Resveratrol, Mechanism of Neuroprotection

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Resveratrol has been suggested as potential preventive medicine, but the underlying cellular mechanisms are still unclear. Knowing that heme oxygenase (HO) also plays various roles in oxidative stress and inflammation, we have tested the hypothesis that heme oxygenase activity could participate in resveratrol neuroprotective function. Heme oxygenase cleaves heme (pro-oxidant) to form biliverdin/bilirubin (anti-oxidant), carbon monoxide (vasodilator), and iron (pro-oxidant). Using primary neuronal cultures, preliminary results reveal that resveratrol is one of the most potent inducers of HO1 within neurons. The results as well indicate that pre-treatment of neurons with resveratrol is sufficient to provide neuroprotection. All together, this implies that specific induction of HO1 could be a mechanism by which resveratrol exerts its neuroprotective actions. This work allows us to propose that some of the attributed neuroprotective effects of resveratrol against ischemic conditions could be mediated through induction of HO1 and the associated beneficial actions of heme degradation and its bioactive metabolites. We will determine the cerebral blood flow and stroke damage in resveratrol-treated wildtype (WT) mice and test whether these effects are decreased in HO1-/- mice. And, we will determine whether resveratrol induces changes in HO1 expression that result in changes in iron homeostasis and cell survival in neuronal cultures derived from these mice. To further address possible cellular mechanisms of action cultured neurons will be used to test their susceptibility to heme toxicity (HO substrate) after pre-treatment with resveratrol and also determine the iron efflux. We will test this new hypothesis that some of the beneficial effects attributed to resveratrol, such as increased cerebral blood flow and reduced ischemic damage, could be attributed to HO1 induction itself and its biological actions. These results will indicate for the first time whether preconditioning is sufficient to afford neuroprotection and whether the effect is modulated by heme oxygenase activity. It will suggest new pathways to explain this neuroprotective effect and how it could provide brain's resistance in acute (such as in ischemia) and chronic neurodegenerative debilitating conditions (such as age/vascular-related dementia and AD).