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Medicinal Plants with Central Nervous Activity-An Overview (Part 1)

April 2019

April 2019
9(3):52-102

Authors:

Ali Esmail Al-Snafi

University of Thi-Qar

Tayseer Ali Talab

University of Thi-Qar

Wajdy J Majid

College of medicine, University of Thi-Qar

The recent studies showed that many plants affected the central nervous system and exerted many pharmacological effects including sedative, anticonvulsant, antidepressant, antipsychotic, anxiolytic, anti-Parkinson, memory-enhancing, locomotor and neuroprotective effects. The current review discuss the central nervous effects of the medicinal plants with special focus on their mode of action.

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IOSR Journal Of Pharmacy www.iosrphr.org (e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219 Volume 9, Issue 3 Series. I (March 2019), PP. 52-102

Medicinal Plants with Central Nervous Activity- An Overview

(Part 1)

Ali Esmail Al-Snafi1, Tayseer Ali Talab1, Wajdy J Majid2

1Dept. of Pharmacology, Thi qar College of Medicine. 2Dept. Biochemistry, Thiqar college of Medicine, Iraq.

Corresponding Author: Ali Esmail Al-Snafi. Department of Pharmacology, College of Medicine, Thi qar

University, Iraq.

Corresponding Author: Ali Esmail Al-Snafi

Abstract: The recent studies showed that many plants affected the central nervous system and exerted many

pharmacological effects including sedative, anticonvulsant, antidepressant, antipsychotic, anxiolytic, anti-

Parkinson, memory-enhancing, locomotor and neuroprotective effects. The current review discuss the central

nervous effects of the medicinal plants with special focus on their mode of action.

Keywords: Medicinal plants, CNS, sedative, Anticonvulsant, Antidepressant, Antiparkinson, Antipsychotic,

Anxiolytic, Memory-enhancing, Locomotor, Neuroprotective.

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Date of Submission: 25-03-2019 Date of acceptance: 09-04-2019

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I. INTRODUCTION

Plants are a valuable source of a wide range of secondary metabolites, which are used for treatment and

prevention of the diseases. Many medicinal plants possessed anticonvulsant, antidepressant, antianxiety,

sedative, locomotor activity and memory enhancement effects. They were also showed beneficial effects in

many neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, dementia, stress and

fatigue.

Medicinal plants exerted antidepressant effects through synaptic regulation of serotonin, noradrenaline,

and dopamine, regulating activity of hypothalamic-pituitary-adrenal axis and antioxidant effects[1]. They

possessed sedative and anxiolytic effects via potentiation of the inhibitory or decreasing the excitotory

neurotransmission. However, in general, the mechanisms of action of the medicinal plants used for treatment

of psychiatric disorders involved modulation of neuronal communication, via specific plant metabolites binding

to neurotransmitter/ neuromodulator receptors, stimulating or sedating CNS activity, and regulating or

supporting the healthy function of the endocrine system[2-3]. The antiepileptic activity of medicinal plant was

mediated by NMDA receptor antagonism, blocking sodium channels, decreasing Ca2+ influx, GABA agonistic

effect, benzodiazepine agonistic activity, reducing dopamine output and interaction with and modulation of

other transmitters[4]. The beneficial effects of medicinal plants in neuro degenerative disorders was mediated

via their antioxidant activity, anti-excitotonic effect, apoptotic inhibition, neurotrophic effects, enhancing

protective signaling, altering membrane microstructures, decreasing inflammation, and preventing accumulation

of polyubiquitinated protein aggregates in critical regions of the brain[5-6]. This review will highlight the

central nervous effects of the medicinal plants.

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Fig 1: The mechanism of central nervous effects of medicinal plants

Plants with anticonvulsant effect:

Bacopa monniera

Crude plant extract of Bacopa monnieri or bacosides have also shown anticonvulsive action. It

possessed neuroprotective effects in glutamate-mediated excitotoxicity during seizures and cognitive damage

occurring inassociation with pilocarpine-induced epilepsy[98]. The ethanolic extract of Bacopa monniera was

tested for anticonvulsant activity using different convulsive models (pentylenetetrazol, maximal electroshock

and strychnine-induced convulsion in rats, as well as hypoxic stress-induced convulsions in mice and lithium–

pilocarpine-induced status epilepticus). The ethanolic extract of Bacopa monniera was administered as 50 and

55 mg/kg orally for rats and mice, respectively, 2 and 4 hours before the respective convulsive stimuli. The

ethanolic extract of leaves produced significant anticonvulsant activity for all the different models studied with a

mechanism of action similar to that of benzodiazepines (GABA agonist)[7].

Benincasa hispida

The anticonvulsant properties of alcoholic extract of Benincasa hispida was studied on maximal

electroshock test (MEST), pentylenetetrazole and strychnine-induced seizures model in mice. The alcoholic

extract of Benincasa hispida protected animals against maximal electroshock-induced convulsion and reduced

the mean recovery time from convulsion. It also showed anticonvulsant activity against pentylenetetrazole-

induced convulsion and protected mice against strychnine-induced convulsions[8].

Brassica nigra

The antiepileptic activity of methanolic extract of Brassica nigra seeds was investigated on maximal

electroshock induced seizures (MES), Pentylene tetrazole (PTZ), Picrotoxin (PIC) and biccuculine induced

seizures in mice. It was found that the extract (200 and 400 mg/kg, orally), significantly prolonged the onset of

tonic seizures and reduced the duration of incidence of seizures in PTZ, PIC and biccuculine induced seizure

models, while in MES model, the extract showed significant effect in abolishing tonic hind limb extensions by

inhibiting voltage dependant Na+ channels or by blocking glutaminergic excitation mediated by the N-methyl-

D-aspartate (NMDA) receptor [9].

The anti-epileptic effect of the methanolic extract of Brassica nigra seeds (75, 150 and 300 mg/Kg; ip)

was evaluated in pentylentetrazole (PTZ) - induced kindling in mice. The methanolic extract of Brassica nigra

seed reduced the intensity and duration of seizure. In addition, the Brassica nigra extract increased the SOD and

NO levels and decreased the MDA level in the brain tissues[10].

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Bryophyllum calycinum

The CH2Cl 2/CH3OH extract reduced seizures induced by pentylenetetrazol, strychnine sulphate and

thiosemicarbazide and increases in the latency period of seizures and reduced the duration of seizures induced

by the three convulsive agents[11-13].

Caesalpinia crista

The anticonvulsive effect of seed extract of Caesalpinia crista was investigated by pentylenetetrazole,

maximal electro shock strychnine- and picrotoxin-induced convulsions models. Diazepam was used as astandard

reference for all models except maximal electro shock model, wherein phenytoin wasused as standard reference.

Seed kernels of Caesalpinia crista were powdered and subjected to successive extraction with petroleum ether,

ethanol, methanol and water. All the extracts were administered as suspension in 2% gum acacia inall the

experiments. In pentylene tetrazole maximal electro shock, strychnine- and picrotoxin-induced convulsion

models, the medium and high doses (600 and 800mg/kg) of the extract showed significant anticonvulsant

activity [14].

Calotropis procera

The anticonvulsant activity of different root extracts of Calotropis procera was studied in rats using

seizures induced by maximal electroshock seizures (MES), pentylenetetrazol (PTZ), lithium-pilocarpine and

electrical kindling seizures. In the MES test, the chloroform extract of Calotropis procera roots showed the

most significant (P<0.01) anticonvulsant effect, it decreased the duration of hind limb extension (extensor

phase), clonus and also the duration of the stupor phase compared with the controls. In the PTZ test, the

chloroform extract exhibited a highly significant (P<0.001) effect, and the aqueous extract had a significant

(P<0.01) effect compared with the controls by delaying the onset of convulsions. The extracts also inhibited

convulsions induced by lithium-pilocarpine and electrical kindling [15].

Carthamus tinctorius

Subcutaneous administration of 1–10 g/kg bw of an aqueous or 50% methanol extract of the flowers

had central nervous system depressant effects and relaxed skeletal muscles in mice. Subcutaneous

administration of 10 g/kg bw of a 50% methanol extract of the flowers inhibited pentylenetetrazole-induced

convulsions in mice [16].

Cicer arietinum

Different doses of dichloromethane extract of Cicer arietinum were administered to the mice, the

pentylenetetrazole induced clonic seizure (occurrence and latency) was recorded 30 min thereafter. The extract

protected mice against clonic seizures induced by pentylenetetrazole, dose-dependently (ED50= 3g/kg) with no

toxic and lethal effects [17-18].

Citrus limon

The central nervous system (CNS) depressant and anticonvulsant activities of Citrus limon essential

oil (EO) were investigated in animal models. The EO (50, 100 and 150 mg/kg) administered by oral route in

mice caused a significant decrease in the motor activity of animals when compared with the control group, up to

thirty days after the administration and the dose of 150 mg/kg significantly reduced the remaining time of the

animals on the Rota-rod apparatus. Additionally, C. limon essential oil was also capable to promote an increase

of latency for development of convulsions induced by pentylenetetrazole. The administration of flumazenil, (10

mg/kg, ip), GABAA-benzodiazepine (GABA-BZD) receptor antagonist, antagonized the effect of C. limon

essential oil at higher dose. C. limon essential oil was also capable to promote an increase of latency for

development of convulsions induced by picrotoxin at higher dose. In the same way, the anticonvulsant effect of

the EO was affected by pretreatment with flumazenil, a selective antagonist of benzodiazepine site of GABAA

receptor [19].

Clitoria ternatea

The spectrum of activity of the methanolic extract of Clitoria ternatea (CT) on the CNS was

determined. The CT was studied for its effect on cognitive behavior, anxiety, depression, stress and convulsions

induced by pentylenetetrazol (PTZ) and maximum electroshock (MES). To explain these effects, the effect of

CT was also studied on behavior mediated by dopamine (DA), noradrenaline, serotonin and acetylcholine. The

extract decreased time required to occupy the central platform (transfer latency, TL) in the elevated plus maze

(EPM) and increased discrimination index in the object recognition test, indicating nootropic activity. The

extract was more active in the object recognition test than in the EPM. The extract increased occupancy in the

open arm of EPM by 160% and in the lit box of the light/dark exploration test by 157%, indicating its anxiolytic

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

activity. It decreased the duration of immobility in tail suspension test (suggesting its antidepressant activity),

reduced stress-induced ulcers and reduced the convulsing action of PTZ and MES. The extract exhibited

tendency to reduce the intensity of behavior mediated via serotonin and acetylcholine. The effect on DA- and

noradrenaline-mediated behavior was not significant. Accordingly, the extract possessed nootropic, anxiolytic,

antidepressant, anticonvulsant and antistress activity [20].

Coriandrum sativum

The effects of hydroalcoholic extract of aerial parts of the plants (100, 500 and 1000 mg/kg) on brain

tissues oxidative damages following seizures induced by pentylenetetrazole (PTZ) was investigated in rats. The

extract significantly increased the MCS (latencies to the first minimal clonic seizures) and GTCS (latencies to

the first generalized tonic-clonic seizures) (P<0.01, P<0.001) following PTZ-induced seizures. The

malondialdehyde (MDA) levels in both cortical and hippocampal tissues of PTZ group were significantly higher

than those of the control animals (P<0.001). Pretreatment with the extract prevented elevation of the MDA

levels (P<0.010 - P<0.001). Following PTZ administration, a significant reduction in total thiol groups was

observed in both cortical and hippocampal tissues (P<0.050). Pre-treatment with the 500 mg/kg of the extract

caused a significant decreased in total thiol concentration in the cortical tissues (P<0.010). Accordingly, the

hydroalcoholic extract of the aerial parts of Coriandrum sativum possessed significant antioxidant and

anticonvulsant activities [21].

