Department of Neurosurgery, The National Key Clinic Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Engineering Technology Research Center of Education Ministry of China, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Hematology, Southern Hospital, Southern Medical University, Guang Zhou, China.
Fundam Clin Pharmacol. 2020 Oct;34(5):559-570. doi: 10.1111/fcp.12543. Epub 2020 Feb 27.
The aim of this study was to estimate whether methotrexate (MTX) promotes cognitive impairment via increased ER stress and disrupted H S signaling in the hippocampus and whether H S may alleviate MTX-induced cognitive impairment by inhibiting ER stress through CHOP and caspase-12. Cognitive impairment behaviors were observed by Morris water maze test, and the apoptosis of neurons was assessed by TUNEL assay. The production of neurons was analyzed by DCX and Ki67 immunohistochemistry. The expressions of CHOP and caspase-12 in the hippocampus were determined by Western blot and immunohistochemistry. MTX increased the expression of CHOP and caspase-12 and the number of TUNEL-positive cells in the hippocampus by inhibiting endogenous H S-induced neuronal pyknosis in the hippocampal CA1 region. MTX decreased the number of DCX- and Ki67-positive cells in the hippocampal DG region. The results of Morris water maze showed that MTX could damage the spatial memory of rats. The changes of MTX-induced Morris water maze test in mice and H S levels in serum and hippocampus, as well as the expression of CHOP and caspase-12 and the number of CHOP and caspase-12-positive neurons in the hippocampus, indicated that H S could alleviate the cognitive impairment induced by methotrexate through CHOP and caspase-12.
本研究旨在评估甲氨蝶呤（MTX）是否通过增加内质网应激和破坏海马 HS 信号转导而导致认知障碍，以及 HS 是否可以通过 CHOP 和 caspase-12 抑制内质网应激来减轻 MTX 诱导的认知障碍。通过 Morris 水迷宫试验观察认知障碍行为，通过 TUNEL 测定评估神经元凋亡。通过 DCX 和 Ki67 免疫组化分析神经元的产生。通过 Western blot 和免疫组化测定海马中 CHOP 和 caspase-12 的表达。MTX 通过抑制内源性 HS 诱导海马 CA1 区神经元固缩，增加 CHOP 和 caspase-12 的表达和 TUNEL 阳性细胞数。MTX 减少海马齿状回区 DCX 和 Ki67 阳性细胞数。Morris 水迷宫的结果表明，MTX 可损害大鼠的空间记忆。MTX 诱导的 Morris 水迷宫试验在血清和海马中的变化，以及 HS 水平，以及 CHOP 和 caspase-12 的表达和 CHOP 和 caspase-12 阳性神经元的数量，表明 HS 可以通过 CHOP 和 caspase-12 减轻 MTX 诱导的认知障碍。
