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Combined mechanical trauma and metabolic impairment in vitro induces NMDA receptor-dependent neuronal cell death and caspase-3-dependent apoptosis

J. W. ALLEN^*,, S. M. KNOBLACH^* and A. I. FADEN^*,1

^* Institute for Cognitive and Computational Sciences,
Interdisciplinary Program in Neuroscience, and
Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA

¹Correspondence: EP-04 Research Building, 3970 Reservoir Road, N.W., Washington, D.C. 20007, USA. E-mail: fadena{at}giccs.georgetown.edu

Neuronal necrosis and apoptosis occur after traumatic brain injury (TBI) in animals and contribute to subsequent neurological deficits. In contrast, relatively little apoptosis is found after mechanical injury in vitro. Because in vivo trauma models and clinical head injury have associated cerebral ischemia and/or metabolic impairment, we transiently impaired cellular metabolism after mechanical trauma of neuronal-glial cultures by combining 3-nitropropionic acid treatment with concurrent glucose deprivation. This produced greater neuronal cell death than mechanical trauma alone. Such injury was attenuated by the NMDA receptor antagonist dizocilpine (MK801). In addition, this injury significantly increased the number of apoptotic cells over that accruing from mechanical injury alone. This apoptotic cell death was accompanied by DNA fragmentation, attenuated by cycloheximide, and associated with an increase in caspase-3-like but not caspase-1-like activity. Cell death was reduced by the pan-caspase inhibitor BAF or the caspase-3 selective inhibitor z-DEVD-fmk, whereas the caspase-1 selective inhibitor z-YVAD-fmk had no effect; z-DEVD-fmk also reduced the number of apoptotic cells after combined injury. Moreover, cotreatment with MK801 and BAF resulted in greater neuroprotection than either drug alone. Thus, in vitro trauma with concurrent metabolic inhibition parallels in vivo TBI, showing both NMDA-sensitive necrosis and caspase-3-dependent apoptosis.—Allen, J. W., Knoblach, S. M., Faden, A. I. Combined mechanical trauma and metabolic impairment in vitro induces NMDA receptor-dependent neuronal cell death and caspase-3-dependent apoptosis.

Key Words: neuronal injury • ischemia • caspases • 3-nitropropionic acid

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