Intraperitoneal injection of decoction and maceration extracts increased the latency of the convulsions

induced by PTZ in albino mice, but failed to produce complete protection against mortality. The anticonvulsant

activities of high dose extracts were similar to that of phenobarbital at a dose of 20 mg/kg in the PTZ test. In the

maximal electroshock seizures, the aqueous extracts of seeds (at a dose of 0.5 g/kg) and the ethanolic extract (at

doses of 3.5 and 5 g/kg) decreased the duration of tonic seizures by 22.30%, 30.43% and 36.96%, respectively

[22].

The anticonvulsant activities of Crocus sativus stigma constituents, safranal and crocin, were studied

using pentylenetetrazole (PTZ)-induced convulsions in mice. Safranal (0.15 and 0.35 mg/kg body weight, ip)

reduced the seizure duration, delayed the onset of tonic convulsions, and protected mice from death. Crocin (22

mg/kg, ip) did not show anticonvulsant activity [23].

Safranal is an effective anticonvulsant, it was an agonist at GABAA receptors, and the nose to brain delivery via

nanoparticle formulation improved its brain delivery [24].

Cuminum cyminum

The effect of the fruit essential oil of Cuminum cyminum on the epileptiform activity induced by

pentylenetetrazol (PTZ) was evaluated using intracellular technique. The results demonstrated that extracellular

application of the essential oil of Cuminum cyminum (1% and 3%) dramatically decreased the frequency of

spontaneous activity induced by PTZ in a time and concentration dependent manner. In addition it showed

protection against pentylenetetrazol-induced epileptic activity by increasing the duration, decreasing the

amplitude of after hyperpolarization potential (AHP) following the action potential, the peak of action potential,

and inhibition of the firing rate [25].

Cuscuta planiflora

The anticonvulsant effect of 80% methanol extract of the plants was investigated in pentylentetrazole

induced seizure in mice. Different doses of extracts delayed the onset of seizure (p<0.01), but the duration of

seizure did not change significantly. Pretreatment of animals with different doses of extracts decreased the

mortality rate significantly (p<0.01), the percent of seizure protection was also greater than control group

significantly (p<0.05) The most effective dose was 50 mg/kg[26].

Cynodon dactylon

The ethanol extract of aerial parts of Cynodon dactylon showed marked protection against convulsions

induced by chemo convulsive agents in mice. The catecholamines contains were significantly increased in the

brains of extract treated mice. The amount of GABA, which was most likely to be involved in seizure activity,

was increased significantly in mice brain after six week treatment. Results revealed that the extract showed a

significant anticonvulsive property by altering the level of catecholamine and brain amino acids in mice [27-28].

The ethanol extract of aerial parts of Cynodon dactylon inhibited the onset and the incidence of

convulsion in a dose dependent manner against pentylenetetrazole-induced convulsion [29].

Anticonvulsant activity of ethanolic extract of Cynodon dactylon was studied against maximal

electroshock and Pentylenetetrazol (PTZ) induced convulsions in mice. The extract (200, 400, 600 mg/kg)

suppressed hind limb tonic extensions induced by MES and also exhibited protective effect in PTZ-induced

seizures[30].

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Cyperus rotuntdus

The anticonvulsant activity of Cyperus rotundus essential oils was evaluated using MES produced

convulsion in rats. The essential oil of Cyperus rotundus 500mg/kg, significantly decreased the duration

(p<0.01), of clonus (12.00 ± 0.7303 s) and stupor (74.20 ± 0.6325 s) phase of MES induced convulsion as

compared to control [31].

The anticonvulsant effect of Cyperus rotundus extract was also experimentally examined in mice.

Mice received Cyperus rotundus rhizome extract at three doses (100, 200 and 400 mg/kg; ip). All groups except

for control group, were kindled by 11 injections of PTZ (35 mg/kg; ip) with an interval of 48 h. In the 12th

injection, all groups except for control group, were tested for PTZ challenge dose (75 mg/kg). The exhibited

phases of seizure (0-6) were observed and noted for 30 min after PTZ injection. All brains of mice were

removed and then malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) levels of brain

tissues were determined. Data analysis showed that the hydroalcoholic extract of Cyperus rotundus reduced

intensity and duration of seizure and increased the level of SOD and NO and decrease MDA level in mice

brain [32].

The anticonvulsant effect of Cyperus rotundus roots and rhizomes was studied in seizures induced by

pentylenetetrazol (PTZ) and picrotoxin (PTX) in mice. Pretreatment with hydroalcoholic extract of

Cyperus rotundus roots and rhizomes (50-200mg/kg) induced a dose-dependent decrease in the incidence of

both clonic and generalized tonic-clonic seizures (p≤0.05) following PTZ and PTX administration. Co-

administration of a sub-effective dose of CR (50 mg/kg, po) with a sub-protective dose of diazepam (0.5 mg/kg,

ip) increased the latency to seizure. The combination significantly enhanced percent protection against PTZ and

PTX induced convulsions. The authors suggested that the anticonvulsant effect of Cyperus rotundus

roots and rhizomes against PTZ and PTX induced convulsions may be mediated, at least partly, through

GABAA-benzodiazepine receptor complex [33].

Pretreatment with the ethanol extract of Cyperus rotundus caused significant protection against

strychnine and leptazol-induced convulsions [34].

Equisetum arvense

In studying of sedative and anticonvulsant effects of Equisetum arvense, hydroalcoholic extract of

Equisetum arvense (200 and 400 mg/kg) showed significant activity on the open-field, enhanced the number of

falls in the rota-rod reducing the time of permanence in the bar and increased the sleeping time (46% and 74%

respectively) in the barbiturate-induced sleeping time. In the pentylenetetrazole-seizure, it increased the first

convulsion latency, diminished the severity of convulsions, reduced the percentage of animals which developed

convulsion (50% and 25% respectively) and protected animals from death. However, in the elevated plus maze,

the doses 50, 100 and 150 mg/kg did not affect the evaluated parameters[35].

Eschscholzia californica

The sedative effects of alkaloids detected in E.californica were attributed to chloride-current

modulation, which were widely expressed in the brain mainly at the inhibitory interneurons.

Electrophysiological studies on a recombinant 𝛼1 𝛽2 𝛾2 GABAA receptor showed no effect of N-

methyllaurotetanine at concentrations lower than 30 𝜇M. However, (𝑆)-reticuline behaved as positive allosteric

modulator at the 𝛼3, 𝛼5, and 𝛼6 isoforms of GABAA receptors. The depressant properties of aerial parts of E.

californica were assigned to chloride-current modulation by (𝑆)-reticuline at the 𝛼𝛽2𝛾2 and 𝛼5𝛽2𝛾2 GABAA

receptors[36].

Protopine, cryptopine and allocryptopine were demonstrated to enhance 3H-gamma-aminobutyric acid

(3H-GABA) binding to rat brain synaptic membrane receptors. This effect might be indicate a benzodiazepine-

like activity of these alkaloids[37].

Gossypium species

The antiepileptic activity of aqueous extract of Gossypium herbaceum (AEGH) at 10, 30, and 100

mg/Kg, po was evaluated by the convulsions induced in mice by maximum electroshock (MES),

pentylenetetrazole (PTZ) and isoniazid (INH). In MES method, aqueous extract of Gossypium herbaceum

inhibited convulsions significantly potent than Diazepam. In PTZ method, aqueous extract of Gossypium

herbaceum inhibited convulsions potent than phenobarbitone sodium. In INH method, aqueous extract of

Gossypium herbaceum delayed the onset of convulsions with a potency less than Diazepam[38].

Hibiscus rosa-sinensis

The ethanolic extracts of flowers of Hibiscus rosa sinesis exhibited anticonvulsant activity. The

bioassay guided fractionation indicated that the anticonvulsant activity lies in the acetone soluble part of

ethanolic extract of H. rosa sinesis flowers. The fraction protected animals from maximum electro shock,

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

electrical kindling and pentylenetetrazole-induced convulsions in mice and inhibited convulsions induced by

lithium-pilocarpine and electrical kindling. It antagonised the behavioral effects of D-amphetamine and

potentiated the pentobarbitone-induced sleep. It raised brain contents of gamma-aminobutyric acid (GABA) and

serotonin[39].

Hyoscyamus niger

The anticonvulsant effects of alcoholic extract of Hyoscyamus niger seed in doses of 50, 100 and 200

mg/kg ip, was evaluated in seizure induced by Pentylene tetrazole. The results showed that administration of

Hyoscyamus niger seed extract possessed inhibitory effect on the steps, progression and duration of seizure,

especially in the last steps of convulsion. However, therapy with henbane seed extract resulted in an efficient

anticonvulsive effect from the 8th injection reaching the highest level of efficiency at the 12th (p<0.001)[40].

The effects of methanolic extract of Hyoscyamus niger on seizures induced by picrotoxin was studied

in mice. Groups of mice were pretreated with methanolic extract of the plant (12.5, 25, 50, 100, 200, 300, 400

mg/kg, ip), 20 minutes prior to the picrotoxin (12 mg/kg, ip)-induced seizures. The latency of seizure (sec),

duration of seizure (sec) and mortality rate were determined in test and control groups. The results showed that

latency of seizure was increased in groups pretreated with 100, 200, 300 and 400 mg/kg of extract, furthermore,

methanolic extract also (200-400 mg/kg) significantly (P<0.01) delayed the death time in mice as compared to

control[41].

Juglans regia

The potential anticonvulsant effect of walnut kernel extract (WKE) was evaluated in

pentylenetetrazole (PTZ; 2 mg/ml/min) induced seizures in rats. WKE administration significantly increased

the PTZ dose needed to induce the first myoclonic jerk (13.09 ± 1.29 vs. 49.71 ± 12.03 mg/kg; p < 0.001),

decreased the severity of seizure grades and reduced the mortality rate to 0%. Flumazenil (FMZ; 5 mg/kg ip),

did not significantly reduce the anticonvulsant effect of WKE. The combination of diazepam (DPZ; 0.5 mg/kg

ip) and WKE showed a synergic anticonvulsant effect, whereas ethosuximide (ESM) had no significant

influence (p > 0.05) on the WKE effects. It seemed that the anticonvulsant effect attributed to signaling

pathways other than benzodiazepine mediated γ-aminobutyric acid receptors[42].

Juniperus oxycedrus

Pretreatment with methanol and dicliloromethanol extracts (200 mg/kg) did not modify the duration of

convulsions induced by electrical stimulation in mice[43].

