In a previous study, we demonstrated that neural damage following middle cerebral artery occlusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2-/- animals. These findings implicate HO as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.

Stroke damage following blood vessel occlusion and reperfusion involves a variety of mechanisms. One component derives from the formation of oxygen-free radicals by hypoxic mitochondria. Hypoxia also triggers a massive release of glutamate, which causes neurotoxicity via stimulation of glutamate receptors, especially the NMDA subtype. We sought to ascertain which mechanisms of stroke damage might be reversed by HO activation and hence contribute to augmented stroke damage in HO2-/- animals. Neurotoxicity can be elicited by direct injections of NMDA into the brain, and we observed substantial neural damage following NMDA injections into the cerebral cortex. The extent of this damage is increased three- to four-fold in HO2-/- mice. Thus, it appears that physiologic HO2 activity is neuroprotective against glutamate excitotoxicity that involves NMDA receptor activation.

Selected References

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