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Studies on neuronal apoptoisis in primary forebrain cultures: Neuroprotective/anti-apoptotic action of NR2B NMDA antagonists

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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 μM) 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 μM) and a novel sodium channel blocker RS100642 (1.0–250 μM) had no significant effects against ST-induced neurotoxicity. Conversely, NR2B-selective NMDA receptor antagonists CGX-1007 (0.01–50 μM) and ifenprodil (0.01–50 μM) 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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Authors and Affiliations

  1. Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Rearch, 20910-7500, Silver Spring, MD, USA

    Jitendra R. Dave, Anthony J. Williams, John R. Moffett & Frank C. Tortella

  2. Department of Neuroendocrinology/Neurochemistry, Division of Neurosciences, Walter Reed Army Institute of Research, 20910-7500, Silver Spring, MD, USA

    Michael L. Koenig

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  1. Jitendra R. Dave
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  2. Anthony J. Williams
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  3. John R. Moffett
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  4. Michael L. Koenig
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  5. Frank C. Tortella
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Correspondence to Jitendra R. Dave.

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Dave, J.R., Williams, A.J., Moffett, J.R. et al. Studies on neuronal apoptoisis in primary forebrain cultures: Neuroprotective/anti-apoptotic action of NR2B NMDA antagonists. neurotox res 5, 255–264 (2003). https://doi.org/10.1007/BF03033383

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