The attenuating effect of memantine on staurosporine-, salsolinol- and doxorubicin-induced apoptosis in human neuroblastoma SH-SY5Y cells.
Memantine, a clinically used N-methyl-D-aspartate (NMDA)-receptor antagonist, has been shown to prevent apoptotic neuronal damage connected with the over-activity of NMDA receptors. In the present study, we examined the effect of memantine on staurosporine-, salsolinol- and doxorubicin-induced apoptosis in the SH-SY5Y cell line which does not possess functional NMDA receptors. Electrophysiological recordings and toxicity studies showed no response to NMDA-evoked currents in this cell line, irrespective of the stage of its neuronal differentiation. Memantine (0.1-2 microM) attenuated staurosporine-induced apoptosis as evidenced by reversal of the changes in mitochondrial membrane potential (DeltaPsi(m)) and decreased caspase-3 activity, lactate dehydrogenase (LDH) release and DNA fragmentation. Wortmannin (10 nM) and LY 294002 (10 microM) (inhibitors of phosphatidylinositol-3-kinase, PI3-K) reversed the inhibitory effect of memantine on the staurosporine-induced LDH release, suggesting that the PI3-K/Akt prosurvival pathway is a possible target for antiapoptotic action of memantine. Memantine at low micromolar concentrations also attenuated salsolinol- and doxorubicin-induced LDH release and DNA fragmentation, but only in the case of salsolinol was this effect accompanied by a decrease in caspase-3 activity. The present data indicate that memantine attenuates the toxic effects of various proapoptotic agents and the cytoprotective effect of memantine does not seem to be connected with its action on NMDA receptor but rather with its influence on intracellular pathways engaged in cellular survival/apoptotic processes.
Jantas
D
D
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland. jantas@if-pan.krakow.pl
Pytel
M
M
Mozrzymas
J W
JW
Leskiewicz
M
M
Regulska
M
M
Antkiewicz-Michaluk
L
L
Lason
W
W
D000730:Androstadienes / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008559:Memantine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000633:toxicity; D018408:Patch-Clamp Techniques; D019311:Staurosporine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D014212:Tretinoin / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D000903:Antibiotics, Antineoplastic; D002867:Chromones; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D007546:Isoquinolines; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014212:Tretinoin; D016202:N-Methylaspartate; D004317:Doxorubicin; C036617:salsolinol; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D019311:Staurosporine; D008559:Memantine; D000077191:Wortmannin