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International Symposium on Neurodegeneration and Neuroprotection 1341
PPAR: a new pharmacological target for
neuroprotection in stroke and
neurodegenerative diseases
R. Bordet*
1
, T. Ouk*, O. Petrault*, P. Gel
´
e*, S. Gautier*, M. Laprais*, D. Deplanque*, P. Duriez†, B. Staels†,
J.C. Fruchart† and M. Bastide*
*EA1046 Department of Medical Pharmacology, Faculty of Medicine, Institute of Predictive Medicine and Therapeutic Research, University Lille 2 and Lille
University Hospital, 1 place de Verdun, 59045 Lille Cedex, France, and †Department of Atherosclerosis, INSERM U545, Institut Pasteur de Lille, 1 rue du Pr.
Calmette B.P. 245, 59019 Lille Cedex, France
Abstract
PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors
belonging to the so-called nuclear receptor family. The three isoforms of PPAR (α, β/δ and γ )areinvolved
in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARα and PPARγ activation also
induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain
why PPARα or PPARγ activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates
and other non-fibrate PPARα activators as well as thiazolidinediones and other non-thiazolidinedione PPARγ
agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective
effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death
by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARα activation
induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction.
These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such
as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation
might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral
ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic
neurodegenerative diseases.
The treatment of ischaemic stroke is limited to the prevention
of cerebrovascular risk factors and to the modulation of the
coagulation cascade during the acute phase. During the last
two decades, many drugs have been developed to induce
neuroprotection during stroke [1,2]. Nevertheless, none of
them has been successful at the clinical step of their devel-
opment, while recent results give hope of a new antioxidant
drug [3]. One of the explanations for this failure is that the
developed drugs are able to modulate only one molecular
pathway, while several pathways are involved spatially and
temporally in the pathophysiology of stroke. One of the
keys to success in inducing neuroprotection in stroke could
be to modulate simultaneously many pathophysiological
pathways with a combination of several drugs or, better,
with only one pharmacological agent with pleiotropic effect.
Such a pleiotropic effect can be induced by drugs acting on
transcription factor receptors (so-called nuclear receptors),
because this subtype of receptor is able to regulate sev-
eral genes simultaneously. Among nuclear receptors, PPAR
(peroxisome-proliferator-activated receptors) have been
Key words: cerebral ischaemia, neurodegenerative disease, neuroprotection, nuclear receptor,
peroxisome-proliferator-activated receptor (PPAR), thiazolidinedione.
Abbreviations used: Aβ,amyloidβ-peptide; CNS, central nervous system; COX, cyclo-
oxygenase; EAE, encephalomyelitis; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-
κB, nuclear factor κB; PPAR, peroxisome-proliferator-activated receptor.
1
To whom correspondence should be addressed (email bordet@univ-lille2.fr).
demonstrated to induce pleiotropic effects in different organs
(vessels, heart and kidney) when activated by agonists. Some
results support the idea that these pleiotropic effects could be
useful to induce a neuroprotective effect in stroke [4,5].
PPARs: function and pharmacology
PPARs are ligand-activated transcription factors belonging
to the nuclear receptor superfamily [6] (Figure 1). Three
isoforms of PPARs (α, β/δ and γ ) have been identified, dis-
playing distinct physiological and pharmacological functions
depending on their target genes and their tissue distribution
[7,8]. Indeed, the activation of PPARα, by both natural
ligands such as fatty acids and eicosanoid derivates or
synthetic ligands (lipid-lowering fibrates), regulates lipid
and lipoprotein metabolism [4] (Figure 2). Activation of
PPARγ by prostaglandins or by synthetic ligands such as
antidiabetic thiazolidinediones regulates glucose m etabolism
by modulation of insulin-sensitivity [4]. Non-steroidal anti-
inflammatory drugs are also weak agonists of PPARγ and
PPARα.PPARβ/ δ is one of the most widely expressed
members of the PPAR family. Until recently, the function
of PPARβ/δ remained elusive, but recent results have shown
that PPARβ/δ plays also a key role in lipid metabolism, as
it regulates serum lipid profiles and fatty acid β-oxidation in
muscle and adipose tissue. Synthetic ligands of PPAR β/δ are
at the moment in preclinical phases of development [9].
