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Peroxisome proliferator-activated receptor-α activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment
- Source :
- Journal of Neuroscience, Journal of Neuroscience, Society for Neuroscience, 2003, 23 (15), pp.6264-6271. ⟨10.1523/JNEUROSCI.23-15-06264.2003⟩, Scopus-Elsevier
- Publication Year :
- 2003
- Publisher :
- HAL CCSD, 2003.
-
Abstract
- International audience; 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. Anew 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-α) activator, fenofibrate, protects against cerebral injury by anti-oxidant and antiinflammatory 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-α-deficient mice, suggesting that PPAR-α 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-α could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-α activators could preventively decrease the severity of stroke in humans.
- Subjects :
- Middle Cerebral Artery
Mouse
Nitric Oxide Synthase Type II
Receptors, Cytoplasmic and Nuclear
Peroxisome proliferator-activated receptor
medicine.disease_cause
Rats, Inbred WKY
Mice
0302 clinical medicine
Fenofibrate
Mice, Knockout
chemistry.chemical_classification
0303 health sciences
biology
General Neuroscience
Infarction, Middle Cerebral Artery
Cerebral Infarction
Intercellular Adhesion Molecule-1
Neuroprotection
Vasodilation
Nitric oxide synthase
Stroke
Neuroprotective Agents
Cerebrovascular Circulation
Middle cerebral artery
medicine.symptom
medicine.drug
PPAR-α
medicine.medical_specialty
Adhesion proteins
Nitric Oxide Synthase Type III
Development/Plasticity/Repair
Ischemia
Vascular Cell Adhesion Molecule-1
Mice, Transgenic
Inflammation
Time
03 medical and health sciences
Apolipoproteins E
medicine.artery
Internal medicine
medicine
Animals
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
030304 developmental biology
business.industry
Prevention
medicine.disease
Rats
Mice, Inbred C57BL
Disease Models, Animal
Endocrinology
chemistry
Oxidative stress
biology.protein
Nitric Oxide Synthase
business
030217 neurology & neurosurgery
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 02706474 and 15292401
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroscience, Journal of Neuroscience, Society for Neuroscience, 2003, 23 (15), pp.6264-6271. ⟨10.1523/JNEUROSCI.23-15-06264.2003⟩, Scopus-Elsevier
- Accession number :
- edsair.doi.dedup.....612e73f0e0e48c018d72d48701b610db