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.

载脂蛋白E（APOE）不仅与慢性退行性神经疾病（例如阿尔茨海默氏病）有关，而且与急性脑部疾病（包括脑外伤）有关。据报道，类视黄醇X受体的选择性激动剂贝沙罗汀可显着增强APOE的表达。先前的研究表明，贝沙罗汀通过调节外周免疫应答和自噬，在缺血性中风的动物模型中发挥神经保护作用。但是，该药物在神经元凋亡中的作用及其潜在的机制尚待阐明。本研究采用短暂性脑中动脉闭塞（t-MCAO）作为急性脑缺血/再灌注损伤的模型。实验是在野生型C57BL / 6小鼠和APOE基因敲除（APOE-KO）小鼠中进行的。在t-MCAO之后，小鼠接受腹腔注射贝沙罗汀（5 mg / kg）或等体积的媒介物。结果测量包括神经功能缺损，学习能力，空间记忆，梗塞体积，组织病理学，细胞凋亡程度以及JNK / caspase-3信号通路蛋白的表达水平。获得的结果表明，贝沙罗汀的给药显着改善了C57BL / 6小鼠的神经功能，学习能力和空间记忆，但未改善APOE-KO小鼠。在C57BL / 6和APOE-KO小鼠中，t-MCAO后，梗死体积，组织损伤，神经元凋亡率和JNK / caspase-3信号通路中涉及的蛋白质表达明显增加。重要的是，贝沙罗汀治疗可显着改善C57BL / 6中的所有这些变化，但不能改善APOE-KO小鼠中的所有这些变化。综上所述，贝沙罗汀显着减轻t-MCAO后小鼠的神经功能缺损，改善组织学结果，并抑制细胞凋亡。该作用至少部分地由APOE的上调介导。因此，贝沙罗汀可能是治疗脑缺血患者的候选药物。