The endozepine ODN stimulates [ 3H]thymidine incorporation in cultured rat astrocytes

Abstract

High concentrations of diazepam-binding inhibitor (DBI) mRNA have been detected in astrocytoma, suggesting that DBI-derived peptides may play a role in glial cell proliferation. In the present study, we have investigated the effect of a processing product of DBI, the octadecaneuropeptide ODN, on DNA synthesis in cultured rat astrocytes. At very low concentrations (10 −14 to 10 −11 M), ODN caused a dose-dependent increase of [ 3H]thymidine incorporation. At higher doses (10 −10 to 10 −5 M), the effect of ODN gradually declined. The central-type benzodiazepine receptor antagonist flumazenil (10 −6 M) completely suppressed the stimulatory action of ODN whereas the peripheral-type benzodiazepine receptor ligand, PK11195 (10 −6 M) had no effect. The ODN-induced stimulation of [ 3H]thymidine incorporation was mimicked by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). The GABA A receptor antagonist bicuculline (10 −4 M) suppressed the effect of both ODN and DMCM on DNA synthesis. Exposure of cultured astrocytes to the specific GABA A agonist 3APS (10 −10 to 10 −4 M) also induced a dose-related increase of [ 3H]thymidine incorporation. The present study indicates that ODN, acting through central-type benzodiazepine receptors associated with the GABA A receptor complex, stimulates DNA synthesis in rat glial cells. These data provide evidence for an autocrine role of endozepines in the control of glial cell proliferation.