Endoplasmic reticulum stress plays an important role in methotrexate-related cognitive impairment in adult rats.

The patients receiving methotrexate (MTX) treatment are inclined to suffer from cognition impairment, since MTX can induce apoptosis of neurons, while the underlying molecular mechanisms remain unknown. Thus we hypothesized that MTX-induced apoptosis of hippocampal neurons via activating endoplasmic reticulum stress (ERS) pathway, which leads to cognitive impairment in adult rats. In order to confirm our hypothesis, twenty male Sprague-Dawley rats weighting 180-220 g were divided into two groups: the control group (physiological saline) and the MTX group (MTX 60 mg/kg). Spatial memory was assayed by the Morris water maze test (MWM). In the mean time, another twenty-four rats were divided into four groups: the control group (physiological saline), MTX (MTX, 60 mg/kg), MTX (MTX, 100 mg/kg) and MTX (MTX, 250 mg/kg). Then, we observed the pathological changes of the hippocampus by hematoxylin-eosin stained. The expressions of C/EBP homologous protein (CHOP) and caspase-12 in the hippocampus were determined by Western blot and immunofluorescence. The apoptosis of neurons were assessed by TUNEL assay. The Morris water maze test showed that MTX induced spatial memory impairment in adult rats (<0.05). The degenerated or apoptotic neurons were condensed and the number of neurons with nuclear pyknosis increased significantly in hippocampus CA1 area of rats in MTX groups. Additionally, both protein expressions of CHOP and caspase-12 and number of TUNEL positive cells were significantly increased in these MTX groups (<0.05). The present results suggested that ERS mediated by apoptosis of hippocampal neurons might play an important role in the mechanism of MTX-induced cognitive impairment in adult rats.