Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment

Excitotoxic stress is potentially an important component of disorders such as stroke and neurodegenerative diseases. Its toxic effects appear to be tr ansduced through mechanisms that result in both acute and delayed forms of death. We examined here whether cyclin dependent kinases (CDKs), molecules normally associated with cell cycle control, may be involved in delayed exc itotoxic death in two different excitotoxin models. We show that nuclear lo calized cyclin D1, an activator of Cdk4/6, is upregulated during kainic aci d evoked death of CA3/CA1 neurons and that this upregulation is associated with increased phosphorylation of a critical CDK substrate, pRb. In additio n, we find that the CDK inhibitor, flavopiridol blocks the delayed death of cultured cortical neurons evoked by 3-nitroproprionic acid, an inhibitor o f the mitochondrial electron transport chain, treatment and that the NMDA a ntagonist, MK801 provides short term protection in this model. Full. long-t erm protection occurs when both flavopiridol and MK-801 are present. Taken together, these data support a role for cell cycle regulators in neuronal d eath evoked by excitotoxic stress and indicate a potential therapeutic targ et for treatment of excitotoxicity-related disorders. (C) 2000 Elsevier Sci ence Inc. All rights reserved.