https://www.ncbi.nlm.nih.gov/pubmed/11462762 June 2001
Abstract
Perturbation
of normal survival mechanisms may play a role in a large number of
disease processes. Glutamate neurotoxicity, particularly when mediated
by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, has
been hypothesized to underlie several types of acute brain injury,
including stroke. Several neurological insults linked to excessive
release of glutamate and neuronal death result in tyrosine kinase
activation, including p44/42 mitogen activated protein (MAP) kinase. To
further explore a role for MAP kinase activation in excitotoxicity, we
used a novel tissue culture model to induce neurotoxicity. Removal of
the endogenous blockade by Mg2+ of the NMDA receptor in cultured
hippocampal neurons triggers a self perpetuating cycle of
excitotoxicity, which has relatively slow onset, and is critically
dependent on NMDA receptors and activation of voltage gated Na+
channels. These injury conditions led to a rapid phosphorylation of
p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK
inhibition was associated with protection against synaptically mediated
excitotoxicity. Interestingly, hippocampal neurons preconditioned by a
sublethal exposure to Mg(2+)-free conditions were rendered resistant to
injury induced by a subsequently longer exposure to this insult; the
preconditioning effect was MAP kinase dependent. The MAP kinase
signaling pathway can also promote polypeptide growth factor mediated
neuronal survival. MAP kinase regulated pathways may act to promote
survival or death, depending upon the cellular context in which they are
activated.
- PMID:
- 11462762
- [Indexed for MEDLINE]
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