Plants with antidepressant activity:

Apium graveolens

The anti-depressant effect of methanolic extract of Apium graveolens seeds (AGM) was investigated

using two behavioral models in in-vivo study, the AGM (100, 200 mg/kg) produced significant anti-depressant

effect on mice and rats in both forced swim test and tail suspension test , its action was found to be similar to

imipramine. The anti-depressant effects of AGM were more prominent at 200 mg/kg when compared to lower

dose of same fraction. The 3, n-butylphthalide and sedanenolide isolated from celery oil showed weak sedative

activity, prolonged pentobarbital narcosis, and induced sleep immediately following recovery from a prior

barbiturate treatment in mice [44].

Avena sativa

The dried seeds and fresh plant exerted antidepressant activity, and it was useful where lowered mood

is associated with anxiety and nervous exhaustion, especially during menopause. The fresh plant is a tonic

remedy for all types of nervous debility, and can help to improve sleep duration and quality where the person is

literally too tired to sleep. Oats also aid withdrawal from tobacco and drug addiction [45]. A dose of 1600 mg of

oat herb extract acutely improve attention and concentration and the ability to maintain task focus in older adults

with differing levels of cognitive status [46].

Bacopa monniera

Bacosides A and B, bacopasides I and II and bacopasaponin C and the extract of Bacopa monniera

exhibited antidepressant activity, while bacopaside VII did not have any antidepressant activity when tested on

forced swimming and tail-suspension models in experimental animals[47-49].

Benincasa hispida

The antidepressant activity of the methanolic extract (50, 100, and 200 mg/kg, administered orally for

14 successive days) was tested in Swiss male albino mice incomparison with classical antidepressant drugs

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

(imipramine 15 mg/kg, fluoxetine 20 mg/kg, and phenelzine 20 mg/kg). The methanolic extract of B. hispida

showed significant antidepressant-like activity in mice probably by inhibiting MAO-A, and through interaction

with dopaminergic, α1- adrenergic, serotoninergic, and GABAergic systems [50].

Citrus limon

Anxiolytic and antidepressant effects and acute toxicity of ethanolic extract (EE) of the aerial parts of

Citrus limon were studied in mice. Anxiolytic activity was evaluated using open field and elevated plus-maze

tests. The antidepressant effect of the extract was studied by forced swimming test in mice. In the open field

test, the oral route administration of EE alone showed significant sedative and antidepressant activities in mice

(p < 0.05). EE did not alter motor coordination. The EE, at three doses tested, showed antidepressant effect and

produced decrease in immobility time. The authors concluded that the EE of the aerial parts of C. limon have a

sedative effect, which may be mediated by benzodiazepine-type receptors, and also an antidepressant effect

where noradrenergic and serotoninergic mechanisms will probably play a role [51].

The sedative, anxiolytic and antidepressant effects of essential oil (EO) of leaves from Citrus limon

were investigated in mice. The effects of EO were demonstrated by open-field, elevated-plus-maze, rota rod,

pentobarbital-induced sleeping time, and forced swimming tests in mice. In the open-field test, EO at the doses

of 50, 100 and 150 mg/kg, after oral administration, significantly decreased the number of crossings, grooming,

and rearing. In the elevated-plus-maze (EPM) test, EO increased the time of permanence and the number of

entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed

arms were decreased. In the rota rod test, EO did not alter motor coordination and, thus, was devoid of effects,

as related to controls. In the pentobarbital-induced sleeping time test, EO at the same doses significantly

increased the animals sleeping time duration. Since EO, at the doses of 50, 100 and 150 mg/kg, did not show a

sedative effect in the open field test, these three doses when used in the forced swimming test, they were

producing a decrease in the immobility time, similarly to that of imipramine (positive control). However, the

antidepressant effects of EO were not altered by the previous administration of paroxetine. In addition, effects of

EO in the forced swimming test were totally blocked by reserpine pretreatment [52].

The behavioral effects of Citrus limon juice was studied in rats at three different doses (0.2, 0.4 and 0.6

ml/kg), considered as low, moderate and high doses. Anxiolytic and antidepressant activities were specifically

assessed twice during 15 days using open field test, elevated plus maze and forced swimming test. In open field

test Citrus limon, revealed increase in distance travelled, number of central entries and number of rearing's at

moderate dose, while in the elevated plus maze, number of open arm entries were found to be increased.

Whereas in forced swimming test, there was decrease in duration of immobility and increase in duration of

climbing [53].

Clitoria ternatea

The effectiveness of Clitoria ternatea in the treatment of obsessive-compulsive was carried out

experimentally. The influence of ethanolic extract of Clitorea ternatea was evaluated in marble-burying

behavior in mice. The results revealed that ethanolic extract of Clitorea ternatea (EECT) (100, 200 and

400mg/kg) reduced the marble burying behavior in mice. It was clear that EECT exhibited significant anti-

compulsive effect in marble-burying behavior test in mice and the effect may be attributed to enhanced

serotonergic function and might have influence on 5-HT reuptake [54].

A Perment polyherbal Ayurvedic formulation that contains equal parts of Clitoria ternatea, Withania

somnifera Dun., Asparagus racemosus Linn., Bacopa monniera Linn., is used clinically as mood elevators. The

behavioural effects and the possible mode of action of Perment was studied in stress induced depressive model.

Chronic unpredictable mild stress (CUMS) was used to induce depression in rats. Open field exploratory

behaviour, elevated plus maze, social interaction and behavioural despair tests were used to assess behaviour.

Plasma noradrenaline, serotonin, corticosterone and brain/adrenal corticosterone levels were measured to

support the behavioural effects of Perment. Exposure to CUMS for 21 days caused anxiety and depression in

rats, as indicated by significant decrease in locomotor activity in the open field exploratory behaviour test and

increased immobility period in the behavioural despair test. Perment predominantly exhibited antidepressant

action than anxiolytic activity. Furthermore, Perment increased the plasma noradrenaline and serotonin levels in

stressed rats. No significant alteration in the brain corticosterone level in stressed rats was observed with

Perment treatment. However the adrenal corticosterone level was decreased with Perment. It can be concluded

that the Perment formulation exhibited synergistic activity, has a significant antidepressant and anxiolytic

activity, which may be mediated through adrenergic and serotonergic system activation [55].

Coriandrum sativum

Diethyl ether extract of seeds of Coriandrum sativum showed more significant antidepressant effect

than that of aqueous extract through interaction with adrenergic, dopamine-ergic and GABA-ergic system [56].

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Crocus sativus

The antidepressant properties of stigmas and corms of Crocus sativus was studied experimentally. The

aqueous ethanol extract of Crocus sativus corms was fractionated on the basis of polarity. Among the different

fractions, the petroleum ether and dichloromethane fractions at doses of 150, 300, and 600 mg/kg showed

significant antidepressant-like activities in dose-dependent manners, by means of behavioral models of

depression. The immobility time in the forced swimming test and tail suspending test was significantly reduced

by the two fractions, without accompanying changes in ambulation when assessed in the open-field test. By

means of a gas chromatography-mass spectrometry technique, twelve compounds of the petroleum ether

fraction were identified. Aqueous stigmas extract also exerted antidepressive effects in the behavioral models.

Crocin 1 and crocin 2 of the aqueous stigmas extract were identified by a reversed-phase HPLC analysis. The

data indicated that antidepressant-like properties of aqueous stigma extracts attributed to crocin 1 [57-58].

The efficacy of hydroalcoholic extract of Crocus sativus (stigma) in comparison with fluoxetine in the

treatment of mild to moderate depression was studied in a 6-week double-blind, randomized trial. Forty adult

outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition for major

depression based on the structured clinical interview for DSM-IV and with mild to moderate depression were

participated in the trial. Patients were randomly assigned to receive capsules of saffron 30 mg/day (BD) (Group

1) and capsule of fluoxetine 20 mg/day (BD) (Group 2) for a 6-week study. Saffron at this dose was found to be

effective similar to fluoxetine in the treatment of mild to moderate depression (F = 0.13, d.f. = 1, P = 0.71).

There were no significant differences between the two groups in terms of observed side effects [59].

The efficacy of petal of Crocus sativus was compared with fluoxetine in the treatment of depressed

outpatients in an 8-week pilot double-blind randomized trial. Forty adult outpatients who met the DSM- IV

criteria for major depression based on the structured clinical interview for DSM- IV were participated in the

trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind and

randomized trial, patients were randomly assigned to receive either capsule of petal of Crocus sativus 15 mg bid

(morning and evening) or fluoxetine 10 mg bid (morning and evening) for a 8-week. At the end of trial, petal of

Crocus sativus was found to be effective similar to fluoxetine in the treatment of mild to moderate depression

(F=0.03, d.f.=1, P=0.84). In addition, in the both treatments, the remission rate was 25%. There were no

significant differences in the two groups in terms of observed side effects [60].

The non selective serotonin (5-HT) receptor agonist mCPP is known to induce obsessive–compulsive

disorder (OCD-like) behavior (excessive self-grooming) in rodents and exacerbated symptoms in patients with

OCD. Crocins (30 and 50 mg/kg, ip) in rats attenuated mCPP-induced excessive self-grooming. The results also

indicated that the effects of crocins on an animal model of OCD cannot be attributed to changes in locomotor

activity, the effect could be attributed to interaction between crocins and the serotonergic system [61].

In a randomized, double-blind study, 30 mg of saffron extract (in capsules) given for 6 weeks resulted

in significant alleviation of depression compared to placeb group, and no side effects were recorded. Many

follow-up double blind trials carried out on saffron preparation compared with imipramine and fluoxetine;

showed that saffron possessed antidepressant effects [59, 62-64].

The molecular mechanism of antidepressant effect of aqueous extract of saffron and its effect on the

levels of brain-derived neurotrophic factor (BDNF), VGF neuropeptide, cyclic-AMP response element binding

protein (CREB) and phospho-CREB (p-CREB) in rat hippocampus, were investigated. The aqueous extract of

saffron (40, 80 and 160 mg/kg/day) and imipramine 10 mg/kg/day were injected intraperitoneally (ip) for 21

days to rats. The FST (forced swimming test) was performed on the days 1st and 21st. The results of FST

showed that saffron reduced the immobility time. The protein levels of BDNF, CREB and p-CREB were

significantly increased in saffron treated rats. VGF protein expression was also increased, but not significantly.

The transcript levels of BDNF was also significantly increased. No significant changes in CREB and VGF

transcript levels were observed. The authors concluded that aqueous extract of saffron has antidepressant effects

and the mechanism of its antidepressant effect may be due to increasing the levels of BDNF, VGF, CREB and

P-CREB in rat hippocampus [65].

Cuscuta planiflora

The effects of Cuscuta planiflora (500mg capsules) were evaluated in patients with major depression

by a randomized triple-blind controlled clinical trial. Patients were taken the treatment for 8 weeks. Depression

was measured before and after the study by Beck depression inventory and Hamilton depression inventory.

There was a significant decrease in mean scores of Beck and Hamilton depression inventories in the group

treated by Cuscuta planiflora (p<0.01) compared with control[66].

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Daucus carota

The antidepressant potential of ethanol root extract of Dacus carota (DC) was studied in different

animal models, forced swim test (FST), tail suspension test (TST), apomorphine induced hypothermia (AIH),

reserpine induced hypothermia (RIH), 5-HTP potentiation of head twitches (HTPPH) in mice. Fluoxetine (25

mg/kg) was used as a standard drug in FST, TST and HTPPH models and desipramine (20 mg/kg) was used as a

standard drug in AIH and RIH models. The antidepressant activity of DC (400 mg/kg) was comparable to that of

standard drugs[67].