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2006 Biochemical Society
1342 Biochemical Society Transactions (2006) Volume 34, part 6
Figure 1 Classical structure of PPAR with the zinc fingers which interact with specific response elements located in DNA
Figure 2 Main physiological effects and pharmacological
modulation of PPAR
PPARs as regulators of inflammation
and oxidative stress
Beyond effects on metabolic pathways, PPAR are also able to
regulate inflammatory pathway by transrepression of trans-
cription factors [NF-κB (nuclear factor κB)] or to regulate the
oxidative pathway [5,6] (Figure 3). PPARα activation induces
expression and activation of antioxidant enzymes such as
superoxide dismutase and glutathione peroxidase. On the
inflammatory pathway, PPARα activation prevents synthesis
and release of cytokines (interleukin-6 and tumour necrosis
factor α) or induction of some inflammatory mediators
such as COX-2 (cyclo-oxygenase 2) and adhesion proteins.
PPARγ activation also reduces the expression of inducible
nitric oxide synthase or COX-2 as well as the production of
pro-inflammatory cytokines. These effects on inflammation
explain why activation of PPAR by synthetic ligands reduces
inflammation in different tissues and in different animal
models of inflammatory diseases (vascular inflammation of
atherosclerosis, inflammatory bowel disease, arthritis etc.)
[4,5].
PPAR in the brain: a potential target
against neuronal death
Previously, it has been supposed that PPAR activation
could also be effective in the regulation of neuronal death
in ischaemic, neurodegenerative or inflammatory cerebral
diseases. Firstly, PPARs have been described in brain and
in spinal cord [10,11]. Beyond expression in cerebral or
spinal blood vessels, PPARs are also expressed in neurons
and in astrocytes, whereas oligodendrocytes exclusively
show PPARβ/δ expression (Figure 4). The extent of this
expression depends on the isoform of PPAR involved.
PPARβ/δ has been found in numerous brain areas, while
PPARα and PPARγ have been localized to more restricted
brains areas [11]. Secondly, whatever the aetiology, neuronal
death is induced by inflammatory and oxidative processes
with a link between the two phenomena [12]. Inflammation
and oxidative stress induce both necrotic and apoptotic
neuronal death. The transcription factor NF-κB plays a
key role in regulation of inflammation and oxidative stress
leading to neuronal death, explaining why PPARs have
been considered as possible targets for neuroprotection [13].
In vitro studies have demonstrated that PPARγ agonists
modulate inflammatory responses to bacterial endotoxin in
brain and also prevent endotoxin-induced neuronal death
[14]. PPARγ agonists are able to prevent neuronal death res-
ulting from NMDA (N-methyl-
D-aspartate) excitotoxicity
induced in brain in vitro or in vivo [15]. PPARα and PPARγ
are able to inhibit macrophage and microglial activation that
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2006 Biochemical Society
International Symposium on Neurodegeneration and Neuroprotection 1343
Figure 3 Inflammation regulation is a common effect of PPAR and results from modulation of NF-κB
PPAR-responsive element; RXR, retinoid X receptor.
Figure 4 Expression of PPAR in the three cellular t ypes of the neuro-glio-vascular unit
contribute to many degenerative, ischaemic or inflammatory
processes leading to neuronal death [16]. Troglitazone and
ciglitazone inhibit both post-glutamate- and low-potassium-
induced neurotoxicity in cerebellar granule neurons [17].
PPARs are also able to inhibit t he entry of inflammatory
cells into the CNS (central nervous system) from the
periphery by inhibition of chemokines, adhesion molecules
and metalloproteinases [16].
PPAR and cerebral ischaemia
PPAR-induced neuroprotection in cerebral
ischaemia
Because fibrates, used as lipid-lowering agents, contribute to
secondary prevention of stroke, it has been supposed that
these PPARα activators could also preventively protect the
brain against noxious biological reactions induced by cerebral
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2006 Biochemical Society
1344 Biochemical Society Transactions (2006) Volume 34, part 6
ischaemia, such as oxidative stress and inflammation. It has
been demonstrated that a 14-day preventive treatment with
fenofibrate reduced susceptibility to stroke in apolipoprotein
E-deficient mice as well as decreased cerebral infarct volume
in wild-type mice [18]. In another study, it was confirmed that
two different PPARα agonists, fenofibrate and Wy-14643,
provided similar brain protection when administered res-
pectively 3 or 7 days before induction of cerebral ischaemia
[19]. More recently, it has been demonstrated that PPARα
agonists could also induce an acute neuroprotection when
administered just before cerebral ischaemia or during the
reperfusion period [20,21].
