cyclic-gmp and domoic-acid

Nefopam hydrochloride is a potent non sedative benzoxazocine analgesic that possesses a profile distinct from that of anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanism remains unclear. We have investigated the actions of nefopam on voltage sensitive calcium channels and calcium-mediated pathways. We found that nefopam prevented N-methyl-D-aspartate (NMDA)-mediated excitotoxicity following stimulation of L-type voltage sensitive calcium channels by the specific agonist BayK8644. Nefopam protection was concentration-dependent. 47 muM nefopam provided 50% protection while full neuroprotection was achieved at 100 muM nefopam. Neuroprotection was associated with a 73% reduction in the BayK8644-induced increase in intracellular calcium concentration. Nefopam also inhibited intracellular cGMP formation following BayK8644 in a concentration-dependent manner, 100 muM nefopam providing full inhibition of cGMP synthesis and 58 muM allowing 50% cGMP formation. Nefopam reduced NMDA receptor-mediated cGMP formation resulting from the release of glutamate following activation of channels by BayK8644. Finally, we also showed that nefopam effectively reduced cGMP formation following stimulation of cultures with domoic acid, while not providing neuroprotection against domoic acid. Thus, the novel action of nefopam we report here may be important both for its central analgesic effects and for its potential therapeutic use in neurological and neuropsychiatric disorders involving an excessive glutamate release.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Analgesics, Non-Narcotic; Animals; Calcium; Calcium Channel Agonists; Calcium Channels; Calcium Signaling; Cells, Cultured; Cyclic GMP; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Kainic Acid; N-Methylaspartate; Nefopam; Neuromuscular Depolarizing Agents; Neurons; Neurotoxins; Rats; Receptors, N-Methyl-D-Aspartate

We have investigated the ability of bFGF to protect cerebellar neurons from neurotoxicity by excitatory amino acids. We have found that preincubation with 1-2.5 nM bFGF for 1-6 days significantly protected neurons from excitotoxic damage via NMDA receptors as well as ionotropic non-NMDA receptors. bFGF neuroprotection appeared not to be dependent upon neuronal differentiation and was not mimicked by other neurotrophins including BDNF, NT-3 and NGF. A greater rise in extracellular calcium-dependent cGMP formation, following either depolarization or excitatory amino acid receptor activation was observed in bFGF-pretreated neurons. We suggest that neuroprotection from excitotoxicity following bFGF treatment may be associated to the modulation of neurochemical pathways dependent upon extracellular calcium influx.

Topics: Animals; Calcium; Cell Differentiation; Cell Survival; Cells, Cultured; Cerebellum; Cyclic GMP; Fibroblast Growth Factor 2; Glutamates; Glutamic Acid; Kainic Acid; Neurons; Rats; Receptors, N-Methyl-D-Aspartate