Novel effect of nefopam preventing cGMP increase, oxygen radical formation and neuronal death induced by veratridine

• Published in: Neuropharmacology Vol. 41; no. 8; pp. 935 - 942
• Main Authors: Fernández-Sánchez, M.Teresa, Dı́az-Trelles, Ramón, Groppetti, Antonio, Manfredi, Barbara, Brini, Anna T, Biella, Gabriele, Sotgiu, Maria Luisa, Novelli, Antonello
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2001; Elsevier
• Subjects: Analgesics, Non-Narcotic - pharmacology; Animals; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - physiology; Cultured cerebellar neurons; Cyclic GMP - antagonists & inhibitors; Cyclic GMP - biosynthesis; Dose-Response Relationship, Drug; Excitotoxicity; Glutamate release; Medical sciences; Nefopam; Nefopam - pharmacology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Rats; Reactive oxygen species; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Sodium channels; Veratridine - pharmacology; Sodium channels; Glutamate release; Reactive oxygen species; Cultured cerebellar neurons; Nefopam; Excitotoxicity; Cerebellum; Rat; Toxicity; Central nervous system; Glutamate receptor; Ionic channel; Free radical; Prevention; Sodium ion; Mechanism of action; Nervous system diseases; Rodentia; 3',5'-GMP; Neuroprotective agent; Glutamate; In vitro; Biological activity; Cerebral disorder; Vertebrata; Chemotherapy; Mammalia; Analgesic; Cell death; Animal; Central nervous system disease; Excitatory aminoacid; NMDA receptor; Brain (vertebrata)
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(01)00139-3

Nefopam hydrochloride is a potent analgesic compound that possesses a profile distinct from that of opiods or anti-inflammatory drugs. Previous evidence suggested a central action of nefopam but the detailed mechanisms remain unclear. Here we have used cultured cerebellar neurons to test the hypothesis that nefopam may modulate voltage sensitive sodium channel (VSSC) activity. Nefopam (100 μM) effectively prevented NMDA receptor-mediated early appearance (30 min) of toxicity signs induced by the VSSC activator veratridine. Delayed neurotoxicity by veratridine occurring independently from NMDA receptor activation, was also prevented by nefopam. In contrast, excitotoxicity following direct exposure of neurons to glutamate was not affected. Neuroprotection by nefopam was dose-dependent. 50% protection was obtained at 57 μM while full neuroprotection was achieved at 75 μM nefopam. Veratridine-induced sodium influx was completely abolished in nefopam-treated neurons. Intracellular cGMP and oxygen radical formation following VSSC stimulation by veratridine were also effectively prevented by nefopam. Our data are consistent with an inhibitory action of nefopam on VSSC and suggest that nefopam may modulate the release of endogenous glutamate following activation of these channels. This novel action of nefopam may be of great interest for the treatment of neurodegenerative disorders involving excessive glutamate release and neurotransmission.