Abstract: Objective To investigate the protective effect and possible mechanism of U0126 on glutamate neurotoxicity in brain. Methods Glutamate neurotoxicity model was established by injecting N-methyl-D-aspartate(NMDA) into the cortex of healthy adult male SD rats. First, the optimal modeling conditions were screened using different concentrations (50, 100, 200 mmol/L) of NMDA and different treatment times (3, 6, 12, 24 h). According to the selected optimal conditions, rats were divided into the control group, MAPK / ERK1 / 2 inhibitor U0126 treatment group (2 g / L),NMDA group (200 mmol / L) and different concentrations (0.5, 1, 2 g / L) of U0126 in combination with the NMDA treatment groups. The animals were sacrificed after treatment for 24 h in each group. The brain tissue sections were stained with HE staining to evaluate the tissue damage. Western blot assay was used to detect cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), Caspase-3 (activated form) and phosphorylated ERK1 /2 (p-ERK1/2) expression levels to determine the protective effect of U0126 in glutamate neurotoxic injury in brain tissue. Results (1) NMDA induced excitotoxic damage in rat cortex in a time - and concentration-dependent manner, activated MAPK / ERK1 / 2 signaling pathway,aggravated brain tissue damage, and 200 mmol/L NMDA for 24 h was selected for modeling. (2) Compared with the control group, the expressions of COX-2, iNOS, Caspase-3 (activated form) and p-ERK1/2 increased significantly in the NMDA group. Compared with the NMDA group, the expression levels of COX-2, iNOS, Caspase-3 (activated form) and p-ERK1/2 decreased with the increased concentration of U0126 in U0126+NMDA treatment group, and the area of brain injury decreased significantly. Conclusion U0126 has a protective effect on glutamate neurotoxicity injury in rat cortex, and its mechanism may be related to the inhibition of ERK1/2 activation and downstream signaling pathways of inflammation and apoptosis.

Key words: glutamic acid, N-methylaspartate, MAP kinase kinase kinases, neurotoxicity, MAPK/ERK1/2, COX-2, iNOS, Caspase-3