Activation of PPAR-β/δ Attenuates Brain Injury by Suppressing Inflammation and Apoptosis in a Collagenase-Induced Intracerebral Hemorrhage Mouse Model

Abstract

Brain injury has been proposed as the major cause of the poor outcomes associated with intracerebral hemorrhage (ICH). Emerging evidence indicates that the nuclear receptor, peroxisome proliferator-activated receptor β/δ (PPAR-β/δ), plays a crucial role in the pathological process of central nervous impairment. The present study was undertaken to evaluate the protective effects of PPAR-β/δ activation using a selective PPAR-β/δ agonist, GW0742, against brain injury after ICH in a mouse model. ICH was induced by intravenous injection of collagenase into the right caudate putamen. To examine the protective effect of PPAR-β/δ activation against ICH-induced brain injury, mice were either intraperitoneally injected with GW0742 (3 mg/kg, body weight) or saline (control group) 30 min before inducing ICH. Behavioral dysfunction was evaluated 24 and 72 h after injury. Then, all mice were killed to assess hematoma volume, brain water content, and blood-brain barrier (BBB) permeability. TUNEL and Nissl staining were performed to quantify the brain injury. The expression of PPAR-β/δ, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, Bcl-2-related X-protein (Bax), and B-cell lymphoma 2 (Bcl-2) in the perihematomal area was examined by immunohistochemistry and western blotting analysis. Mice treated with GW0742 showed significantly less severe behavioral deficits compared to the control group, accompanied by increased expression of PPAR-β/δ and Bcl-2, and increased expression of IL-1β, TNF-α, and Bax decreased simultaneously in the GW0742-treated group. Furthermore, the GW0742-pretreated group showed significantly less brain edema and BBB leakage. Neuronal loss was attenuated, and the number of apoptotic neuronal cells in perihematomal tissues reduced, in the GW0742-pretreated group compared to the control group. However, the hematoma volume did not decrease significantly on day 3 after ICH. These results suggest that the activation of PPAR-β/δ exerts a neuroprotective effect on ICH-induced brain injury, possibly through anti-inflammatory and anti-apoptotic pathways.

Peroxisome Proliferator-Activated Receptor-δ Deficiency in Microglia Results in Exacerbated Axonal Injury and Tissue Loss in Experimental Autoimmune Encephalomyelitis

“…These findings of a role for endogenous PPAR-δ in neuroprotection does correspond with past reports of neuroprotective effects of synthetic PPAR-δ agonists GW0742 and GW501516 in cultured neurons ( 64 , 65 ) and in murine models of Alzheimer's disease ( 66 , 67 ), stroke ( 68 – 71 ), Parkinson's disease ( 72 , 73 ), and Huntington's disease ( 65 ). In a stroke model, activating PPAR-δ limited infarct size in the CNS by mitigating oxygen-glucose-deprivation-induced death in the vascular endothelial cells ( 71 ).…”

Dissecting the Roles of LncRNAs in the Development of Periventricular White Matter Damage

“…Nevertheless, it has been shown that activation of the PPAR pathway prevents inflammatory responses throughout the body and reverses tissue damage (Kurtak, 2014). Besides, PPAR pathway is an important factor in reparative processes of various forms of brain injury (Li et al, 2019;Oyagbemi et al, 2020;Tang et al, 2020). On the other hand, our analysis showed that Parkinson's disease pathway was negatively enriched in the up-regulated lncRNAs.…”

Neuroprotective Effect of Cyclo-(L-Pro-L-Phe) Isolated from the Jellyfish-Derived Fungus Aspergillus flavus

“…5 µm). 13 C NMR spectra were obtained using a Varian UNITY 400 spectrometer and 1 H NMR spectra were recorded using a Varian INOVA 500 spectrometer. Optical rotation was detected using a Jasco P-1020 polarimeter.…”