PERIPHERAL-TYPE BENZODIAZEPINES INHIBIT PROLIFERATION OF ASTROCYTES IN CULTURE

Peripheral-type benzodiazepine (BZD) receptors have been identified in brain and are predominantly localized to astrocytes. To determine their potential role in controlling astroglial proliferation, DNA synthesis, growth curves and mitotic index were investigated in primary astrocyte cultures which had been exposed to Ro5-4864 (a peripheral-type BZD ligand) and PK11195 (a peripheral-type BZD receptor antagonist). There was a dose-dependent inhibition of mitosis when two-week-old cells in culture were exposed to 50 nM, 500 nM, 1-mu-M and 10-mu-M Ro5-4864 for 24 b. Exposure of 5-, 8-, 12- and 15-day-old cultures to Ro5-4864 and PK11195 for 24 h did not affect growth rate and DNA synthesis; however, continuous exposure to 10-mu-M Ro5-4864 caused a persistent inhibition of cell growth and [H-3]thymidine incorporation (P < 0.05) while nanomolar concentrations did not cause any significant change. Concurrent administration of Ro5-4864 with PK11195 resulted in a partial reversal of Ro5-4864-induced inhibition in DNA synthesis and mitosis. These results indicate that peripheral-type BZDs are capable of inhibiting proliferation of astrocytes in culture.