Endothelins stimulate the expression of neurotrophin-3 in rat brain and rat cultured astrocytes

Neuroscience. 2005;136(2):425-33. doi: 10.1016/j.neuroscience.2005.08.004. Epub 2005 Sep 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Brain Chemistry / drug effects*
  • Cells, Cultured
  • Endothelin-1 / analogs & derivatives
  • Endothelin-1 / pharmacology
  • Endothelins / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Injections, Intraventricular
  • Nerve Growth Factors / metabolism
  • Neurotrophin 3 / biosynthesis*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Receptor, Endothelin B / agonists
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Stimulation, Chemical


  • Endothelin-1
  • Endothelins
  • Nerve Growth Factors
  • Neurotrophin 3
  • RNA, Messenger
  • Receptor, Endothelin B