Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 563, Issue 1-3, Pages 117-123Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2007.01.069
Keywords
histamine H-3 receptor; clobenpropit; NMDA; excitotoxicity; GABA; intracellular calcium level
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Using the histamine H-3 receptor antagonist clobenpropit, the roles of histamine H-3 receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Clobenpropit reversed the neurotoxicity in a concentration-dependent manner, and showed peak protection at a concentration of 10(-7) M. This protection was antagonized by the histamine H-3 receptor agonist (R)-alpha-methylhistamine, but not by the histamine H-1 receptor antagonist pyrilamine or the histamine H-2 receptor antagonist cimetidine. In addition, the protection by clobenpropit was inhibited by the GABA(A) receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by clobenpropit was due to increased GABA release. The inducible GABA release was also inhibited by (R)-alpha-methylhistamine, but not by pyrilamine or cimetidine. Furthermore, both the adenylyl cyclase inhibitor SQ-22536 and the protein kinase A (PKA) inhibitor H-89 reversed the protection and the GABA release by clobenpropit. In addition, clobenpropit reversed the NMDA-induced increase in intracellular calcium level, which was antagonized by (R)-alpha-methylbistamine. These results indicate that clobenpropit enhanced GABA release to protect against NMDA-induced excitotoxicity, which was induced through the cAMP/PKA pathway, and reduction of intracellular calcium level may also be involved. (c) 2007 Elsevier B.V All rights reserved.
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