Administration of the PPARγ agonists troglitazone or
pioglitazone 24 or 72 h before and at the time of cerebral
infarction dramatically reduced infarction volume and
improved neurological function following transient middle
cerebral artery occlusion in rats [22,23]. This effect is exerted
in a dose-dependent manner. This neuroprotection has been
reproduced by an intracerebroventricular administration of
pioglitazone, proving that it is the activation of intracerebral
PPARγ that confers neuroprotection and neurological
improvement following ischaemic injury [24]. Moreover,
a non-thiazolidinedione PPARγ agonist (L-796449) also
had a neuroprotective effect in experimental stroke and was
also found to activate 15-deoxy-
12,14
-prostaglandin J
2
by
adenoviral transfer of COX-2 [25,26]. In a first study, PPARγ
agonists had no effect in a permanent model of cerebral
ischaemia, suggesting that mechanisms of action could take
place during reperfusion [23], while recent results give the
opposite effect [25].
Mechanisms of PPAR-induced neuroprotection
Cerebral mechanisms
The neuroprotection observed after treatment with PPAR
agonists is related to several mechanisms including both
oxidative stress modulation and anti-inflammatory effect.
PPARα agonist-induced neuroprotective effect is associated
with a decrease in cerebral oxidative stress depending on
the increase in activity of numerous antioxidant enzymes,
in particular Cu/Zn superoxide dismutase and glutathione
peroxidase [18]. This modulation of antioxidant enzymes
is responsible for a decrease in ischaemia-induced reactive
oxygen species production and lipid peroxidation [21,27].
This effect on oxidative stress could be related to a direct
effect on antioxidant enzymes expression, because PPREs
(PPAR-response elements) have been found in the gene of
Cu/Zn superoxide dismutase [5].
The neuroprotective effects of PPAR agonists are also
related to inhibition of ischaemia-induced inflammatory
markers (interleukin-1β, COX-2 and inducible nitric oxide
synthase) [21,27]. The different PPAR isoforms do not modu-
late the inflammatory pathways involved in neuroprotection
in a similar manner. For instance, ischaemia-induced COX-2
overexpression is prevented by PPARγ agonists but not by
PPARα agonists [21,22,27]. There is a link between PPAR-
induced modulation of oxidative stress and inflammation,
since prevention of COX-2 induction results from oxidative
stress inhibition [28]. The cellular target of these anti-
inflammatory effects is probably microglial cells, since
PPARγ agonists, such pioglitazone, are able to decrease mi-
croglial activation when administered intracerebrally [24,29].
The key target of this anti-inflammatory effect is NF-κB,
which plays a crucial role in neuronal death [30]. PPARγ and
PPARα activation is responsible for inhibition of the NF-κB
p65 monomer as well as induction of IκBα (inhibitory κB)
[25,31]. The role of suppression of activation of p38 mitogen-
activated protein kinase has also been demonstrated recently
[21,27].
Beyond this direct effect on ischaemia-induced deleterious
pathways explaining neuroprotection, the challenge will be
to demonstrate that a part of the neurological improvement
induced by PPAR activators could be the result of
neurorepair, since P PARγ s are also involved in the regulation
of neural stem cell proliferation and differentiation [32].
Vascular mechanisms
Because PPARs are mainly expressed in cerebral vascular
wall, in particular in endothelium, it has been supposed that
vascular mechanisms could be involved in neuroprotection.
Thus preventive neuroprotection by PPARα is associated
with an improvement in middle cerebral artery sensitivity
to endothelium-dependent relaxation unrelated to an in-
crease in endothelial nitric oxide synthase expression [18].
More recently, it has been demonstrated that preventive
or acute PPARα agonist-induced neuroprotection paral-
leled the prevention of ischaemia-induced endothelial dys-
function [20]. This vascular effect could be related to: (i) the
prevention of ischaemia-induced vascular expression of
adhesion molecules; (ii) the antioxidant effect of PPAR
activation; and (iii) the inhibition of ischaemia-induced
metalloproteinase expression [18,25]. In addition, PPAR
could also be involved in endothelial regeneration as has been
demonstrated in other arterial areas [33].
PPAR and neuroprotection: beyond
cerebral ischaemia
Other acute cerebral injuries such as traumatic brain injury
or chronic neurological diseases such as neurodegenerative
diseases or multiple sclerosis also need pleiotropic neuro-
protective drugs, explaining why PPAR activators have also
been tested in experimental models mimicking these different
disorders.