Eschscholtzia californica

The aqueous-alcoholic extract from Eschscholtzia californica inhibited the enzymatic degradation of

catecholamines as well as the synthesis of adrenaline. The extract also dramatically shorten the lag phase in the

catalysis of phenolase probably due to their o-diphenol content, furtheremore, dopamine beta-hydroxylase,

monoamine oxidase (MAO-B) and diamine oxidases were inhibited by Eschscholtzia californica extracts. These

mechanisms could explain the antidepressive and hypnotic activities of Eschscholtzia californic[68].

The protopine was also act as an inhibitor of both serotonin transporter and noradrenaline transporter

in vitro assays. 5-hydroxy-DL-tryptophan(5-HTP)-induced head twitch response (HTR) and tail suspension test

were adopted to study whether protopine has anti-depression effect in mice using reference antidepressant

fluoxetine and desipramine as positive controls. In HTR test, protopine at doses of 5, 10, 20 mg/kg dose

dependently increase the number of 5-HTP-induced HTR. Protopine at doses of 3.75 mg/kg, 7.5 mg/kg and 30

mg/kg also produces a dose-dependent reduction in immobility in the tail suspension test[69].

Foeniculum vulgare

The antidepressant effect of Vetiveria zizanioides and Foeniculum vulgare in comparison with

antidepressant drug fluoxetine was investigated in depressive behavior in albino rats. Both Forced swimming

test and Tail suspension test were used for screening antidepressant effect. The ethanolic extract of Vetiveria

zizanioides(100mg/kg) and Foeniculum vulgare (200mg/kg) together, fluoxetine(10mg/kg) and saline were

administered 30mts prior to the tests and the immobility period was recorded for 6mts.The antidepressant effect

of both were compared to that of fluoxetine. Vetiveria zizanioides(100mg/kg) and Foeniculum vulgare

(200mg/kg) produced significant antidepressant effect by reduction in immobility period as compared to control.

But as a group together they are equally effective as fluoxetine (10mg/kg)[70].

The antidepressant effects of methanolic extract of Foeniculum vulgare fruits (MEFV) was

investigated using force swim test in rats (FST), potentiation of norepinephrine (NE) toxicity in mice and

haloperidol induce catalepsy (HIC) in mice. The extract of F.vulgare (250 and 500 mg/kg) was administered

orally to rats used in FST and 500mg/kg was administered in HIC and same dose administered in NE toxicity in

mice. The dose of 250mg/kg and 500mg/kg of extract significantly (p<0.001) reduced the immobility times in

rats, 500 mg/kg showed more potent effect than imipramine (30mg/kg). In NE toxicity model it was observed

that MEFV dose not interfere with adrenergic system. A significant (P<0.001) reduction in the duration of

catalepsy was observed in the MEFV treated group and Fluoxetine group as compared to the haloperidol treated

group. In HIC, mice were sacrificed on the seventh day and TBARS, glutathione, nitrite activities were

estimated. Monoamine oxidase inhibiting effect and anti-oxidant effect of Foeniculum vulgare may be

contributing favorably to the antidepressant-like activity[71].

Glycyrrhiza glabra

The effects of aqueous extract of Glycyrrhiza glabra on depression was investigated in mice using

forced swim test (FST) and tail suspension test (TST). The extract of G. glabra (75, 150, and 300 mg/kg) was

administered orally for 7 successive days in separate groups of male mice. The dose of 150 mg/kg of the

extract significantly reduced the immobility times of mice in both FST and TST, without any significant effect

on locomotor activity of mice. The efficacy of extract was found to be comparable to that of imipramine (15

mg/kg ip) and fluoxetine (20 mg/kg ip). Liquorice extract reversed reserpine-induced extension of immobility

period of mice in FST and TST. Sulpiride (50 mg/kg ip, a selective D2 receptor antagonist) and prazosin (62.5

μg/kg ip, an α1-adrenoceptor antagonist) significantly attenuated the extract-induced antidepressant-like effect in

TST. On the other hand, p-chlorophenylalanine (100 mg/kg ip, an inhibitor of serotonin synthesis) did not

reverse antidepressant-like effect of liquorice extract. It seemed that the antidepressant-like effect of liquorice

extract mediated by increase of brain norepinephrine and dopamine, but not by increase of serotonin[72].

Gossypium species

Aqueous extract of detoxified Gossypium herbaceum seeds showed antidepressant-like effect due to

activation of adenyl cyclase-cAMP pathway in signal transduction system. Aqueous extract of detoxified

Gossypium herbaceum seeds 0.01, 0.03, 0.10, 0.30 mg/ml was incubated directly with the synaptic membrane

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

extracted from the cerebral cortex in rats, and adenylyl cyclase activity was detected by radio-immunoassay.

Antidepressant and anxiolytic effects of the aqueous extract of detoxified Gossypium herbaceum seeds were

caused by activation of AC-cAMP pathway in signal transduction system, thus protecting neurons from the

lesion[73-74].

Haplophyllum species

The oil showed weakly acetylcholinesterase (AChE) inhibitory activity, compared to standard

substances, whereas no inhibition on butyrylcholinesterase (BuChE) activity was observed[75]. The inhibitory

activity of acetyl cholinestrase was mainly accumulated in the chloforom and ethyl acetate fractions of different

parts extracts of H. tuberculatum. The most active was the stem ethyl acetate fraction with an inhibitory effect of

79% and IC50 of 0.45 μg/ml. Other fractions possessed an inhibitory effect at arrange between 70 – 77%[76].

Helianthus annuus

The methanolic extract of Helianthus annuus seeds also caused remarkable antidepressant activity (tail

suspension test). H. annuus showed significant antidepressant activity (p<0.05) by decreasing the immobility

time (H. annuus 100mg/kg, 93±0.47; H. annuus 200mg/kg, 78±1.3) as compared with Imipamine (60mg/kg,

30.2±0.64) and control (190.8±0.75)[77].

Hibiscus rosa-sinensis

The anti-depressant activity of methanol extract containing anthocyanins (MHR) (30 and 100 mg/kg)

and anthocyanidins (AHR) (30 and 100 mg/ kg) of H. rosa-sinensis flowers were evaluated in mice using

behavioral tests [ tail suspension test (TST) and forced swim test (FST)]. The mechanism of action involved in

antidepressant activity was investigated by observing the effect of extract after pre-treatment with low dose

haloperidol, prazosin and para-chlorophenylalanine (p-CPA). The results revealed that extract caused significant

decrease in immobility time in TST and FST, similar to that of imipramine (10 mg/kg, ip) which served as a

positive control. The extract significantly attenuated the duration of immobility induced by Haloperidol (50 μg/

kg, ip., a classical D(2)-like dopamine receptor antagonist), Prazosin (62.5 μg/kg, ip, an α1-adrenoceptor

antagonist) and p-chlorophenylalanine (100 mg/kg, ip, × 3 days; an inhibitor of serotonin synthesis) in both TST

and FST[78].

Hyoscyamus niger

The antidepressant effect of Hyoscyamus niger was evaluated in animal models [forced swim test

(FST) and tail suspension test (TST) in mice] of depression with studying the possible mechanism underlying

the antidepressant effect. Locomotor and anxiolytic activity was also studied. Hyoscyamus niger leaves

ethanolic extract was administered to mice by oral route at dose of 25, 50, 100, 200 and 400 mg/kg for 14 days.

Further an interaction of Hyoscyamus niger ethanolic extract with conventional antidepressant drugs were also

studied at sub-effective doses. The ethanolic extract significantly reduced immobility duration of mice in FST

and TST. The same doses did not change the motor activity in mice. However, high dose of extract showned

anxiolytic activity. Interaction study with conventional antidepressant drugs reduced the duration of immobility

count suggested, possible involvement of biogenic amine in antidepressant action[79].

Juglans regia

The antidepressant effect of Juglans regia fruit extract (100 and 150 mg/kg bw ) was studied in animal

models of depression (forced swimming test and tail suspension test). Both doses significantly decreased

duration of immobility in both models of depression. The effect of extract was less significant than standard

drug fluoxetine. The antidepressant activity could be attributed to the presence of omega 3 fatty acid in

extract[80].

Plant with sedative and anxiolytic effects:

Anthemis nobelis

In mice, apigenin had a clear affinity for central benzodiazepine receptors. Apigenin competitively

inhibited the binding of flunitrazepam, a benzodiazepine, but had no effect on muscarinic receptors, alpha 1-

adrenoceptors, or the binding of muscimol to GABA receptors. Apigenin had clear anxiolytic activity in mice

without incidence of sedation or muscle relaxation effects at doses similar to those used for classical

benzodiazepines; no anticonvulsant action was detected. Increasing dosages produced mild sedation and a

reduction in ambulatory locomotor activity [81-82].

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Arachis hypogaea

Arachis hypogaea leaf aqueous extracts have received a long reputation as an abirritative remedy to

ease various sleep disorders. The clinical studies confirmed the hypnotic effects of Arachis hypogaea [83-

84].The sedative effects of Arachis hypogaea leaf aqueous extracts on brain ATP, AMP, adenosine and

glutamate/GABA of rats was investigated. Intragastrically administrated Arachis hypogaea leaf aqueous

extracts( PLAE , 100 and 500 mg/kg body weight BW) and peanut stem aqueous extracts (PSAE, 500 mg/kg

BW) for at least 14 days showed that brain lactate were significantly elevated (p < 0.05) in rat cerebrums after

PLAE administrations, compared with control and PSAE groups. A significant degradation of the brain

adenosine triphosphate (ATP) (p < 0.05) was observed in the brain-stems and even the whole brains of rats of

PLAE treatments. Moreover, the brain adenosine monophosphate (AMP) were clearly decreased (p < 0.05) in

rat cerebrum and brainstem regions, while the brain adenosine revealed an increasing propensity (p = 0.076) in

the cerebrums of freely behaving rats. The γ-aminobutyric acid (GABA) concentrations were statistically (p <

0.05) enhanced and the ratios of Glutamate/GABA were simultaneously reduced (p < 0.05) in rat brainstems, no

matter which dose (100 or 500 mg/kg BW) of PLAE were used [85].

Arctium lappa

The anti-fatigue effect of the extract of Arctium lappa L. was studied in male mice by forced

swimming test. The swimming time of mice treated by 4 and 6 g/kg of an extract of Arctium lappa was

significantly prolonged as compared with control group. The hepatic glycogen storage in the groups treated with

2, 4 and 6 g/kg of Arctium lappa extract was significantly increased. Lactic acid clearance in the groups treated

with 4, and 6 g/kg of Arctium lappa extract was significantly accelerated after mice swimming [86].

Asparagus officinalis

Asparagus officinalis exerted antifatigue effects, enhanced anoxia tolerance, induced analgesia and

improved memory, as well as decreased the contents of lipid peroxide in plasma, liver and brain of the animal

[87].

Avena sativa

An extract of wild green oat (Avenasativa L.), was tested in vivo in rats for its behavioural effects after

chronic oral administration via extract-admixed food. Rats received 10 g/kg and 100 g/kg extract-admixed food

showed slight decreased food and fluid intake in the high dose group , with no side effects observed during the

treatment. The low dose led to an improvement of active stress response, an enhancement of shock avoidance

learning and an increased synchrony in social behavior [88].

