T-477, a novel Ca(2+)- and Na(+) channel blocker, prevents veratridine-induced neuronal injury.
To evaluate the effect of (R)-(+)-2-(4-chlorophenyl)-2, 3-dihydro-4-diethyl aminoacetyl-4H-1,4-benzothiazine hydrochloride (T-477), a novel Na(+)- and Ca(2+) channel blocker, on neuronal injury in vitro, we studied veratridine-induced injury in cultured rat hippocampal neurons. Neurons swelled extensively 10 min after the addition of veratridine, and returned to their initial size within 2 h. Intracellular Na(+) and Ca(2+) concentrations and amino acid release from the cells, in particular, that of glutamate, increased after the treatment with veratridine. Approximately 70% of neurons died within 24 h. T-477 inhibited both veratridine-induced swelling and death in a concentration-dependent manner. Moreover, T-477 concentration dependently reduced the increases in Na(+) and Ca(2+) influx and amino acid release. These results suggest that T-477 prevented the veratridine-induced influx of Na(+) and, thereby, reduced neuronal swelling. This, combined with the effects of T-477 on the inhibition of Ca(2+) influx and glutamate release, possibly by the blockade of Na(+) channels, may be the mechanism by which T-477 protects neurons from death induced by veratridine.
Okuyama
K
K
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda-shi, Saitama, 335-8505, Japan.
Kiuchi
S
S
Okamoto
M
M
Narita
H
H
Kudo
Y
Y
D000596:Amino Acids / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013843:Thiazines / Q000494:pharmacology*; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology*
D000596:Amino Acids; D002121:Calcium Channel Blockers; C108900:T 477; D013843:Thiazines; D013779:Tetrodotoxin; D014701:Veratridine; D012964:Sodium; D002118:Calcium