Antihistamine terfenadine potentiates NMDA receptor-mediated calcium influx, oxygen radical formation, and neuronal death

We previously reported that the histamine H1 receptor antagonist terfenadin e enhances the excitotoxic response to N-methyl-D-aspartate (NMDA) receptor agonists in cerebellar neurons. Here we investigated whether this unexpect ed action of terfenadine relates to its antihistamine activity, and which s pecific events in the signal cascade coupled to NMDA receptors are affected by terfenadine. Low concentrations of NMDA (100 muM) or glutamate (15 muM) that were only slightly (< 20%) toxic when added alone, caused extensive c ell death in cultures pre-exposed to terfenadine (5 <mu>M) for 5 h. Terfena dine potentiation of NMDA receptor response was mimicked by other H1 antago nists, including chlorpheniramine (25 muM), oxatomide (20 muM), and triprol idine (50 muM). was prevented by histamine (1 mM), and did not require RNA synthesis. Terfenadine increased NMDA-mediated intracellular calcium and cG MP synthesis by approximately 2.4 and 4 fold respectively. NMDA receptor-in duced cell death in terfenadine-treated neurons was associated with a massi ve production of hydrogen peroxides, and was significantly inhibited by the application of either (+)-alpha-tocopherol (200 muM) or the endogenous ant ioxidant melatonin (200 muM) 15 min before or up to 30 min after receptor s timulation. This operational time window suggests that an enduring producti on of reactive oxygen species is critical for terfenadine-induced NMDA rece ptor-mediated neurodegeneration, and strengthens the importance of antioxid ants for the treatment of excitotoxic injury. Our results also provide dire ct evidence for antihistamine drugs enhancing the transduction signaling ac tivated by NMDA receptors in cerebellar neurons. (C) 2000 Elsevier Science B.V. All rights reserved.