Memantine depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase C in rat cerebral cortex nerve terminals: an NMDA receptor-independent mechanism.
Memantine has been used to treat several neurological diseases, including those associated with excessive glutamate release. It has been believed that the neuroprotective effect of memantine results from its inhibitory effect on glutamate-induced neurotoxicity via postsynaptic N-methyl-d-aspartate receptor (NMDAR) antagonism. However, the presynaptic effect of memantine on glutamate release has never been examined. Therefore, the aim of this study was to investigate the effect of memantine on the release of glutamate from rat cerebral cortex nerve terminals (synaptosomes). Results showed that memantine inhibited the release of glutamate evoked by 4-aminopyridine (4-AP) in a concentration-dependent manner. The effect of memantine on the evoked glutamate release was insensitive to the NMDAR antagonist D-AP5, but prevented by the chelating intrasynaptosomal Ca2+ ions, and by the vesicular transporter inhibitor bafilomycin A1. In addition, memantine reduced depolarization-induced increase in cytosolic Ca2+ without any effect on synaptosomal excitability, and the reduction of glutamate release could be prevented by blocking the N and P/Q type Ca2+ channels. Furthermore, the memantine-mediated inhibition on 4-AP-evoked glutamate release could be diminished by the protein kinase C (PKC) inhibitors, and memantine significantly reduced the depolarization-induced phosphorylation of PKC, and PKCalpha. Thus, the effect of memantine on evoked glutamate release is linked to a decrease in [Ca2+]i contributed by Ca2+ entry through presynaptic voltage-dependent Ca2+ channels and to the subsequent suppression of the PKC signaling cascade.
Lu
Cheng-Wei
CW
Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao, Taipei County, 220, Taiwan.
Lin
Tzu-Yu
TY
Wang
Su-Jane
SJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D015761:4-Aminopyridine; D011493:Protein Kinase C; D008559:Memantine