Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury

• Published in: Journal of neurotrauma Vol. 24; no. 7; p. 1119
• Main Authors: Chen, Xiao Ru, Besson, Valerie C, Palmier, Bruno, Garcia, Yannick, Plotkine, Michel, Marchand-Leroux, Catherine
• Format: Journal Article
• Language: English
• Published: United States 01-07-2007
• Subjects: Aldehydes - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antioxidants - pharmacology; Antioxidants - therapeutic use; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Brain Injuries - drug therapy; Brain Injuries - metabolism; Brain Injuries - physiopathology; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - metabolism; Encephalitis - drug therapy; Encephalitis - metabolism; Encephalitis - physiopathology; Fenofibrate - pharmacology; Fenofibrate - therapeutic use; Glutathione - metabolism; Male; Matrix Metalloproteinase 9 - drug effects; Matrix Metalloproteinase 9 - metabolism; Nitric Oxide Synthase Type II - drug effects; Nitric Oxide Synthase Type II - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; PPAR alpha - agonists; PPAR alpha - metabolism; Rats; Rats, Sprague-Dawley; Recovery of Function - drug effects; Recovery of Function - physiology; Treatment Outcome; Tyrosine - analogs & derivatives; Tyrosine - metabolism
• ISSN: 0897-7151
• DOI: 10.1089/neu.2006.0216

We previously demonstrated that fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, reduced the neurological deficit, the edema and the cerebral lesion induced by traumatic brain injury (TBI). In order to elucidate these beneficial effects, in the present study, we investigated, in the same TBI model, fenofibrate's effects on the inflammation and oxidative stress. Male Sprague Dawley rats were randomized in four groups: non-operated, sham-operated, TBI + vehicle, TBI + fenofibrate. TBI was induced by lateral fluid percussion of the temporoparietal cortex. Rats were given fenofibrate (50 mg/kg) or its vehicle (water containing 0.2% methylcellulose), p.o. 1 and 6 h after brain injury. A neurological assessment was done 24 h after TBI, then rats were killed and the brain COX2, MMP9 expression, GSx, GSSG levels were determined. The same schedule of treatment was used to evaluate the effect of fenofibrate on immunohistochemistry of 3NT, 4HNE and iNOS at 24 h post-injury. Our results showed that fenofibrate promotes neurological recovery by exerting anti-inflammatory effect evidenced by a decrease in iNOS, COX2 and MMP9 expression. In addition, fenofibrate showed anti-oxidant effect demonstrated by a reduction of markers of oxidative stress: loss of glutathione, glutathione oxidation ratio, 3NT and 4HNE staining. Our data suggest that PPARalpha activation could mediate pleiotropic effects and strengthen that it could be a promising therapeutic strategy for TBI.