Anti-apoptotic effect of memantine against staurosporine- and low-potassium-induced cell death in cerebellar granule cells: a development-dependent effect.
Memantine, a NMDA receptor antagonist used in several experimental models of neuronal cell injury, is a neuroprotective agent that can attenuate neuronal apoptosis connected with over-stimulation of NMDA receptors. In the present study, we evaluated the impact of memantine on apoptosis in primary cerebellar granule cell (CGC) cultures at 7 and 12 day in vitro (DIV). Cell death was induced by staurosporine (St, 0.5 microM) or by decreasing the level of potassium in the culture medium (LP, 5 mM KCl). Both treatments induced cell death in CGC with higher cell-damaging effects at 12 DIV and 7 DIV neurons for St and LP, respectively. Memantine (0.1-2 microM) partially attenuated St-induced apoptosis only in 7 DIV CGC as assessed by DNA fragmentation and LDH release, but not caspase-3 activity. During LP-induced apoptosis, memantine decreased LDH release and DNA fragmentation, but not affected caspase-3 activity in 7 and 12 DIV CGC. Interestingly, we found no beneficial effects of other NMDA antagonists, including a competitive antagonist such as AP-5 (100 microM) and an uncompetitive antagonist such as MK-801, (1 microM). In conclusion, our data suggest that the anti-apoptotic effects of memantine in CGC are developmentally regulated and its neuroprotective action occurs through an NMDAR-independent mechanism.
Jantas
Danuta
D
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. jantas@if-pan.krakow.pl
Lasoń
Władysław
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000633:toxicity; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D019311:Staurosporine; D011188:Potassium; D008559:Memantine