethoxyphenyl)ethyl]adenosine (DPMA) and metrifudil were investigated for their ability to prevent the loss of pyramidal CA1 neurons in the hippocampus following 5 min of severe temporary forebrain ischemia in mongolian gerbils. CGS 21680, when administered at 18.7 μmol/kg 30 and 120 min following reperfusion, exhibited highly significant protection against neuronal loss, but was inactive at 5.6 μmol/kg. DPMA, a more potent agonist at A1 and A2A receptors, was inactive up to a dose of 19 μmol/kg. Metrifudil (equipotent with CGS 21680 at A2A >25 times more potent at A1) gave a modest degree of protection at 26 μmol/kg and was inactive at 7.8 μmol/kg. CGS 21680 showed an equal degree of hypothermia at 5.6 and 18.7 μmol/kg, suggesting that this was not the prime mode of action. While the effect of metrifudil may be the result of its higher A1 receptor affinity, the mode of action of CGS 21680 has not been established; the data, however, suggest that a non-A1 non-A2A receptor mechanism may possibly be involved. Drug Dev. Res. 39:108–114 © 1997 Wiley-Liss, Inc.

Purinergic drugs: Opportunities in the 1990s

Article

Mar 1993
DRUG DEVELOP RES

Michael Williams

The premise that purinergic nucleosides and nucleotides subserve roles as autocrine agents, neurotransmitters, or neuromodulators has been well established over the past 20 years. Mechanistically, adenosine, the endogenous ligand for P 1 type purinoceptors, acts to modulate the release of a variety of neurotransmitters as well as modulating the effects of such agents at the postsynaptic level. P 2 receptor agonists, including ATP and ADP, appear to act more like traditional neurotransmitters undergoing quantal release and producing their effects directly through G‐protein linked receptors or ligand gated ion channels. There is, however, little direct evidence at this time for pathophysiologies directly attributable to purinoceptor malfunction. Nonetheless, the adenosine formed from ATP breakdown appears to play a protective role in hypoxic and ischemic situations. And adenosine A 1 agonists as well as agents that act to potentiate the actions of endogenous adenosine (AICA riboside, adenosine uptake blockers, adenosine kinase inhibitors etc.) are being evaluated for use in stroke and reperfusion injury. A 1 receptor agonists may also have potential as anticonvulsants and in the treatment of type II diabetes. A 2a receptor ligands because of their unique co‐localization with D 2 receptor containing neurons in the striatopalladial pathway of the basal ganglia may have potential use in the treatment of diseases involving dopaminergic malfunction for instance, Parkinsonism and schizophrenia. Agonists therapy may, however, be limited by the non‐specific actions of agonists at nontarget tissues and the tolerance typically associated with chronic agonist therapy. As a result, there is increased focus on indirect modulation of adenosine systems by either adenosine potentiators or allosteric modulators, the latter class including PD 81, 723 and the newly discovered peptide, adenoregulin. Approaches to adenosine antagonists and therapeutic agents have resulted in the identification of 8‐substituted xanthines including KFM 19 and MDL 102, 234 that are currently being evaluated as cognition enhancers with potential use in Alzheimer's disease. While chemistry in the area of P 2 purinoceptor has been limited, ATP itself may have potential use in the treatment of cancer and shock. Continued progress in the understanding of the physiological role of the various classes of purinoceptor has the potential to lead to novel therapeutics in the 1990s. © 1993 Wiley‐Liss, Inc.

Propentofylline protects neurons in culture from death triggered by macrophage or microglial secretory products

Article

Apr 1999
J NEUROSCI RES

We recently demonstrated that conditioned medium (CM) from peritoneal macrophages or activated microglia triggers a predominantly apoptotic death in hippocampal neurons in culture. We tested the effects of propentofylline (ppf), an agent that is neuroprotective in focal ischemia and is also associated with reduced microglial antigen expression after insult. Ppf had no impact on the secretion of neurotoxin from microglia. However, ppf significantly attenuated the effects of macrophage and microglial conditioned medium on neurons. Ppf did not attenuate neuronal hypoxic injury but did reverse the exaggeration of hypoxic injury exerted by subsequent addition of macrophage CM. A1 and A2 adenosine receptor inhibitors and an inhibitor of adenosine uptake each mimicked the effect of ppf. Neither ATP nor a deaminase inhibitor blocked the effect of microglial CM. These findings may be relevant to the neuroprotective effects of ppf in ischemia and dementia. J. Neurosci. Res. 56:54–59, 1999. © 1999 Wiley-Liss, Inc.

Effects of nigrostriatal lesions on the levels of messenger RNAs encoding two isoforms of glutamate decarboxylase in the rat Globus pallidus and entopeduncular nucleus of the rat

Article

Jun 1992
SYNAPSE

The neurotransmitter γ‐aminobutyric acid (GABA) is present in efferent neurons of the striatum and of the pallidum, one of the main striatal target areas. Dopaminergic nigrostriatal neurons play a critical role in the regulation of GABAergic neurotransmission in the striatum. In the present study, we investigated their role in the regulation of glutamate‐decarboxylase (GAD) mRNA expression in two divisions of the pallidum in rats: the globus pallidus and entopeduncular nucleus, equivalent to the external and internal pallidum, respectively, of primates. Dopaminergic neurons were lesioned by unilateral injections of 6‐hydroxydopamine (6‐OHDA) in the substantia nigra of adult rats. Two or 3 weeks after the lesion, frontal cryostat‐cut sections of the brain were processed for in situ hybridization histochemistry with ³⁵ S‐labeled RNA probes synthesized from cDNAs encoding two distinct isoforms of GAD of respective molecular weight 67,000 (GAD67) and 65,000 (GAD65). The number of labeled cells was determined, and intensity of labeling in individual cells was analyzed by computerized image analysis on emulsion radioautographs. In the globus pallidus, the number of labeled neurons and intensity of labeling per cell were increased on the side ipsilateral to the lesion as compared with control rats in sections hybridized with the GAD67 RNA probe. No changes were detected on the side contralateral to the lesion or in the levels of labeling for GAD65 mRNA. Confirming previous data, the level of labeling for GAD65 mRNA was much higher than for GAD67 mRNA in the entopeduncular nucleus of control rats. In rats with a 6‐OHDA lesion, labeling for both GAD67 and GAD65 mRNAs was decreased on the side contralateral, but not ipsilateral, to the lesion, as compared with control rats. The results show that lesions of the nigrostriatal pathway in rats affect the levels of mRNAs encoding two distinct isoforms of GAD in neurons of the globus pallidus and entopeduncular nucleus differently. In addition, results in the entopeduncular nucleus further support a bilateral effect of unilateral dopaminergic lesions. © 1992 Wiley‐Liss, Inc.

Adenosine A3 receptors in the rat hippocampus: Lack of interaction with A1 receptors

Article

Apr 2003
DRUG DEVELOP RES

Adenosine acts as a neuromodulator in the hippocampus essentially through activation of inhibitory A1 receptors. Using single-cell PCR analysis, we found that CA1 pyramidal cells coexpress A1 receptor mRNA together with that of another adenosine receptor, the A3 receptor. As occurs for the A1 receptor, Western blot analysis indicated that the A3 receptor is also located in hippocampal nerve terminals. However, activation of A3 receptors with its purportedly selective agonist Cl-IBMECA (0.1–10 µM) failed to affect hippocampal synaptic transmission or to modify the evoked release of glutamate or GABA. Also, blockade of A3 receptors with MRS 1191 (5 µM) failed to affect either hypoxia- or ischemia-induced depression of hippocampal synaptic transmission. Activation of A3 receptors also failed to control A1 receptor function, as Cl-IBMECA (100 nM) did not modify the ability of CPA to displace [3H]DPCPX binding to hippocampal membranes or the A1 receptor-mediated inhibition of hippocampal synaptic transmission. However, ligand binding studies revealed that Cl-IBMECA displaced the binding of an A1 receptor agonist ([3H]R-PIA, Ki=47 nM) or antagonist ([3H]DPCPX, Ki=130 nM), which suggests that A3 receptor ligands also act on native A1 receptors. We believe that A3 receptors are expressed in hippocampal neurons and are located in hippocampal nerve terminals, though their function remains elusive. Drug Dev. Res. 58:428–438, 2003. © 2003 Wiley-Liss, Inc.

Adenosine in the Central Nervous System: Effects on Neurotransmission and Neuroprotection

Abstract

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