Studies on neuronal apoptoisis in primary forebrain cultures: Neuroprotective/anti-apoptotic action of NR2B NMDA antagonists |
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Authors: | Email author" target="_blank">Jitendra?R?DaveEmail author Anthony?J?Williams John?R?Moffett Michael?L?Koenig Frank?C?Tortella |
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Institution: | (1) Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12 Street, 31-343 Krakow, Poland |
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Abstract: | While the role of apoptosis in neuronal injury is continually being re-defined, approaches to intervene in the progression of apoptotic injury have been documented to provide neuroprotection against a variety of insults. The present studies were undertaken to systematically study the effects of certain neuroprotective agents against neuronal apoptosis mediated by staurosporine (ST). ST (0.01-5 micro M) produced a dose-related apoptotic injury (as characterized by cellular morphology, 'Comet' assay analysis single cell gel electrophoresis] and caspase-3 activation) in primary cultures of forebrain neurons. ST significantly increased caspase-3 activity. The NMDA receptor subtype non-selective antagonist dizocilpine (+) MK-801; 0.1-50 micro M] and a novel sodium channel blocker RS100642 (1.0-250 micro M) had no significant effects against ST-induced neurotoxicity. Conversely, NR2B-selective NMDA receptor antagonists CGX-1007 (0.01-50 micro M) and ifenprodil (0.01-50 micro M) provided dose-dependent neuroprotection against ST-induced neurotoxicity (as measured by neuronal viability and comet assay analysis). CGX-1007 had no significant effect on ST-induced caspase-3 activity; however, ifenprodil did block activation of caspase-3. These studies demonstrate that NR2B NMDA receptor antagonists are anti-apoptotic and may mediate their action via mechanism(s) that are dependent or independent of caspase-3 activation. |
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