Data_Sheet_1_HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia.pdf

Exploring and expanding the indications of common clinical drugs, such as statins, is important to improve the prognosis of patients with permanent cerebral infarction. It has been suggested that reversing the defects in cellular autophagy and ER stress with statin therapy may be a potential treatment option for reducing ischemic damage. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO) by electrocoagulation surgery. Atorvastatin (ATV, 10 mg/kg/day) or vehicle was administered intraperitoneally. Rats were divided into the vehicle-treated (SHAM), ATV pretreatment for MCAO (AMCAO), and 3-methyladenine (3MA) combined with ATV pretreatment (3MAMCAO) groups. Magnetic resonance imaging, as well as immunohistochemical and Western blot assessments, were performed 24 h after MCAO. Each ATV-treated group demonstrated significant reductions in infarct volume compared with that in the vehicle-treated group at 24 h after MCAO, which was associated with autophagy reduction and ER stress attenuation in neurons and neovascularization. Next, Western blotting was used to detect the levels of the autophagy-related proteins LC3B and P62 and of ER stress pathway proteins. However, 3MA significantly partially inhibited the ER stress pathway via limiting the autophagic flux in the AMCAO group. In conclusion, our results imply that the neuroprotective function of ATV depends on autophagic activity to diminish ER stress-related cell apoptosis in rats with PMCAO and suggest that compounds that inhibit autophagic activity might reduce the neuroprotective effect of ATV after brain ischemia.

深入探究并拓展常见临床药物，如他汀类药物的适应症，对于改善永久性脑梗塞患者的预后具有重要意义。有研究表明，通过他汀类药物疗法逆转细胞自噬缺陷和内质网应激，可能成为减少缺血性损伤的一种潜在治疗选择。雄性Sprague-Dawley大鼠通过电凝手术进行永久性大脑中动脉闭塞（PMCAO）。给予阿托伐他汀（ATV，剂量为10 mg/kg/天）或溶剂进行腹腔注射。大鼠被分为溶剂处理组（SHAM）、ATV预处理MCAO组（AMCAO）和3-甲基腺嘌呤（3MA）联合ATV预处理组（3MAMCAO）。在MCAO后24小时进行磁共振成像、免疫组化和Western blot评估。与溶剂处理组相比，每个ATV处理组在MCAO后24小时均显示出梗死体积的显著减少，这与神经元中自噬减少和内质网应激缓解以及新生血管化有关。随后，通过Western blot技术检测自噬相关蛋白LC3B和P62以及内质网应激通路蛋白的水平。然而，3MA通过限制AMCAO组中的自噬通量，显著部分抑制了内质网应激通路。总之，我们的研究结果暗示了ATV的神经保护功能依赖于自噬活性以减轻PMCAO大鼠的内质网应激相关细胞凋亡，并提出抑制自噬活性的化合物可能会降低脑缺血后ATV的神经保护作用。