Eschemia

Energy Failure

Energy Failure

Glutamate Accumulation

I Kainate R~j

| Fast Excitotoxicity | | Slow Excitotoxicity |

FIGURE 4.1 Scheme of excitotoxic neuronal death in hypoxic-ischemic brain injury.

Glutamate Accumulation

I Kainate R~j

preceded with downregulation of GluR2 mRNA expression.72181 NADPH di-aphorase-containing neurons in the cortex and striatum express Ca2+-permeable AMPA receptors and can undergo degeneration following a brief (~10 min) exposure to AMPA.249 Single-cell RT-PCR analysis has demonstrated that striatal diaphorase-containing neurons reveal reduced ratio of GluR2/GluR1 and unedited expression of GluR2 mRNA.113 This altered expression of GluR2 results in Ca2+-dependent AMPA neurotoxicity that may underlie potential mechanisms for selective neuronal death following hypoxic-ischemic brain injury.

The GluR5-7 and KA1-2 proteins comprise the subunits for functional KA receptors permeable to Na+ and K+. Administration of kainate produces nondesensitiz-ing currents at AMPA receptors and fast desensitizing currents at kainate receptors. Like AMPA-mediated slow excitotoxicity, a prolonged (1 h>) exposure to kainate is needed to trigger neuronal death. Whereas it has been well documented that Ca2+ entry through NMDA or AMPA receptors mediates the fast excitotoxicity, it remains to be delineated how slow excitotoxicity is triggered and propagated. One possibility is that Na+ entry through AMPA or kainate receptors likely contributes to AMPA-or kainate-mediated slow excitotoxicity.

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