Endothelins stimulate the expression of neurotrophin-3 in rat brain and rat cultured astrocytes.
Endothelins play a role in the regulation of astrocytic functions in brain pathologies such as hyperplasia and neurotrophic factor production. The present study examined the effects of endothelins on production of neurotrophin-3, a member of the neurotrophin family of neurotrophic factors, in cultured astrocytes and rat brain. Quantitative reverse transcription-PCR analysis of mRNA copy numbers showed that cultured astrocytes expressed comparable numbers of neurotrophin-3 and neurotrophin-4/5 mRNA copies to nerve growth factor and brain-derived neurotrophic factor. Endothelin-1 (100 nM) and Ala1,3,11,15-endothelin-1 (an endothelinB receptor agonist, 100 nM) caused a transient increase in neurotrophin-3 mRNA levels, but not in neurotrophin-4/5 levels, in cultured astrocytes. The increases in mRNA levels were accompanied with that in extracellular release of neurotrophin-3. The effects of endothelin-1 on neurotrophin-3 mRNA levels were reduced by BQ788, an endothelinB receptor antagonist. I.c.v. administration of 500 pmol/day Ala1,3,11,15-endothelin-1 increased mRNA and peptide levels of neurotrophin-3 in rat caudate putamen and cerebrum. On the other hand, neurotrophin-3 production in hippocampus was not affected by Ala1,3,11,15-endothelin-1. Immunohistochemical examination of Ala1,3,11,15-endothelin-1-infused rats showed that neurotrophin-3 was mainly expressed in glial fibrillary acidic protein-positive astrocytes in caudate putamen and cerebrum. endothelin-induced increases in neurotrophin-3 expression in cultured astrocytes were inhibited by chelation of intracellular Ca2+ and PD98095 (an ERK inhibitor). These results suggest that endothelin is an extracellular signal that stimulates astrocytic neurotrophin-3 production in brain pathologies.
Koyama
Y
Y
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-Oka 1-6 Suita, 565-0871, Japan.
Baba
A
A
Matsuda
T
T
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D009414:Nerve Growth Factors / Q000378:metabolism; D020933:Neurotrophin 3 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical
D019332:Endothelin-1; D016232:Endothelins; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D012333:RNA, Messenger; D044023:Receptor, Endothelin B