The histamine H3 receptor antagonist clobenpropit enhances GABA release to protect against NMDA-induced excitotoxicity through the cAMP/protein kinase A pathway in cultured cortical neurons

Eur J Pharmacol. 2007 Jun 1;563(1-3):117-23. doi: 10.1016/j.ejphar.2007.01.069. Epub 2007 Feb 8.


Using the histamine H3 receptor antagonist clobenpropit, the roles of histamine H3 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 H3 receptor agonist (R)-alpha-methylhistamine, but not by the histamine H1 receptor antagonist pyrilamine or the histamine H2 receptor antagonist cimetidine. In addition, the protection by clobenpropit was inhibited by the GABAA 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-methylhistamine. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcium / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cytoprotection / drug effects
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / toxicity*
  • GABA Antagonists / pharmacology
  • Histamine Agonists / pharmacology
  • Histamine Antagonists / pharmacology*
  • Imidazoles / pharmacology*
  • N-Methylaspartate / toxicity*
  • Necrosis
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Histamine H3 / drug effects*
  • Receptors, Histamine H3 / metabolism
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology
  • gamma-Aminobutyric Acid / metabolism*


  • Excitatory Amino Acid Agonists
  • GABA Antagonists
  • Histamine Agonists
  • Histamine Antagonists
  • Imidazoles
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Receptors, Histamine H3
  • gamma-Aminobutyric Acid
  • N-Methylaspartate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Thiourea
  • clobenpropit
  • Calcium