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The Journal of Neuroscience, July 16, 2003, 23(15):6264-6271
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Peroxisome Proliferator-Activated Receptor- Activation as a Mechanism of Preventive Neuroprotection Induced by Chronic Fenofibrate Treatment
Dominique Deplanque,1,4 *
Patrick Gelé,1 *
Olivier Pétrault,1
Isabelle Six,1
Christophe Furman,2
Muriel Bouly,2
Stéphane Nion,3
Bernard Dupuis,1
Didier Leys,4
Jean-Charles Fruchart,2
Roméo Cecchelli,3
Bart Staels,2
Patrick Duriez,2 and
Régis Bordet1
1Laboratoire de Pharmacologie, Université
de Lille 2, Faculté deMédecine, Lille, 59045 France,
2Département de Recherches sur les
Lipoprotéines et l'Athérosclérose, Institut Pasteur de
Lille, Institut National de la Santé et de la Recherche Médicale
UR545 et Université de Lille 2, Faculté de Pharmacie, Lille,
59019 France, 3Unité Mixte Université
d'Artois–Institut Pasteur de Lille, Faculté des Sciences Jean
Perrin, Université d'Artois, Lens, 62307 France, and
4Service de Neurologie et Pathologie Neurovasculaire,
Centre Hospitalier Régional et Universitaire de Lille, Lille, 59037
France
The treatment of ischemic strokes is limited to the prevention of
cerebrovascular risk factors and to the modulation of the coagulation cascade
during the acute phase. A new therapeutic strategy could be to preventively
protect the brain against noxious biological reactions induced by cerebral
ischemia such as oxidative stress and inflammation to minimize their
neurological consequences. Here, we show that a peroxisome
proliferator-activated receptor (PPAR- ) activator, fenofibrate,
protects against cerebral injury by anti-oxidant and anti-inflammatory
mechanisms. A 14 d preventive treatment with fenofibrate reduces
susceptibility to stroke in apolipoprotein E-deficient mice as well as
decreases cerebral infarct volume in C57BL/6 wild-type mice. The
neuroprotective effect of fenofibrate is completely absent in
PPAR--deficient mice, suggesting that PPAR- activation is
involved as a mechanism of the protection against cerebral injury.
Furthermore, this neuroprotective effect appears independently of any
improvement in plasma lipids or glycemia and is associated with (1) an
improvement in middle cerebral artery sensitivity to endothelium-dependent
relaxation unrelated to an increase in nitric oxide synthase (NOS) type III
expression, (2) a decrease in cerebral oxidative stress depending on the
increase in numerous antioxidant enzyme activities, and (3) the prevention of
ischemia-induced expression of vascular cell adhesion molecule-1 and
intercellular adhesion molecule-1 in cerebral vessels without any change in
NOS II expression. These data demonstrate that PPAR- could be a new
pharmacological target to preventively reduce the deleterious neurological
consequences of stroke in mice and suggest that PPAR- activators could
preventively decrease the severity of stroke in humans.
Key words: stroke; PPAR-; neuroprotection; prevention; oxidative stress; inflammation; adhesion proteins; mouse
Received Nov. 12, 2002;
revised May. 6, 2003;
accepted May. 9, 2003.
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