Department of Psychiatry, Faculty of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran.
Faculty of Pharmacy, Central Branch of Islamic Azad University, Tehran, Iran.
Toxicol Mech Methods. 2023 Sep;33(7):607-623. doi: 10.1080/15376516.2023.2202785. Epub 2023 Apr 26.
Tramadol (TRA) causes neurotoxicity whereas trimetazidine (TMZ) is neuroprotective. The potential involvement of the PI3K/Akt/mTOR signaling pathway in the neuroprotection of TMZ against TRA-induced neurotoxicity was evaluated. Seventy male Wistar rats were divided into groups. Groups 1 and 2 received saline or TRA (50 mg/kg). Groups 3, 4, and 5 received TRA (50 mg/kg) and TMZ (40, 80, or 160 mg/kg) for 14 days. Group 6 received TMZ (160 mg/kg). Hippocampal neurodegenerative, mitochondrial quadruple complex enzymes, phosphatidylinositol-3-kinases (PI3Ks)/protein kinase B levels, oxidative stress, inflammatory, apoptosis, autophagy, and histopathology were evaluated. TMZ decreased anxiety and depressive-like behavior induced by TRA. TMZ in tramadol-treated animals inhibited lipid peroxidation, GSSG, TNF-α, and IL-1β while increasing GSH, SOD, GPx, GR, and mitochondrial quadruple complex enzymes in the hippocampus. TRA inhibited Glial fibrillary acidic protein expression and increased pyruvate dehydrogenase levels. TMZ reduced these changes. TRA decreased the level of JNK and increased Beclin-1 and Bax. TMZ decreased phosphorylated Bcl-2 while increasing the unphosphorylated form in tramadol-treated rats. TMZ activated phosphorylated PI3Ks, Akt, and mTOR proteins. TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades.
曲马多（TRA）会导致神经毒性，而曲美他嗪（TMZ）则具有神经保护作用。评估了 PI3K/Akt/mTOR 信号通路在 TMZ 对 TRA 诱导的神经毒性的神经保护作用中的潜在作用。70 只雄性 Wistar 大鼠被分为几组。第 1 组和第 2 组接受生理盐水或 TRA（50mg/kg）。第 3、4 和 5 组接受 TRA（50mg/kg）和 TMZ（40、80 或 160mg/kg）14 天。第 6 组接受 TMZ（160mg/kg）。评估了海马神经退行性变、线粒体四重复合体酶、磷脂酰肌醇-3-激酶（PI3Ks）/蛋白激酶 B 水平、氧化应激、炎症、细胞凋亡、自噬和组织病理学。TMZ 可减轻 TRA 引起的焦虑和抑郁样行为。在 TRA 处理的动物中，TMZ 抑制脂质过氧化、GSSG、TNF-α 和 IL-1β，同时增加海马中的 GSH、SOD、GPx、GR 和线粒体四重复合体酶。TRA 抑制胶质纤维酸性蛋白表达并增加丙酮酸脱氢酶水平。TMZ 减少了这些变化。TRA 降低了 JNK 水平，增加了 Beclin-1 和 Bax。TMZ 降低了磷酸化 Bcl-2 的水平，同时增加了 TRA 处理大鼠中未磷酸化的形式。TMZ 激活了磷酸化的 PI3Ks、Akt 和 mTOR 蛋白。TMZ 通过调节 PI3K/Akt/mTOR 信号通路及其下游的炎症、细胞凋亡和自噬相关级联来抑制 TRA 诱导的神经毒性。
