title: Intracerebroventricular administration of an endothelin ETB receptor agonist increases expressions of GDNF and BDNF in rat brain.
abstract: Endothelins (ETs) are suggested to be involved in functional alterations of astrocytes after brain injury, including proliferation, hypertrophy and production of neurotrophic factors. In this study, effects of Ala1,3,11,15-endothelin-1 (Ala1,3,11,15-ET-1), an ETB receptor selective agonist, on neurotrophic factor production were examined in rat brain. A continuous intracerebroventricular administration of Ala1,3,11,15-ET-1 (500 pmol/day for 7 days) increased the numbers of GFAP- and vimentin-positive astrocytes in the hippocampus, caudate putamen and cerebrum. Ala1,3,11,15-ET-1 did not induce neuronal degeneration and activation of microglia/macrophage in these brain regions. The intracerebroventricular administration of Ala1,3,11,15-ET-1 for 7 days caused two- to three-fold increases in glial cell line-derived neurotrophic factors (GDNF) mRNA in the hippocampus and cerebrum. The mRNA levels of brain-derived neurotrophic factors (BDNF) in caudate putamen were increased by Ala1,3,11,15-ET-1. Expressions of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) mRNA in these regions were not largely affected by Ala1,3,11,15-ET-1, except cerebral NGF mRNA level was increased. The Ala1,3,11,15-ET-1-induced increases in GDNF and BDNF mRNA levels were accompanied by increases in immunoreactive GDNF and BDNF. Immunohistochemical observations showed that GFAP-positive astrocytes expressed GDNF and BDNF in the brain regions of Ala1,3,11,15-ET-1-infused rats. In cultured rat astrocytes, Ala1,3,11,15-ET-1 (100 nm) increased mRNA levels of GDNF and BDNF. These results suggest that activation of brain ETB receptors induced GDNF and BDNF expression in astrocytes.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-Oka 1-6 Suita, Osaka 565-0871, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Koyama
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tsujikawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002452:Cell Count; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019332:Endothelin-1; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin