Endogenous hydrogen sulfide alleviates methotrexate‐induced cognitive impairment by attenuating endoplasmic reticulum stress‐induced apoptosis via CHOP and caspase‐12

The aim of this study was to estimate whether methotrexate (MTX) promotes cognitive impairment via increased ER stress and disrupted H2S signaling in the hippocampus and whether H2S 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 H2S‐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 H2S 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 H2S could alleviate the cognitive impairment induced by methotrexate through CHOP and caspase‐12.