Histamine protects against NMDA‐induced necrosis in cultured cortical neurons through H2 receptor/cyclic AMP/protein kinase A and H3 receptor/GABA release pathways

Abstract Using histamine and the H 3 receptor antagonist thioperamide, the roles of histamine receptors in NMDA‐induced necrosis were investigated in rat cultured cortical neurons. Within 3 h of intense NMDA insult, most neurons died by necrosis. Histamine 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 H 2 receptor antagonists cimetidine and zolantidine but not by the H 1 receptor antagonists pyrilamine and diphenhydramine. In addition, the selective H 2 receptor agonist amthamine mimicked the protection by histamine. This action was prevented by cimetidine but not by pyrilamine. 8‐Bromo‐cAMP also mimicked the effect of histamine. In contrast, both the adenylyl cyclase inhibitor 9‐(tetrahydro‐2‐furanyl)‐9H‐purine‐6‐amine and the cAMP‐dependent protein kinase inhibitor N ‐[2‐( p ‐bromocinnamylamino) ethyl]‐5‐isoquinolinesulfonamide reversed the protection by histamine. Thioperamide also attenuated NMDA‐induced excitotoxicity, which was reversed by the H 3 receptor agonist (R)‐α‐methylhistamine but not by pyrilamine and cimetidine. In addition, the protection by thioperamide was inhibited by the GABA A receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by thioperamide was due to increased GABA release in NMDA‐stimulated samples. These results indicate that not only the H 2 receptor/cAMP/cAMP‐dependent protein kinase pathway but also the H 3 receptor/GABA release pathway can attenuate NMDA‐induced neurotoxicity.