Dietary oat β-glucan enhanced the endurance capacity of rats and facilitated their recovery from stress

and fatigue. Sparsgue-Dawley rats, fed with/without oat β-glucan 312.5 mg/ kg/day for 7 weeks, were subjected

to run on a treadmill system to make them exhausted. All rats were immediately sacrificed after prolonged

exercise, and the major metabolic substrates were measured in serum and liver. The results showed feeding

dietary oat β-glucan to rats significantly reduce the body weight and increase the maximum running time

compared with normal control (P<0.05). Furthermore, dietary oat β-glucan decreased the levels of blood urea

nitrogen, lactate acid, and creatine kinase activity in serum, and increased the levels of non-esterified fatty acids,

lactic dehydrogenase activity in serum, and the content of liver glycogen [89].

Avenasativa improved overall mental fitness and supported cognitive performance in stressful

situations. Avenasativa has been shown to positively affect the activity of brain enzymes closely related to

mental health and cognitive function in-vitro. Additionally, preclinical and clinical studies have confirmed that

Avena sativa specifically interacted with brain structures and neurotransmitters implicated in cognition, memory

and motivation. Avena sativa boasted a dual activity profile on monoamino oxidase-B( MAO-B) and

phosphodiestrase 4 (PDE4)thus displayed in its ability to meditate a strengthening and balancing effect on the

brain and mind [90].

Bacopa monniera

Crude plant extract of Bacopa monnieri or bacosides have also shown anxiolytic effects, antidepressant

activity, anticonvulsive action and antioxidant activity[91].

Bacopa monnieri was highly effective as an adaptogen, it normalized acute and chronic stress induced

corticosterone changes in rats. It also normalized noradrenalin (NA), 5-HT, and DA in cortex and hippocampus

of rats in acute and chronic unpredictable stress[92].

Bacopa monniera lowered norepinephrine and increases the 5-hydroxytryptamine levels in

hippocampus, hypothalamus and cerebral cortex. The higher doses of Bacopa monniera extracts produced

significantly greater anxiolytic effects compared to lorazepam, a standard anxiolytic drug from benzodiazepine

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

group [93]. However, acute and sub chronic (one week) treatment of Bacopa monnieri methanolic extract (10,

20 or 30 mg/kg) didn’t affected dopamine (DA) and serotonin (5-HT) turnover in mice whole brain[94-95].

Ballota nigra

Phenylpropanoid derivatives isolated from Ballota nigra showed neurosedative activity and exhibit

potent antioxidant activities which are of therapeutic interest [96]. The ability of five phenylpropanoids

(verbascoside, forsythoside B, arenarioside, ballotetroside, and caffeoyl malic acid) isolated from a

hydroalcoholic extract, to bind to benzodiazepine, dopaminergic, and morphinic receptors was investigated. To

carry out these studies, affinity tests with rat striata, entire brains and receptor rich preparations were employed.

Results show that four of the five compounds are able to bind to the studied receptors. Inhibitory concentrations

at 50% were determined and vary from 0.4 to 4.7 mg/ml. This may be in relation with the Ballota nigra known

neurosedative activities [97].

Bryophyllum calycinum

The methanolic extract of Bryophyllum calycinum Salisb showed neuro-pharmacological effects in

experimental animals (rats and mice). The fraction produced alteration of behavior pattern, caused dose-

dependent potentiation of pentobarbitone sleeping time and had significant analgesic activity and possesses a

potent CNS depressant action. The saline leaf extract of Bryophyllum calycinum Salisb produced a dose-

dependent prolongation of onset and duration of pentobarbitone-induced hypnosis, reduction of exploratory

activities in the head-dip and evasion tests. Moreover, a dose-dependent muscle in-coordination was observed in

the inclined screen, traction and climbing tests in mice. The saline leaf extract produced a dose-dependent

prolongation of onset and duration of pentobarbitone-induced hypnosis, reduction of exploratory activities in the

head-dip and evasion tests and a dose-dependent muscle incoordination in the inclined screen, traction and

climbing tests[98-100].

Caesalpinia crista

The anxiolytic activities of seed extract of Caesalpinia crista in experimental animals, mice and rats

were investigated by stair-case model, Three doses (400, 600 and 800mg/kg) showed a significant and dose

dependent anxiolytic activity by increasing the number of steps climbed, without any significant effect on

rearings by all the three doses. Similarly in EPM model medium, high doses, but not the low dose had

significantly enhanced both number of entries and time spent in open arms and decreased in number of entries

and time spent in closed arms. In Hole- board model, medium and high doses 600 and 800mg/kg but not the low

dose 400mg/kg had significantly enhanced the number, latency and the duration of head dipping but not the

rearings. However in LDT model high doses 800mg/kg had significantly exhibited anxiolytic activity by

increasing time spent, number of crossings in light compartment and decreased the time spent in dark

compartment and decreased the number of rearings in both light and dark compartments. In OFT models,

medium and high doses 600 and 800mg/kg but not the low dose 400mg/kg had significantly enhanced total

locomotion, central locomotion, number of grooming but the immobility time has drastically reduced. All doses

have not exerted any significant effect with rearing, defecation and urination. Moreover in Mirror-chamber

model of anxiety, both medium and high doses 600 and 800mg/kg but not the low dose 400mg/kg had

significantly reduced the time latency to enter into the mirror chamber and increased the number of entries and

time spent in the chamber. These result confirmed the anxiolytic activity of Caesalpinia crista [101].

Caesalpinia crista seed extracts were screened for adaptogenic activity using cold stress and swim

endurance models. The seed coat as well as kernel extracts administered orally at a dose of 300mg/kg

significantly increased the swim endurance time. The extracts also corrected hyperglycemia, the depletion in

serum cortisol level, increased total leukocyte count, and controlling the hyperlipidaemic condition associated

with to stress [102].

Carum carvi

The aqueous extract of Carum carvi was evaluated for antistress activity in normal and stress induced

rats. The extract was studied for nootropic activity in rats and in vitro antioxidant potential to be correlated with

its antistress activity. For the evaluation of antistress activity groups of rats were subjected to forced swim stress

one hour after daily treatment of Carum carvi extract. Urinary vanillylmandelic acid (VMA) and ascorbic acid

were selected as non invasive biomarkers to assess the antistress activity. The 24 h urinary excretion of

vanillylmandelic acid (VMA) and ascorbic acid was determined in all groups under normal and stressed

conditions. The nootropic activity of the extract as determined from acquisition, retention and retrieval in rats

was studied by conditioned avoidance response using Cook’s pole climbing apparatus. Daily administration of

Carum carvi at doses of 100, 200 and 300 mg/kg body weight one hour prior to induction of stress inhibited the

stress induced urinary biochemical changes in a dose dependent manner. However no change in the urinary

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

excretion of VMA and ascorbic acid was observed in normal animals. The cognition, as determined by the

acquisition, retention and recovery in rats was observed to be dose dependent. The in vitro antioxidant activity

was determined based on the ability of Carum carvi to inhibit lipid peroxidation in liver and brain homogenates.

The extract produced significant inhibition of lipid peroxide formation in comparison with ascorbic acid in a

dose dependent manner in both liver and brain [103].

Citrus species

The effects of apigenin, a bioflavonoid widely found in citrus fruits, on behavioral changes and

inflammatory responses induced by chronic unpredictable mild stress (CUMS) was investigated in rats. When

GW9662, a selective peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor, administered 30min

before apigenin, apigenin (20mg/kg, intragastrically) for three weeks remarkably ameliorated CUMS-induced

behavioral abnormalities, such as decreased locomotor activity and reduced sucrose consumption. In response to

oxidative stress, the NLRP3 inflammasome was activated and IL-1β secretion increased in the prefrontal cortex

(PFC) of CUMS rats. However, apigenin treatment upregulated PPARγ expression and downregulated the

expression of NLRP3, which subsequently downregulated the production of IL-1β. In addition, GW9662

diminished the inhibitory effects of apigenin on the NLRP3 inflammasome. Accordingly, the results

demonstrated that apigenin exhibited antidepressant-like effects in CUMS rats, possibly by inhibiting IL-1β

production and NLRP3 inflammasome expression via the up-regulation of PPARγ expression [104].

The sedative effects of essential oil (EO) of leaves from Citrus limon were investigated in mice. EO

150 mg/kg, orally significantly increased the animals sleeping time duration [105].

The effects of Citrus sinensis essential oil was evaluated in the elevated plus-maze followed by the

light/dark paradigm in rats. The animals were exposed to the orange aroma (100, 200 or 400 microl) for 5 min,

while in a Plexiglas chamber and were then immediately submitted to the behavioural tests. At all doses, C

sinensis oil demonstrated anxiolytic activity in at least one of the tests and, at the highest dose, it presented

significant effects in both animal models, as indicated by increased exploration of the open arms of the elevated

plus-maze (time: p=0.004; entries: p=0.044) and of the lit chamber of the light/dark paradigm (time: p=0.030).

In order to discard the possibility that this outcome was due to non-specific effects of any odour exposure, the

behavioural response to Melaleuca alternifolia essential oil was also evaluated, using the same animal models,

but no anxiolytic effects were observed [106].

Coriandrum sativum

The anxiolytic effect of aqueous extract (50, 100, 200 mg/kg, ip) was examined in male albino mice

using elevated plus- maze as an animal model of anxiety. In the elevated plus-maze, aqueous extract at 200

mg/kg showed an anxiolytic effect by increasing the time spent on open arms and the percentage of open arm

entries, compared to control group [107-108].

The anxiolytic effect of Coriandrum sativum (CS) aqueous extract was evaluated in mice. The

antianxiety effect was assessed by elevated plus maze (EPM). In EPM, 50, 100, and 200 mg/kg of CS were

significantly (P<0.001) increases the number of entries in open arms compared to control. The time spent in

open arms also increased in all the doses of CS extract significantly [109].

The anti-anxiety activity of hydroalcoholic extract of Coriandrum sativum was studied using different

animal models (elevated plus maze, open field test, light and dark test and social interaction test) of anxiety in

mice. Diazepam (0.5 mg/kg) was used as astandard drug and hydroalcoholic extract of Coriandrum sativum

fruit was used in dose of (50, 100 and 200 mg/kg) to study the antianxiety effect. Results revealed that the

extract of Coriandrum sativum at 100 and 200 mg/kg dose produced anti-anxiety effects almost similar to

diazepam, while, at 50 mg/kg dose, it did not produce anti-anxiety activity in all models [110].

The anxiolytic effect of the aqueous extract of Coriandrum sativum seed and its effect on

spontaneous activity and neuromuscular coordination were evaluated in mice. The anxiolytic effect of aqueous

extract (10, 25, 50, 100 mg/kg, ip) was examined in male albino mice using elevated plus-maze as an animal

model of anxiety. The effects of the extract on spontaneous activity and neuromuscular coordination were

assessed using Animex Activity Meter and rotarod. In the elevated plus-maze, 100 mg/kg of the aqueous extract

showed an anxiolytic effect by increasing the time spent on open arms and the percentage of open arm entries,

compared to control group. Aqueous extract at 50, 100 and 500 mg/kg significantly reduced spontaneous

activity and neuromuscular coordination, compared to control group [111-112].

