Neurological recovery-promoting, anti-inflammatory, and anti-oxidative effects afforded by fenofibrate, a PPAR alpha agonist, in traumatic brain injury.
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.
Chen
Xiao Ru
XR
Laboratoire de Pharmacologie de la Circulation Cérébrale, Faculté de Pharmacie, Université Paris Descartes, Paris, France.
Besson
Valerie C
VC
Palmier
Bruno
B
Garcia
Yannick
Y
Plotkine
Michel
M
Marchand-Leroux
Catherine
C
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000447:Aldehydes; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D047493:PPAR alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D011345:Fenofibrate