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 mu M) 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 mu M) 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, bill 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 mu M) and an uncompetitive antagonist such as MK-801, (1 mu M). 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.