The aqueous, hydroalcoholic extracts and essential oil of coriander seeds possessed sedative-hypnotic

activity. The aqueous, hydroalcoholic extracts and essential oil of coriander seeds (100, 200, 400 and 600

mg/kg) were intraperitoneally administered to male albino mice, 30 minutes before pentobarbital injection (40

mg/kg). Latency to sleep and sleep duration were recorded. Aqueous extract prolonged pentobarbital-induced

sleeping time at 200, 400 and 600 mg/kg. Hydroalcoholic extract at doses of 400 and 600 mg/kg increased

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

pentobarbital induced sleeping time compared to saline-treated group. The essential oil increased pentobarbital-

induced sleeping time only at 600 mg/kg [113].

The sleep-prolonging effect of Coriandrum sativum was investigated in mice. The hydroalcoholic

extract (HAE) and its three fractions, water (WF), ethyl acetate (EAF) and N-butanol (NBF) were prepared from

Coriandrum sativum aerial parts and administrated to mice. The HAE, EAF and NBF significantly prolonged

sleep duration. Only the NBF was significantly decreased sleep latency. No decrease in the neuronal surviving

was observed either by HAE or by its fractions. The data indicated that Coriandrum sativum exerted sleep-

prolonging action without major neurotoxic effect [114].

Crocus sativus

The anxiolytic and hypnotic effects of saffron aqueous extract and its constituents, crocin and safranal

were studied in mice. Agents were administered intraperitoneally in mice before the experiments for the

evaluation of hypnotic activity (induced by sodium pentobarbital, 30 mg/kg, ip), anxiolytic activity (elevated

plus maze test), locomotor activity (open field test) and motor coordination (Rotarod test). The

aqueous extract reduced the locomotor activity dose dependently. At low doses, saffron showed a significant

increase in the time on the open arms of the maze. When using the Rotarod method, the aqueous extract showed

considerable effect on motor coordination of the mice. In the hypnotic test, only a dose of 0.56 g/kg of saffron

increased the total sleep. Crocin showed no anxiolytic, hypnotic or myorelaxation effects. Safranal, in higher

doses, 0.15 and 0.35 ml/kg, showed anxiolytic effects. Safranal increased the total sleep time dose dependently.

This constituent at lower doses (0.05 and 0.15 ml/kg) decreased some locomotion activity parameters. Safranal

demonstrated no effects on motor coordination. Based on the results, saffron aqueous extract and safranal

showed anxiolytic and hypnotic effects [115].

Intragastric administration of 125–250 mg/kg bw of a 50% ethanol extract of the stigmas showed

tranquillizing effect and potentiated the sedative effects of barbiturates in mice [116].

The anxiolytic properties of crocins was investgated in rodents via light/dark test. Crocins, at a dose

which did not influence animals’ motor activity (50 mg/kg), or diazepam (1.5 mg/kg), increased the rats latency

to enter the dark compartment and prolonged the time spent in the lit chamber. Lower doses of crocin (15-30

mg/kg) did not modify animals behavior [117].

Antianxiety-like behavior of aqueous, ethanolic and acetonitrile Crocus sativus extracts have been

investigated in forced-swimming stress in rats. Different doses of extracts (10, 30, 60 mg/kg) were injected

intraperitoneally (ip) in a 9-day period, meanwhile, swimming stress was performed for 15 minutes in four

sessions (days 3, 5, 7 and 9). The time performing the followings: immobility, swimming and struggling was

measured. Moreover, free fatty acids, glucose, corticosterone and HSP70 were also measured. The outcomes

demonstrated that saffron decreased stress significantly by prolonging immobility and decreasing the active

behavior swimming, without much effect on struggling. The extracts also showed significant reduction in levels

of the stress biomarkers. Acetonitrile was identified as the most effective extract in reducing anxiety. The

saffron extracts probably proved anti-stress and sedative properties, partly due to distinct proportion and

synergistic impact of the active constituents. On the other hand, crocin and safranal have anti-oxidant and anti-

inflammatory powers that may aid to mediate this protective central impact[118].

The effects of saffron water extract and its constituent, safranal was studied on the behavioral and

metabolic signs induced by electroshock stress in male Wistar. Animals were received intra-amygdala (1, 5, and

10 µg/rat) or intraperitoneal (1, 5, and 10 mg/kg) of the extract, safranal, or saline 5 or 30 min before stress

induction. The results showed that stress elevated the corticosterone plasma concentration (115 nmol/l) in the

control and intra-amygdala (1, 5, and 10 µg/rat)-treated groups but not in groups received extract or safranal (55

nmol/l) intraperitoneally (1, 5, and 10 mg/kg). Moreover, anorexia was reduced only in groups received

the extract (1, 5, and 10 mg/kg) or safranal (1, 5, and 10 mg/kg) intraperitoneally (50 sec). Stress increased

sniffing, rearing, locomotion, and coping time, which were decreased by intraperitoneal (1, 5, and 10 mg/kg) but

not by intra-amygdala (1, 5, and 10 µg/rat) administration of saffron extract and safranal. The results revealed

that saffron water extract and safranal had an important impact on the reduction of both metabolic and

behavioral signs of stress in male rats [119].

Cynodon dactylon

The dried extracts of aerial parts of Cynodon dactylon were evaluated for CNS activities in mice. The

ethanol extract of aerial parts of Cynodon dactylon (EECD) was found to cause significant depression in

general behavioral profiles in mice. EECD also significantly potentiated the sleeping time in mice induced by

standard pentobarbitone sodium, diazepam, and meprobamate in a dose dependant manner [120].

The effects of ethanol extract of aerial parts of Cynodon dactylon (EECD) were studied to investigate

its CNS depressant pharmacological properties in the classical behavioral models (open-field, elevated plus

maze-EPM, Rota-rod, and barbiturate-induced sleeping time) in mice. Extract was given in 50% propylene

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

glycol as a solvent, as a single dose of 50, 75 and 100mg/kg ip. No significant effect was evident on motor

coordination of the animals in the rotarod test. On EPM, all the doses of EECD caused significant reduction in

the time of permanence in the open arms. In addition, EECD increased the immobility time in the forced

swimming test and potentiated pentobarbital-induced sleeping time in mice, confirmed a probable sedative and

central depressant effect in the animals [121].

Cyperus rotuntdus

The ethanolic extract of Cyperus rotundus showed potent tranquilizing activity in many tests. It

reduced the spontaneous motor activity, potentiated the pentobarbital narcosis and deranged the motor

coordination and abolished the conditioned avoidance response in animals [122-123].

The behavioral studies on mice indicated CNS depressant activity of the ethanol extract of

Cyperus rotundus. The ethanol extract of Cyperus rotundus significantly potentiated the sleeping time of mice

induced by standard hypnotics (pentobarbitone sodium, diazepam, and meprobamate) in a dose dependent

manner [124].

Four sesquiterpenes (beta-selinene, isocurcumenol, nootkatone and aristolone) and one triterpene

(oleanolic acid) were isolated from the ethylacetate fraction of the rhizomes of Cyperus rotundus and tested for

their ability to modulate gamma-aminobutyric acid (GABAA)-benzodiazepine receptor function by radioligand

binding assays using rat cerebrocortical membranes. Among these compounds, only isocurcumenol was found

to inhibit [3H]Ro15-1788 binding and enhance [3H]flunitrazepam binding in the presence of GABA. The results

suggested that isocurcumenol may serve as a benzodiazepine receptor agonist and allosterically modulated

GABAergic neurotransmission via enhancement of endogenous receptor ligand binding [125].

Datura species

25 g/kg of methanolic crude extract induced behavioural sleep patterns (EEG) similar to that of

thiopental in rats[126].

Echium italicum

The anxiolytic and hypnotic effects of the aqueous and ethanolic extracts of aerial parts of E. italicum

was evaluated in mice. Mice were administered the extracts intraperitoneally before the start of the

experiments for evaluation of hypnotic activity (induced by sodium pentobarbital, 30 mg/kg, ip), anxiolytic

activity (elevated plus-maze [EPM] test), locomotor activity (open field test), and motor coordination (rotarod

test). The ethanolic and aqueous extracts of E. italicum, at doses of 1.2 and 2.1 g/kg, increased the percentage of

time-spent and the percentage of arm entries in the open arms of the EPM and decreased the percentage of time-

spent in the closed arms of the EPM. Both extracts decreased the pentobarbital-induced latency to sleep and

significantly increased the total sleeping time induced by pentobarbital. Locomotor activity was affected by

aqueous extracts and ethanolic extract (at higher doses). Both extracts showed no effect in the rotarod test.

According to these results, both ethanolic and aqueous extracts of E. italicum showed anxiolytic and sedative

activity but not muscle relaxant activity[127].

Equisetum arvense

Hydroalcoholic extract of Equisetum arvense (200 and 400 mg/kg) increased the sleeping time (46%

and 74% respectively) in the barbiturate-induced sleeping time[128].

The effects of sedative, pre-anesthetic and anti-anxiety of Equisetum arvense with diazepam were

studied in rats. The extract of Equisetum arvense was given at doses of (100,200,400 mg/kg , ip) and

Diazepam with dose of( 0.5 mg/kg , ip). The hydroalcoholic extract of E. arvense caused a significant increase

in ketamine induced sleep and showed anxiolytic, sedative and preanesthetic effects at a dose of 200 mg/kg

i.p[129].

Eschsholzia californica

A multicenter, double-blind, randomized, placebo-controlled study was carried out in general practice

offices in Paris, France and the Paris area. Men and women (N = 264) with mild to moderate generalized

anxiety disorder as diagnosed according to the DSMIII- R criteria participated. Patients received either 2 tablets

of placebo or Sympathyl® (Laboratoire Innotech International, Arcueil, France) twice daily for 3 months.

Sympathyl contains 75 mg of dry hydro-alcoholic extract of the flowering head of hawthorn, 20 mg of dry

aqueous extract of California poppy, and 75 mg of elemental magnesium. Efficacy was assessed by change in

Hamilton anxiety scale total and somatic scores, change in patient self-assessment, number and percentage of

responsive subjects (reduction of at least 50% in Hamilton or self-assessment score) and the physician's clinical

global impression. Treatment produced a rapid and progressive fall in anxiety. There was a significant

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

improvement in the total anxiety score (P = 0.005), somatic score (P = 0.054), and self-assessment (P = 0.005)

in patients taking Sympathyl for 3 months[130].

The aqueous extract of Eschsholzia californica reduced the behavioural parameters measured in a

familiar environment test in mice (novelty preference, locomotion and rearings in two compartments test) at

doses above 100 mg/kg and in non-familiar environment tests (staircase test) at doses above 200 mg/kg. The

aqueous extract of Eschsholzia californica at a dose a of 25 mg/kg, E. californica also possessed anxiolytic

action since it produced an increase of the number of steps climbed by mice in the staircase test (anticonflict

effect) and that of the time spent by animals in the lit box when they were confronted with the light/dark choice

situation[131].

