Anti-apoptotic effect of memantine against staurosporine- and low-potassium-induced cell death in cerebellar granule cells: a development-dependent effect

Abstract

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, 0.5μM) or by decreasing the level of potassium in the culture medium (LP, 5mM 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 (0.1–2μM) 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 (100μM) and an uncompetitive antagonist such as MK-801, (1μM). 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.