Neurotoxic effect of 11?-dehydrocorticosterone on hippocampal neuron and its mechanism / 第二军医大学学报

ABSTRACT

Objective:To study the toxicity of 11 dehydrocorticosterone on hippocampal neurons and to determine whether 11? hydroxysteroid dehydrogenase (11? HSD1) is involved in the neurotoxity. Methods:Western blotting, radiometric enzyme activity assay and MTT assay were employed in this study. Results:Both 11? HSD1 protein and bioactivity were positive in the hippocampal neurons as demonstrated by Western blotting and radiometric enzyme activity assay. At concentration of 10 -6 mol/L, 11 dehydrocorticosterone was neurontoxic to hippocampal neurons cultured in serum free DMEM medium. This neurotoxic effect of 11 dehydrocorticosterone was blocked by 11? HSD1 inhibitor carbenoxolone (CBX) and glucocorticoid receptor (GR) antagonist RU38486, but not by mineralcocorticoid receptor (MR) antagonist spironolatone. Corticosterone and its derivative 11 dehydrocorticosterone up regulated 11? HSD1 level. Conclusion:11 dehydrocorticosterone has toxicity on hippocampal neurons, and it can be blocked by CBX, suggesting 11? HSD1 may convert biologically inactive 11 dehydrocorticosterone to active corticosterone. The up regulation of 11? HSD1 by glucocorticoids in return exaggerates the neurotoxic effect of corticosterone, which may play a positive role in the delayed neuron death during stress.