Neuroprotective effects of chronic fenofibrate treatment via modulating the immunoreactivity of cleaved caspase-3 in stroke induced by transient middle cerebral occlusion rat model

Abstract

AIm: Current stroke therapies include lipid-lowering drugs, which reduce inflammation and serve to stabilize the atherosclerotic plaque to demonstrate better outcome and neuroprotection. Peroxisome proliferator activated receptors (PPAR) α regulates lipid homeostasis and is a target of fibrates, which have a neuroprotective function by various mechanisms. In this study, we aimed to evaluate the role of the PPARα agonist, fenofibrate, in the modulation of cleaved caspase-3 immunoreactivity and at the final infarct volume in an experimental ischemia/reperfusion rat model by induced transient proximal middle cerebral artery occlusion. mATERIAl and mEThODS: A total of 65 male Sprague Dawley rats were allocated into 4 groups; sham (n =5), experiment 1 (n=20), experiment 2 (n=20), experiment 3 (n=20). All experiment groups were divided to 3 subgroups in order to evaluate the final infarct volume at 24 th hour (n=5) and the immunoreactivity of cleaved caspase -3 at different time periods [at first hour (n=5), at 6 th hour (n=5), at 24 th hour (n=5)] after transient middle cerebral artery occlusion (MCAo). At the study, the experiment groups (Experiment 1 and Experiment 2) were received the fenofibrate-diet during 14 days before ischemia procedure. All animals were sacrificed at 24 th hours after MCAo. Infarction volumes were calculated from 2,3,5,triphenyltetrozolium chloride (TTC)-stained brain sections. RESUlTS:We found that fenofibrate-therapy reduced significantly more body weight than the other experiment groups (p<0.05). At the time intervals, a decrease of immunoreactivity of cleaved caspase-3 was significantly observed with fenofibrate therapy after MCAo (p<0.05). Chronic fenofibrate treatment before cerebral ischemia significantly reduced the infarction size after MCAo compared with the other groups (respectively; p = 0.011 and p< 0.000). CONClUSION:Fenofibrate treatment has neuroprotective effects on middle cerebral artery infarcts.

Exploring Biomarkers and Therapeutic Targets for Ischemic Stroke Through Integrated Microarray Data Analysis

“…Feno brate could signi cantly reduce the volume of cerebral infarction, the activation of microglia and the in ltration of neutrophils in the ischemic area to play a protective effect on the brain, which may be related to the acute effect and preconditioning mechanism (Ouk et al 2009). Feno brate played a preventive and protective effect on cerebral ischemia by reducing the infarct volume, and the related mechanism may be related to the genome regulation in the apoptosis pathway (Altintas et al 2017). Cyclosporine A had potential neuroprotective properties in ischemic stroke, which interfered with the typical NF-κB signaling pathway, and the Akt pathway may also participate in the role of Cyclosporine A (Deng et al 2020;Nighoghossian et al 2016).…”

Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression

“…Other effects the pemafibrate could have are protective effects against atherosclerosis and inflammation in hyperlipidemic condition [42]. It has been reported that oral fenofibrate reduced caspase-3 immunoreactivity in a rat stroke model and that prior administration of fenofibrate resulted in a significant reduction in infarct size [43]. Therefore, it is possible that the neuroprotective effect of pemafibrate is accompanied by an anti-apoptotic effect.…”

Role of Cav2.1 Channel Signaling in Glutamate-Related Brain Injury

“…Overactivation of NMDA and AMPA receptors results in neuronal death and dysfunction [43,44]. Induced middle cerebral artery occlusion has been used in numerous cerebral ischemia models [45][46][47][48]. In such models, the caudate putamen and cerebral cortex become the ischemic core and penumbra area, respectively [43,44].…”