Foeniculum vulgare

The anxiolytic activity of the essential oil of Foeniculum vulgare (50, 100, and 200 and 400 mg/kg

doses) was studied in mice using elevated plus maze (EPM), staircase test (SCT) and open field test (OFT). In

EPM test, 100 and 200 mg/kg doses of the essential oil significantly increased percent number of entries and

time spent in open arms compared to control. In SCT these doses also reduced rearing significantly compared to

controls, while only the 200 mg/kg dose significantly increased number of squares crossed at the center in the

OFT test[132].

The anxiolytic activity of ethanolic extracts of Foeniculum vulgare fruit was evaluated by elevated

plus maze, rota rod, open field test, and hole board model in mices. The efficacy of extract (100-200mg/kg) was

compared with standard anxiolytic drugs diazepam (1mg/kg). Extract administered animals showed exploratory

behavior with all tests similar to diazepam. The results showed that the extract significantly increased the

number of entries and time spent in the open arm in the elevated plus maze apparatus. In open field test, the

extract showed significant increase in number of rearings, assisted rearing and number of square crossed[133].

The anxiolytic activity of the crude ethanolic extract of Foeniculum vulgare

was studied in albino mice by elevated plus-maze model. The extract at doses of 200 mg/kg and 400

mg/kg has been found to possess significant anti-anxiety activity on the tested experimental models. The extract

(400 mg/kg) exhibited maximum anti-anxiety effect. At a higher dose the extract (400 mg/kg) showed increase

number of entries and time spent in open arm of elevated plus-maze model. The effect produced by the extract

was comparable to that of diazepam[134].

The anti-stress and memory-enhancing properties of F. vulgare boiling water extract (50, 100 and 200

mg/kg, orally) were studied in experimental rats. Urinary levels of vanillylmandelic acid (VMA) and ascorbic

acid in rats were used to evaluate anti-stress activity. Conditioned avoidance response was measured in normal

and scopolamine-induced amnesic rats to study the memory-enhancing effects. Lipid peroxidation inhibition

assay in liver and brain homogenates of rats was used to evaluate antioxidant activity. Daily administration of F.

vulgare extract (50, 100 and 200 mg/kg body weight) 1 h prior to induction of stress significantly (p < 0.05)

altered the stress-induced urinary biochemical levels of VMA from 395.79 ± 11.23 to 347.12 ± 12.28, 311.21 ±

12.48 and 258.86 ± 10.26 μg/kg, respectively, in 24 h, as well as ascorbic acid excretion levels from 65.74 ±

9.42 to 78.59 ± 8.44, 108.41 ± 15.62 and 125.82 ± 16.94 μg/kg also within the same period, respectively. These

changes occurred in a dose-dependent fashion, and the levels in the control groups were unchanged within the

same period. The memory deficits induced by scopolamine (1mg/kg, ip) in rats was reversed by F. vulgare dose-

dependently. The extract also exhibited potent antioxidant effect by inhibition of lipid peroxidation in both rat

liver and brain homogenates to a greater extent than the standard antioxidant, ascorbic acid [135].

Helianthus annuus

The methanolic extract of Helianthus annuus seeds also caused moderate anxiolytic activity (light-

dark box and elevated plus maze test). H. annuus showed moderate increase in the latency of entry into the light

box with peak effect produced at the dose of 200 mg/kg (72±0.85 seconds) compared to control (34±5.63

seconds). In respect of latency of entry into the light box and number of entries, the values for H. annuus

showed moderately significant anxiolytic effect at the dose of both 100mg/kg (63±0.62 seconds) and 200 mg/kg

(72±0.85 seconds). H. annuus produced a significant increase in the time spent in the open arms with peak effect

produced at the dose of 100 mg/kg (51±0.62 seconds) relative to control (30.23±0.62 seconds). In respect of

entry into open arms, the extract at the dose of 100 mg/kg significantly (p<0.05) increased the number of entries

compared to control. The number of entries into the closed arms was reduced by H. annuus at doses of 100 and

200 mg/kg[136].

Jasminum sambac

The anxiolytic and antidepressant activities of ethanolic extract of Jasminum sambac flowers were

evaluated using elevated plus maze, actophotometer, froced swim test and tail suspension test in mice. The

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

ethanolic extracts of flowers of J.Sambac at a dose of 200 and 400mg/kg ip, significantly possessed

antidepressant and anxiolytic activity[137].

The antistress activity of the methanolic extract of Jasminum sambac (MEJS) leaves was studied

against swimming stress induced gastric ulceration in rats and swimming endurance test in mice. Swimming

stress induced changes in Ulcer index and histopathology in rats were compared with the standard. The

biochemical parameters such as Urea, Triglycerides, Cholesterol, Alkaline phosphatase, SGPT, SGOT etc were

examined in stressed and treated groups of rats. MEJS at a dose of 100 mg/kg and 200 mg/kg po, exhibited good

antistress effect in both tested models. MEJS reduced the incidence of gastric ulceration in stressed rats. It also

prevented the biochemical changes induced by forced swimming stress such as increase in plasma alkaline

phosphatase, SGPT, SGOT, Urea, Triglycerides and Cholesterol. The stress induced rise in cholesterol and urea

levels were significantly lowered by the extract. Also, the stress induced rise in plasma enzyme levels of SGPT

and SGOT were significantly reduced when treated with the methanolic extract of Jasminum sambac at

100mg/kg and 200mg/kg bw and was comparable with the standard drug Geriforte at 43mg/kg bw. The MEJS

treated animals also showed an increase in swimming endurance time, which was almost comparable with that

of standard drug[138].

Juglans regia

The anxiolytic effect of hydroalcoholic extract of Juglans regia fruit (200 and 400 mg/kg bw) was

studied on the basis of effect on exploration behaviour and anxiety in elevated plus maze, zero maze, and light-

dark model. Juglans regia extract produced significant effect on exploration and time spent in open area of

elevated plus maze and zero maze. Extract also increased time spent in lighten area in light and dark model.

Increase in number of head twitches was also observed at selected doses[139].

Plants affected locomotion activity:

Alhagi maurorum

Alhagi maurorum decreased the locomotion activity of the animals and skeletal muscle relaxation.

Exposure of the frog’s rectus abdomen is muscle to the extract in a concentration of 4 μg/ml bathing fluid for

5min antagonize ACh (3 μg/ml)-induced contraction by 70 ± 2.1% (N = 4). When the dose of ACh was

increased up to 8 μg/ml in presence of the extract blockade, it did not reverse completely the blockade. The

maximum reversal of antagonism was 27.7, suggesting that the extract blocked the action of ACh in a non-

competitive manner. Intraperitoneal administration of the ethanolic extract (EE) of Alhagi maurorum powdered

roots into conscious mice in doses of 1.6 g/kg produced mild sedation. The extract also decreased the

locomotion activity of the animals and skeletal muscle relaxation suggesting an action at the skeletal muscles

neuromuscular junctions [140].

Anthemis nobelis

In mice, apigenin had a clear affinity for central benzodiazepine receptors. Apigenin competitively

inhibited the binding of flunitrazepam, a benzodiazepine, but had no effect on muscarinic receptors, alpha 1-

adrenoceptors, or the binding of muscimol to GABA receptors. Apigenin had clear anxiolytic activity in mice

without incidence of sedation or muscle relaxation effects at doses similar to those used for classical

benzodiazepines; no anticonvulsant action was detected. Increasing dosages produced mild sedation and a

reduction in ambulatory locomotor activity [81-82,141-142].

Arundo donax

Bufotenidine isolated from Arundo donax showed neuromuscular blocking activity [143].

Benincasa hispida

The anxiolytic effects of alcoholic extract of B. hispida were evaluated in mice using elevated plus

maze and light-dark transition test and spontaneous motor activity measured by actophotometer. The extract

possessed anxiolytic activity but was not able to modify the spontaneous motor activity measured in

actophotometer [144].

However, the methanolic extract of fruit of Benincasa hispida caused reduction in spontaneous motor

activity with no muscle relaxant activity [145].

Caesalpinia crista

The effects of Caesalpinia crista extract on gallamine-induced relaxation in rat tibial muscle

contractility were studied via measurement of isometric-tension-anesthetized, 10-12-week-old, male rats.

Caesalpinia crista extract administered intravenously (iv) increased twitch contractions in a dose-dependent

manner. The ED50 value was 2.75 x 10-4 g/kg bw. Treatment with Caesalpinia crista extract or neostigmine,

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

however, reversed the relaxation induced by either gallamine or puff adder venom. The authors concluded that

Caesalpinia crista extract stimulates the muscle contractile activity via activation of the cholinergic

mechanism[146].

Carthamus tinctorius

Subcutaneous administration of 1–10 g/kg bw of an aqueous or 50% methanol extract of the flowers

had central nervous system depressant effects and relaxed skeletal muscles in mice [147].

Datura species

The neuropsychopharmacological effects of aqueous extracts of leaves and seeds of D. fastuosa, were

studied in rat and mice . The leaf and seed extracts at doses of 400 and 800 mg/kg increased motor activity,

reduced slightly the duration of barbituric sleeping, antagonized catalepsy and ptosis induced by haloperidol and

the immobility induced by forced swimming. The results also showed that, D. fastuosa has some

antidepressant profile at low doses[148].

Equisetum arvense

Ethanolic extract (100 mg/kg) prolonged the ketamine-induced total sleeping time and decreased the

locomotor activity in mice[149].

Fumaria officinalis

The muscle relaxant and sedative activities of ethanolic extract of Fumaria officinalis were evaluated

in experimental animal models. Fumaria officinalis (FO) (at 100,200 and 500 mg/kg body weight, ip) was

evaluated for muscle relaxants activity by using Rota rod, Traction test and fall off time. The results revealed

significant (p< 0.001) and dose dependent muscle relaxant and sedative potentiating effects of ethanolic extract

of Fumaria officinalis, it demonstrated its depressant action on the central nervous system[150].

Hibiscus sabdariffa

The neuropharmacological effects of the aqueous extract of Hibiscus sabdariffa (HS) calyx were

studied in rodents. HS (100, 200 and 400 mg/kg, i.p.) caused a remarkable dose-dependent decrease in

spontaneous motor activity in mice [151].

Plant beneficial in Parkinson’s disease:

Antirrhinum majus

Aurones belong to the family of flavonoids, structurally isomers of flavones, were synthesied in

Antirrhinum majus. Aurones and extracts comprising them were useful in the prophylactic and/or therapeutic

treatment of an animal (including a human) with a phosphodiesterase (PDE) dependent disease or condition of

the central nervous system. Among the diseases and conditions of the nervous system to be treated

prophylactically or therapeutically, neurodegenerative disorders, such as Parkinson's disease, Alzheimer's

disease, age related dementia or dementia in general, neurological trauma including brain or central nervous

system trauma, depression, anxiety, psychosis, cognitive dysfunction, mental dysfuntion, learning and memory

disorders, and ischemia of the central and/or peripheral nervous systems [152].

Bacopa monnieri

Bacopa monnieri, in pharmacological Caenorhabditis elegans models of Parkinson’s, reduced alpha

synuclein aggregation, prevents dopaminergic neurodegeneration and restores the lipid content in nematodes,

thereby proving its potential as a possible anti-Parkinsonian agent[153].

