Neurological Recovery-Promoting, Anti-Inflammatory, and Anti-Oxidative Effects Afforded by Fenofibrate, a PPAR Alpha Agonist, in Traumatic Brain Injury

Abstract

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.

Formulation, Optimization, <i>in Vivo</i> Pharmacokinetic, Behavioral and Biochemical Estimations of Minocycline Loaded Chitosan Nanoparticles for Enhanced Brain Uptake

“…cMHNP treatment resulted in improved antioxidant and hence improved pharmacodynamic activity because of improved uptake of MH by brain via this formulation. These results are in accordance with previous findings where PPAR-α activators produced neuroprotection by decreasing oxidative stress as well as reactive nitrogen species (RNS) via reduction in free radical generation [46][47][48][49] and increasing antioxidant enzymes such as catalase and endogenous antioxidant GSH. 47,49,50) In the present investigation; pure MH, positive control Piracetam treated group and cMHNP administered batches revealed memory enhancing activity in mice as indicated by decrease in TL and increase in TSTQ; but MHNP treated group failed to show improved memory compared to saline treated control group.…”

Fibrates but not statins increase plasma selenium in dyslipidemic aged patients – The EVA study

“…Fibrates decrease triglycerides and increase weakly HDL-cholesterol [1,2] whereas statins reduce LDLcholesterol [2]. In addition, both drugs have anti-inflammatory properties [2], statins modulate oxidative stress and NO synthase [2], whereas fibrates act as antioxidants [4] but have also been reported to oxidize DNA [2].…”

Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”?

“…Promising new findings have been made in molecular mechanisms of TBI, and many experimental substances await testing in the clinical setting. For example, peroxisome proliferator-activated receptors have recently emerged as potent antiinflammatory transcription factors that when used alone or in combination with endocannabinoids may prove to be pivotal antiinflammatory and neuroprotective agents in the setting of TBI (124,125). In addition, selective targeting of the innate immune response after trauma, such as by pharmacological inhibition of the complement cascade at various levels of its activation pathways, has recently emerged as a new promising therapeutic strategy in experimental TBI models (126)(127)(128)(129).…”