Apolipoprotein E (APOE) is implicated not only in chronic degenerative neurological diseases, such as Alzheimer's disease, but also in acute brain disorders, including traumatic brain injury. Bexarotene, a selective agonist of the retinoid X receptor, has been reported to enhance markedly the expression of APOE. Previous studies have indicated that bexarotene exerts neuroprotective effects in animal models of ischemic stroke by modulating the peripheral immune response and autophagy. However, the role of this drug in neuronal apoptosis and the potential mechanisms involved have yet to be elucidated. The present study employed transient middle cerebral artery occlusion (t-MCAO) as a model of acute cerebral ischemia/reperfusion injury. The experiments were performed in wild-type C57BL/6 mice and APOE gene knockout (APOE-KO) mice. After t-MCAO, mice received intraperitoneal injection of bexarotene (5 mg/kg) or an equal volume of the vehicle. The outcome measurements included neurological deficits, learning ability, spatial memory, infarct volume, histopathology, magnitude of apoptosis, and the level of expression of proteins of the JNK/caspase-3 signaling pathway. The obtained results demonstrated that bexarotene administration significantly improved neurological function, learning ability, and spatial memory in C57BL/6 mice, but not in APOE-KO mice. Infarct volume, tissue damage, neuronal apoptosis rate, and the expression of proteins involved in the JNK/caspase-3 signaling pathway were markedly increased after t-MCAO in both C57BL/6 and APOE-KO mice. Importantly, bexarotene treatment significantly ameliorated all these changes in C57BL/6, but not in APOE-KO mice. In conclusion, bexarotene markedly alleviates the neurological deficits, improves the histological outcome, and inhibits cell apoptosis in mice after t-MCAO. This effect is mediated, at least in part, by up-regulation of APOE. Thus, bexarotene may be a candidate drug for the treatment of cerebral ischemia patients.
Keywords: Apolipoprotein-E; Apoptosis; Bexarotene; Ischemia/reperfusion; Neuroprotection.