Traumatic brain and spinal cord injury
Because many mechanisms that are involved in cerebral
ischaemia are also involved in traumatic nervous tissue injury,
the effect of PPARα activation has been tested in models of
traumatic spinal cord and brain injury, and a neuroprotective
effect has been observed with some similar mechanisms to
those in cerebral ischaemia [34,35].
Alzheimer’s disease
PPARγ and PPARα agonists have been tested in models of
Alzheimer’s disease. The classical histopathological hallmarks
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2006 Biochemical Society
International Symposium on Neurodegeneration and Neuroprotection 1345
of Alzheimer’s disease include extracellular Aβ (amyloid
β-peptide) deposition in neuritic plaques and intracellular
deposits of hyperphosphorylated tau protein, causing form-
ation of neurofibrillary tangles and finally neuronal death,
responsible for progressive memory loss and decline of
cognitive functions. While it has been demonstrated that
aPPARα agonist inhibited Aβ-stimulated expression of
tumour necrosis factor α and interleukin-6 reporter genes in a
dose-dependent manner, but failed to inhibit Aβ-stimulated
elaboration of neurotoxic factors [36], some recent experi-
mental data suggest that fenofibrate could raise Aβ-(1–42)
production [37], suggesting that PPARα remains a contro-
versial target in Alzheimer’s disease. PPARγ agonists were
also shown to inhibit the β-amyloid-stimulated expression
of inflammatory cytokines and COX-2 [38]. In addition to
inhibition of Aβ-induced inflammation, PPARγ could also
induce clearance of the β-amyloid peptide [39]. In addition to
in vitro data, recent in vivo data also indicate a beneficial effect
of PPARγ activation, since an acute 7-day oral treatment
with the PPARγ agonist pioglitazone resulted in a reduction
in glial activation as well as a reduction in the number of
Aβ-positive plaque areas in the hippocampus and cortex
of a murine transgenic model of the amyloid pathology of
Alzheimer’s disease [40].
Parkinson’s disease
PPAR agonists have also been assessed in a model of
Parkinson’s disease. Parkinson’s disease is characterized by
a progressive loss of dopaminergic neurons in the substantia
nigra, which is experimentally mimicked by systemic
administration of the neurotoxin MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine). Oral administration of the
PPARγ agonist pioglitazone attenuated the MPTP-induced
glial activation and prevented dopaminergic cell loss in the
substantia nigra pars compacta. Pioglitazone also prevented
MPTP-induced expression of inducible nitric oxide synthase
[41]. This protective effect of pioglitazone is also associated
with an increase in inhibitory protein-κBα expression and to
inhibition of translocation of the NF-κB subunit p65 to the
nucleus in dopaminergic neurons, glial cells and astrocytes
[42]. Preliminary results demonstrate that PPARα activation
prevents death of dopaminergic neurons of substantia nigra
pars compacta in the MPTP model of Parkinson’s disease [43].
Multiple sclerosis
Microglial activation and inflammation are the key to the
pathophysiology of multiple s clerosis, explaining why PPAR
agonists have been tested in this disease, in particular in
the model of experimental autoimmune EAE (encephalo-
myelitis), which is characterized by CNS inflammation and
demyelination, together with remittent paralysis [16]. Oral
administration of gemfibrozil and fenofibrate, two PPARα
agonists, also inhibits clinical signs of EAE by mechanisms
involving secretion of interferon-γ and interleukin-4 [44].
Oral administration of the PPARγ agonist pioglitazone
reduces the motor symptoms’ severity in monophasic EAE,
without delaying the disease onset. In a relapsing model of
EAE, pioglitazone reduces the severity of relapses and overall
mortality without affecting t he onset and severity of the
initial disease attack [45]. The mechanisms of action of PPAR
agonists in EAE are complex, involving regulation of the
inflammatory pathway and also modulation of the maturation
and differentiation of oligodendrocytes [16].
Conclusion
The hypothesis that the pleiotropic effects of PPAR
agonist could decrease neuronal death is supported by
much experimental data showing that PPAR agonists exert
neuroprotective effects in models of cerebral ischaemia,
neurodegenerative diseases and multiple sclerosis, with some
clinical data confirming these experimental results. These res-
ults have been essentially obtained with PPARγ and PPARα
activators, while the PPARβ/δ pathway remains largely
unexplored despite interest in the target. Development of new
and more potent PPAR activators as well as combined action
of the different isoforms of PPAR are also future prospects
in terms of neuroprotection and also in terms of neurorepair.
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