1. ¹Institute of Animal Sciences, ETHZ, Zurich, Switzerland
2. ²Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland
3. ³Service of Old Age Psychiatry, University of Lausanne, Prilly, Switzerland
4. ⁴Département d'Anatomie et Physiologie, Faculté de Médecine, Université Laval, Québec, Canada

Correspondence: Dr D Arsenijevic, Institute of Animal Sciences, ETHZ, Schorenstrasse 16, 8604 Schwerzenbach, Switzerland. E-mail: denis.arsenijevic@inw.agrl.ethz.ch

⁵These authors contributed equally to this work.

Received 17 May 2005; Revised 28 June 2005; Accepted 28 June 2005; Published online 10 August 2005.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are involved in energy expenditure, regulation of inflammatory processes, and cellular protection in peripheral tissues. Among the different types of PPARs, PPAR is the only one to be widely expressed in cortical neurons. Using PPAR knockout (KO) mice, we report here a detailed investigation of the role of PPAR in cerebral ischemic damage, associated inflammatory and antioxidant processes as well as food intake regulation after middle cerebral artery occlusion (MCAO). The PPAR KO mice had a two-fold increase in infarct size compared with wild-type (WT) mice. Brain oxidative stress was dramatically enhanced in these KO mice, as documented by an increased content of malondialdehyde, decreased levels of glutathione and manganese superoxide dismutase, and no induction of uncoupling protein 2 (UCP2) mRNA. Unlike WT mice, PPAR KO mice showed a marked increase of prooxidant interferon-gamma but no induction of nerve growth factor and tumor necrosis factor alpha after MCAO. In WT mice, MCAO resulted in inflammation-specific transient hyperphagia from day 3 to day 5 after ischemia, which was associated with an increase in neuropeptide Y (NPY) mRNA. This hyperphagic phase and NPY mRNA induction were not observed in PPAR KO mice. Furthermore, our study also suggests for the first time that UCP2 is involved in MCAO food intake response. These data indicate that PPAR plays an important role in integrating and regulating central inflammation, antioxidant mechanisms, and food intake after MCAO, and suggest that the use of PPAR agonists may be of interest for the prevention of central ischemic damage.