Carthamus tinctorius

The neuroprotective efficacy of the combination of (astragali, ligusticum wallichii, angelica sinensis

and Carthamus tinctorius) on mitigating brain infarction and global ischemia as well as preventing the

neurodegeneration following ischemia was studied. They improved cerebral blood circulation, which refer to a

potential to alleviate the symptoms of degenerative diseases, Alzheimer's disease and Parkinson's disease [154].

The neuroprotective effects of hydroxysafflor yellow A (HSYA) on cerebral ischemic injury in both in vivo and

in vitro were studies. In in vivo experiment, male Wistar-Kyoto (WKY) rats with middle cerebral artery

occlusion (MCAO) were evaluated for neurological deficit scores followed by the treatment with a single dose

of HSYA. Furthermore, the infarction area of the brain was assessed in the brain slices. In in vitro experiment,

the effect of HSYA was tested in cultured fetal cortical cells exposed to glutamate and sodium cyanide (NaCN)

to identify its neuroprotection against neurons damage. The results of in vivo study showed that sublingular vein

injection of HSYA at doses of 3.0 mg/kg and 6.0 mg/kg exerted significant neuroprotective effects on rats with

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

focal cerebral ischemic injury by significantly decreasing neurological deficit scores and reducing the infarct

area compared with the saline group, HSYA at a dose of 6.0 mg/kg, gave a similar potency as nimodipine at a

dose of 0.2 mg/kg. Sublingular vein injection of HSYA at the dose of 1.5 mg/kg showed a neuroprotective

effect, however, with no significant difference when compared with the saline group. In vitroresults showed that

HSYA significantly inhibited neuron damage induced by exposure to glutamate and sodium cyanide (NaCN) in

cultured fetal cortical cells, however, the neuroprotective action of HSYA on glutamate-mediated neuron injury

was much better than that of HSYA on NaCN-induced neuron damage [155].

Cuminum cyminum

The inhibitory effects of the Cuminum cyminum essential oil on the fibrillation of α-SN, which was a

critical process in the pathophysiology of several neurodegenerative diseases, especially Parkinson's disease,

was investigated. Analysis of different fractions from the total extract, identified cuminaldehyde as the active

compound involved in the antifibrillation activity. In comparison with baicalein, a well-known inhibitor of α-SN

fibrillation, cuminaldehyde showed the same activity in some aspects and a different activity on other

parameters influencing α-SN fibrillation. The presence of spermidine, an α-SN fibrillation inducer, dominantly

enforced the inhibitory effects of cuminaldehyde even more intensively than baicalein. Furthermore, the results

from experiments using preformed fibrils and monobromobimane-labeled monomeric protein also suggested

that cuminaldehyde prevents α-SN fibrillation even in the presence of seeds, having no disaggregating impact on

the preformed fibrils. Structural studies showed that cuminaldehyde stalls protein assembly into β-structural

fibrils, which might be achieved by the interaction with amine groups through its aldehyde group as a Schiff

base reaction. This assumption was supported by FITC labeling efficiency assay. In addition, cytotoxicity assays

on PC12 cells showed that cuminaldehyde is a nontoxic compound, treatment with cuminaldehyde throughout

α-SN fibrillation showed no toxic effects on the cells [29, 156].

Cyperus rotuntdus

The neuroprotective effects of a water extract of Cyperus rotundus rhizoma against 6-

hydroxydopamine (6-OHDA)-induced neuronal damage were evaluated in an experimental model of Parkinsons

disease. In PC12 cells, water extract of Cyperus rotundus rhizoma showed a significant protective effect on cell

viability at 50 and 100 microg/ml. Water extract of Cyperus rotundus rhizoma inhibited generation of reactive

oxygen species and nitric oxide, reduction of mitochondrial membrane potential, and caspase-3 activity, which

were induced by 6-OHDA. Water extract of Cyperus rotundus rhizoma also showed a significant protective

effect against damage to dopaminergic neurons in primary mesencephalic culture [157].

Geum urbanum

The presence of Lewy bodies and Lewy neurites is a major pathological hallmark of Parkinson's

disease and is hypothesized to be linked to disease development. . Lewy bodies and Lewy neurites primarily

consist of fibrillated α-Synuclein. The inhibitory activity of an ethanolic extract of Geum urbanum against α-

Synuclein fibrillation was studied. The anti-fibrillation and anti-aggregation activities of the plant extract were

monitored by thioflavin T fibrillation assays and size exclusion chromatography, while structural changes were

followed by circular dichroism, Fourier transform infrared spectroscopy, intrinsic fluorescence, small angle X-

ray scattering and electron microscopy. Geum urbanum inhibited α-Synuclein fibrillation in a concentration

dependent way, and to partly disintegrate preformed α-Synuclein fibrils. Based on the structural changes of α-

Synuclein in the presence of extract, It appeared that Geum urbanum delayed α-Synuclein fibrillation either by

reducing the fibrillation ability of one or more of the aggregation prone intermediates or by directing α-

Synuclein aggregation towards a non-fibrillar state [158].

Hyoscyamus niger

The neuroprotective potential, of petroleum ether and aqueous methanol extracts of Hyoscyamus niger

seeds was evaluated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson disease in

mice. Parkinsonian mice were treated twice daily with the extracts (125–500 mg/kg, po.) for two days and motor

functions and striatal dopamine levels were assayed. Administration of the aqueous methanol extract (containing

0.03% w/w of L-DOPA), but not petroleum ether extract, significantly attenuated motor disabilities (akinesia,

catalepsy and reduced swim score) and striatal dopamine loss in MPTP treated mice. The extract caused

significant inhibition of monoamine oxidase activity and attenuated 1-methyl-4-phenyl pyridinium (MPP+)-

induced hydroxyl radical (OH) generation in isolated mitochondria, Accordingly, the protective effect of the

methanolic extract of Hyoscyamus niger seeds against parkinsonism in mice could be attributed to its ability to

inhibit increased ·OH generated in the mitochondria [159].

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

Juglans regia

The neuro protective efficacy of dietary supplementation of walnut (6 %) for 28 days was examined in

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurodegeneration in a Mouse model of

Parkinson's disease (20 mg/kg bw/day, ip) for four consecutive days. MPTP injection diminished the levels of

GSH, dopamine and metabolites along with decreased activities of GPx and mitochondrial complex I. The levels

of TBARS and enzymatic antioxidants such as SOD and catalase, MAO-B activities were enhanced by MPTP

treatment. Behavioral deficits and lowered TH expression were also proved in MPTP induced neurotoxicity.

Dietary supplementation of walnut attenuated MPTP-induced impairment in PD mice could be attributed to its

MAO-B inhibitory, antioxidant and mitochondrial protective actions[160].

Juniperus communis

The effect of methanolic extract of Juniperus communis (MEJC) leaves on reserpine induced catalepsy

was studied in rats. Catalepsy was induced by intra administration of reserpine (2.5 mg/kg, ip). The methanolic

extract at 100 and 200 mg/kg, ip were screened for its efficacy against reserpine induced catalepsy in rats. The

MEJC extract reduced catalepsy significantly (p<0.001) as compared to the reserpine treated rats, maximum

reduction was observed at a dose of 200 mg/kg. Accordingly, J. Communis possessed a therapeutic effect

against Parkinson’s disease in reserpine induced animal Parkinson’s disease models[161].

The neuroprotective activity of methanolic extrct of J. communis (MEJC) was evaluated in

chlorpromazine (CPZ) induced Parkinson’s model in rats (100 and 200mg/kg, ip). The neuroprotective

activity was evaluated using behavior parameters like catalepsy (bar test), muscle rigidity (rot rod test), and

locomotor activity (actophotometer) and its effect on biochemical parameters (TBARS, GSH, nitrite, and total

protein) in rats brain. J. communis possessed significant (𝑃 <0.001) neuroprotective effect against CPZ induced

Parkinson’s like symptoms[162].

Plants beneficial in Alzheimer’s disease and memory deficits:

Alzheimer’s disease:

Antirrhinum majus

Aurones and extracts comprising them were useful in the prophylactic and/or therapeutic treatment of

an animal (including a human) with a phosphodiesterase (PDE) dependent disease or condition of the central

nervous system. Among the diseases and conditions of the nervous system to be treated prophylactically or

therapeutically, neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, age related

dementia or dementia in general, neurological trauma including brain or central nervous system trauma,

depression, anxiety, psychosis, cognitive dysfunction, mental dysfuntion, learning and memory disorders, and

ischemia of the central and/or peripheral nervous systems [152].

Bacopa monniera

The effect of sub-chronic administration (14 days) of a standardized extract of Bacopa monniera (BM)

(bacoside A content 82.0 ± 0.5%) on two animal models of Alzheimer's disease, induced by administration of

colchicine and by lesioning of nucleus basalis magnocellularis (nbm) with ibotenic acid. Lesioning with

colchicine or ibotenic acid induced marked deficits in the retention of active avoidance learning, which was

evident on day 7, after lesioning, and increased progressively by day 14. Subchronic administration of BM

reduced the magnitude of memory deficits induced by both colchicine and ibotenic acid, which was significant

at days 7 and 14 with the higher dose, 10 mg/kg, orally, and on day 14 only with the lower dose, 5 mg/kg orally,

of BM. BM (10 mg/kg,orally) reversed colchicine-induced reduction in frontal cortex and hippocampal Ach,

ChAT activity and MCR binding. The effect of the lower dose of BM (5 mg/kg, orally) was evident only after

14 days[163].

Benincasa hispida

The chronic treatment with the aqueous extract of Benincasa hispida pulp (400mg/kg bw) appeared

beneficial in the management of colchicines-induced rat model of Alzheimer's disease. It was also increased

antioxidants in different brain areas and increased the number of correct choices out of 10 daily trials and

decreased latency time dose dependently [164-165].

Caesalpinia crista

Amyloid beta (A beta) is the major etiological factor implicated in Alzheimer's disease. The ability of

Caesalpinia crista leaf aqueous extract was studied on the prevention of (i) the formation of oligomers and

aggregates from monomers (Phase I: A beta(42) + extract co-incubation); (ii) the formation of fibrils from

oligomers (Phase II: extract added after oligomers formation); and (iii) dis-aggregation of pre-formed fibrils

(Phase III: aqueous extract added to matured fibrils and incubated for 9 days). The aggregation kinetics was

Medicinal Plants With Central Nervous Activity- An Overview (Part 1)

monitored using thioflavin-T assay and transmission electron microscopy. The results showed that Caesalpinia

crista aqueous extract was able to inhibit the A beta(42) aggregation from monomers and oligomers and also

able to dis-aggregate the pre-formed fibrils [166].

Carthamus tinctorius

The neuroprotective efficacy of the combination of (astragali, ligusticum wallichii, angelica sinensis

and Carthamus tinctorius ) on mitigating brain infarction and global ischemia as well as preventing the

neurodegeneration following ischemia was studied. They improved cerebral blood circulation, which refer to a

potential to alleviate the symptoms of degenerative diseases, Alzheimer's disease and Parkinson's disease [145,

167].

The neuroprotective effects of hydroxysafflor yellow A (HSYA) on cerebral ischemic injury in both in

vivo and in vitro were studies. In in vivo experiment, male Wistar-Kyoto (WKY) rats with middle cerebral artery