Midazolam Impairs Learning and Memory Ability Through ERK/CREB Signaling Pathway and Oxidative Damage of Hippocampus in Rats

This study aimed to elucidate whether midazolam affected the learning and memory of rats through the extracellular signalregulated kinase（ERK）/cyclic adenosine monophosphate response element-binding（CREB） signaling pathway and hippocampal oxidative damage. Overall 120 Wistar rats were randomly assigned to four groups, including one control and three midazolam-exposed groups(20, 60 and 150 mg · kg^-1). After an intraperitoneal injection of midazolam/physiological saline for both 1 h（n=15） and 24 h（n=15）, 10 rats（five came from 1 h, and the remaining five came from 24 h） were randomly selected from each group for the Morris water maze test. The hippocampus tissue samples were harvested for the assessment of superoxide dismutase（SOD） and catalase（CAT） activities as well as glutathione peroxidase（GPx）, malonyl dialdehyde（MDA）, nitric oxide（NO） and inducible nitric oxide synthase（iNOS） levels. The remaining 80 rats were euthanized, and the hippocampal tissue was isolated. The expressions of ERK1, ERK2 and CREB mRNA were tested using RT-qPCR. The protein expressions of p-ERK1/2 and p-CREB were tested using Western blotting. The Morris water maze tests indicated that midazolam-treated rats have weaker learning and memory ability compared to the control rats. Midazolam increased MDA, NO, iNOS and CAT, and decreased GPx and SOD activities compared to the control group. The expression levels of ERK1/2 and CREB in the hippocampus of rats in the midazolam treatment groups were significantly lower compared to the control group at 1 h after intraperitoneal injection of midazolam, and in a dose-dependent relationship but returning it to normal levels at 24 h after midazolam intraperitoneal injection. Therefore, it was concluded that the learning and memory impairment of midazolam might be associated with the down-regulation of the ERK/CREB signaling pathway and oxidative damage in rat hippocampus.