Fangchinoline inhibits glutamate release from rat cerebral cortex nerve terminals (synaptosomes).
Fangchinoline, an active component of radix stephaniae tetrandrinea, has been shown to possess neuroprotective properties. It has been reported that excessive glutamate release has been proposed to be involved in the pathogenesis of several neurological diseases. The primary purpose of the present study was to investigate the effect of fangchinoline on glutamate release in rat cerebral cortex nerve terminals and to explore the possible mechanism. Fangchinoline inhibited the release of glutamate evoked by 4-aminopyridine (4-AP) in a concentration-dependent manner, and this phenomenon resulted from a reduction of vesicular exocytosis but not from an inhibition of Ca(2+)-independent efflux via glutamate transporter. Fangchinoline did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization, but significantly reduced depolarization-induced increase in [Ca(2+)](C). Fangchinoline-mediated inhibition of glutamate release was significantly prevented by the N- and P/Q-type Ca(2+) channel blocker omega-conotoxin MVIIC, and by the PKC inhibitors, GF109203X and Ro318220. In addition, the glutamate release mediated by direct Ca(2+) entry with Ca(2+) ionophore (ionomycin) was unaffected by fangchinoline, which suggests that the inhibitory effect of fangchinoline is not due to directly interfering with the release process at some point subsequent to Ca(2+) influx. These results suggest that fangchinoline inhibits glutamate release from the rat cortical synaptosomes through the suppression of voltage-dependent Ca(2+) channel activity and subsequent reduces Ca(2+) entry into nerve terminals, rather than any upstream effect on nerve terminal excitability. This inhibition appears to involve the suppression of PKC signal transduction pathway. This finding may explain the neuroprotective effects of fangchinoline against neurotoxicity.
Lin
Tzu-Yu
TY
Department of Anesthesiology, Far Eastern Memorial Hospital, 21, Section 2, Nan-Ya south Road, Pan-Chiao, Taipei 220, Taiwan.
Lu
Cheng-Wei
CW
Tien
Lu-Tai
LT
Chuang
Shu-Han
SH
Wang
Yu-Ru
YR
Chang
Wen-Hsuan
WH
Wang
Su-Jane
SJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007476:Ionophores; D026902:Potassium Channel Blockers; D018698:Glutamic Acid; D015759:Ionomycin; C060802:fangchinoline; D015761:4-Aminopyridine; D011493:Protein Kinase C; D002118:Calcium