triprolidine and oxatomide

We previously reported that the histamine H1 receptor antagonist terfenadine enhances the excitotoxic response to N-methyl-D-aspartate (NMDA) receptor agonists in cerebellar neurons. Here we investigated whether this unexpected action of terfenadine relates to its antihistamine activity, and which specific events in the signal cascade coupled to NMDA receptors are affected by terfenadine. Low concentrations of NMDA (100 microM) or glutamate (15 microM) that were only slightly (<20%) toxic when added alone, caused extensive cell death in cultures pre-exposed to terfenadine (5 microM) for 5 h. Terfenadine potentiation of NMDA receptor response was mimicked by other H1 antagonists, including chlorpheniramine (25 microM), oxatomide (20 microM), and triprolidine (50 microM), was prevented by histamine (1 mM), and did not require RNA synthesis. Terfenadine increased NMDA-mediated intracellular calcium and cGMP synthesis by approximately 2.4 and 4 fold respectively. NMDA receptor-induced cell death in terfenadine-treated neurons was associated with a massive production of hydrogen peroxides, and was significantly inhibited by the application of either (+)-alpha-tocopherol (200 microM) or the endogenous antioxidant melatonin (200 microM) 15 min before or up to 30 min after receptor stimulation. This operational time window suggests that an enduring production of reactive oxygen species is critical for terfenadine-induced NMDA receptor-mediated neurodegeneration, and strengthens the importance of antioxidants for the treatment of excitotoxic injury. Our results also provide direct evidence for antihistamine drugs enhancing the transduction signaling activated by NMDA receptors in cerebellar neurons.

Topics: Animals; Biological Transport; Calcium; Cell Death; Cell Survival; Cells, Cultured; Cerebellum; Chlorpheniramine; Cyclic GMP; Dizocilpine Maleate; Drug Synergism; Glutamic Acid; Histamine; Histamine H1 Antagonists; N-Methylaspartate; Neurons; Piperazines; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Terfenadine; Triprolidine

For the immunopharmacological characterization of murine passive anaphylactic shock, the effects of antihistaminics and/or anti-platelet-activating factor (anti-PAF) agents were studied on the shock mediated by allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum. IgE antibody-mediated shock was strongly suppressed by cyproheptadine (10 mg/kg, ip) in every strain regardless of the age and sex of the mice and the presence or absence of a shock potentiator. As far as tested with CTS, DS, and B6D2F1 mice, IgE antibody-mediated shock was also suppressed by the other two antihistamines, triprolidine (10 mg/kg, ip) and oxatomide (100 mg/kg, po). This type of shock was not suppressed by an anti-PAF agent, CV-6209 (3.3 mg/kg, iv), when tested on aged CTS mice given no shock potentiator and young DS mice given a potentiator such as Bordetella pertussis organisms or DL-propranolol. IgG1 antibody-mediated shock was also suppressed by cyproheptadine in general except for CTS mice. Suppression in the DL-propranolol-treated DS and C3H/He mice was not very marked on sensitization with undiluted or slightly diluted IgG1 ascites but quite striking on sensitization with properly diluted ascites. In contrast with the effect of cyproheptadine, suppression by CV-6209 was obvious in aged CTS mice but not in young DL-propranolol-treated DS mice. The shock in DL-propranolol-treated DS mice sensitized with undiluted or slightly diluted ascites was completely abolished by the combined use of these two agents. These results suggest that histamine and/or PAF play a major role in IgE antibody- and IgG1 antibody-mediated shock. However, so far as tested in young DS mice, the shock mediated by hyperimmune serum differed in drug susceptibility from that mediated by the monoclonal antibodies. In the absence of shock potentiators, prevention was produced by cyproheptadine in the males which had been sensitized with the 1:4 or 1:8 dilution of the immune serum. In the presence of DL-propranolol, prevention was not produced even by the combined treatment with cyproheptadine and CV-6209. Therefore, it is likely that some mediators other than histamine and PAF, whose release is triggered by antibody isotypes other than IgE and IgG1, play a greater role for the shock mediated by hyperimmune serum than for the shock mediated by IgE or IgG1 antibody, especially in the presence of shock potentiators.

Topics: Anaphylaxis; Animals; Antibodies, Monoclonal; Cattle; Cyproheptadine; Female; Histamine H1 Antagonists; Immunoglobulin E; Immunoglobulin G; Immunosuppressive Agents; Isoantibodies; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Nude; Piperazines; Platelet Activating Factor; Propranolol; Pyridinium Compounds; Serum Albumin, Bovine; Triprolidine