Midazolam is a benzodiazepine derivative drug that has powerful anxiolytic, amnestic, hypnotic, and sedative properties. The cytoprotective effect of midazolam on brain astrocytes is poorly understood. This study aimed to investigate the cytoprotective effect of midazolam on astrocytes exposed to corticosterone, a stress-produced glucocorticoid. We found that midazolam stimulated pregnenolone and progesterone secretion in astrocytes in a dose-dependent manner. Midazolam protected astrocytes from corticosterone-induced damages in a dose-dependent manner. In addition, we demonstrated that progesterone reduced corticosterone-induced damages. Finally, we applied trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, to inhibit pregnenolone metabolism and found that pretreatment with trilostane significantly inhibited the cytoprotective effect of midazolam on corticosterone-induced cytotoxicity in rat astrocytes in a dose-dependent manner. Taken together, these results demonstrate that midazolam has cytoprotective effect on astrocytes. This is, at least partially, derived from midazolam-induced steroidogenesis including progesterone and downstream products in astrocytes. Our data provide new insights into the cytoprotective effect of midazolam.
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