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Eur J Neurosci. 2003 Aug;18(4):887-94.

Intracerebroventricular administration of an endothelin ETB receptor agonist increases expressions of GDNF and BDNF in rat brain.

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Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-Oka 1-6 Suita, Osaka 565-0871, Japan.


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.

[Indexed for MEDLINE]

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