Resveratrol, Mechanism of Neuroprotection

描述（由申请人提供）：白藜芦醇已被认为是潜在的预防药物，但潜在的细胞机制仍不清楚。已知血红素加氧酶（HO）在氧化应激和炎症中也起着各种作用，我们已经验证了血红素加氧酶活性可能参与白藜芦醇神经保护功能的假设。血红素加氧酶切割血红素（促氧化剂）以形成胆绿素/胆红素（抗氧化剂）、一氧化碳（血管扩张剂）和铁（促氧化剂）。使用原代神经元培养物，初步结果显示，白藜芦醇是神经元内HO 1最有效的诱导剂之一。结果还表明，用白藜芦醇预处理神经元足以提供神经保护。总之，这意味着HO 1的特异性诱导可能是白藜芦醇发挥其神经保护作用的机制。这项工作使我们能够提出，白藜芦醇对缺血性疾病的一些归因的神经保护作用可以通过诱导HO 1以及血红素降解及其生物活性代谢物的相关有益作用来介导。我们将确定白藜芦醇治疗的野生型（WT）小鼠的脑血流量和中风损伤，并测试这些影响是否在HO 1-/-小鼠中降低。并且，我们将确定白藜芦醇是否诱导HO 1表达的变化，从而导致来自这些小鼠的神经元培养物中铁稳态和细胞存活的变化。为了进一步解决可能的细胞作用机制，培养的神经元将用于测试它们在用白藜芦醇预处理后对血红素毒性（HO底物）的易感性，并且还确定铁流出。我们将测试这一新的假设，即白藜芦醇的一些有益作用，如增加脑血流量和减少缺血性损伤，可能归因于HO 1诱导本身及其生物学作用。这些结果将首次表明预处理是否足以提供神经保护，以及这种作用是否受到血红素加氧酶活性的调节。它将提出新的途径来解释这种神经保护作用，以及它如何在急性（如缺血）和慢性神经退行性衰弱疾病（如年龄/血管相关性痴呆和AD）中提供大脑的抵抗力。

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).