Induction of heme oxygenase-1 with hemin attenuates hippocampal injury in rats after acute carbon monoxide poisoning.

Carbon monoxide (CO) poisoning is a major cause of brain injury and mortality; delayed neurological syndrome (DNS) is encountered in survivors of acute CO exposure. The toxic effects of CO have been attributed to oxidative stress induced by hypoxia. Heme oxygenase-1 (HO-1) is the inducible heme oxygenase isoform, and its induction acts as an important cellular defense mechanism against oxidative stress, cellular injury and disease. In this study, we examined the functional roles of HO-1 induction in a rat model of CO-exposured hippocampal injury. We report that acute CO exposure produces severe hippocampal injury in rats. However, hemin pretreatment reduced both the CO-induced rise in hippocampal water content and levels of neuronal damage in the hippocampus; survival rates at 24 h were significantly improved. Upregulation of HO-1 by hemin pretreatment resulted in a significant decrease in hippocampal levels of malondialdehyde (MDA), a marker of oxidative stress; levels of pro-apoptotic caspase-3 were also reduced. In contrast, inhibition of HO activity by administration of tin protoporphyrin IX (SnPP, a specific inhibitor of HO) abolished the neuroprotective effects of HO-1 induction. These data suggested that the upregulation of endogenous HO-1 expression therefore plays a pivotal protective role in CO neurotoxicity. Though the precise mechanisms underlying hemin-mediated HO-1 induction and neuroprotection are not known, these may involve the anti-oxidant and anti-apoptotic effects of HO-1 enzyme activity.