Inhibition of growth factor-induced DNA synthesis in astrocytes by ligands of peripheral-type benzodiazepine receptors.
The effect of diazepam and specific ligands of peripheral-type benzodiazepine receptors (PBRs) on growth factor-induced DNA synthesis in quiescent cultures of rat astrocytes has been examined. It was found that diazepam inhibited the ability of basic fibroblast growth factor (bFGF) to stimulate [3H]thymidine incorporation; the IC50 was approximately 5 microM. Ro5-4864, a specific agonist of PBRs, also blocked bFGF-induced DNA synthesis. PK11195, which in some cases functions as an antagonist of PBRs, did not prevent the effect of Ro5-4864 on bFGF-induced DNA synthesis; rather, addition of PK11195 also inhibited bFGF-induced DNA synthesis. In addition, diazepam reduced the stimulation of DNA synthesis caused by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), polypeptide growth factors coupled to receptor tyrosine kinases, as well as thrombin, an activator of G protein-coupled receptors. These data suggest that ligands of PBRs may limit astrocyte mitosis, a phenomenon that occurs following CNS injury.
Neary
J T
JT
Laboratory of Neuropathology, VA Medical Center, Miami, FL 33125, USA.
Jorgensen
S L
SL
Oracion
A M
AM
Bruce
J H
JH
Norenberg
M D
MD
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001570:Benzodiazepinones / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D003975:Diazepam / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D008938:Mitosis / Q000187:drug effects; D017933:Peripheral Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism
D001570:Benzodiazepinones; D003292:Convulsants; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D008024:Ligands; D011963:Receptors, GABA-A; D016222:Fibroblast Growth Factor 2; C028513:4'-chlorodiazepam; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D003975:Diazepam; D013936:Thymidine; C037850:PK 11195