Resveratrol, Mechanism of Neuroprotection

描述(申请人提供)：白藜芦醇已被建议作为潜在的预防药物，但其潜在的细胞机制仍不清楚。了解到血红素加氧酶(HO)在氧化应激和炎症中也发挥着不同的作用，我们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说。血红素加氧酶分解血红素(促氧化剂)，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)。利用原代神经元培养，初步结果显示，白藜芦醇是神经元内HO1最有效的诱导剂之一。结果还表明，用白藜芦醇对神经元进行预处理足以提供神经保护。总之，这意味着HO1的特异性诱导可能是白藜芦醇发挥神经保护作用的一种机制。这项工作允许我们提出，白藜芦醇对缺血条件的一些归属神经保护作用可能是通过诱导HO1和相关的血红素降解及其生物活性代谢物的有益作用来介导的。我们将确定白藜芦醇治疗野生型(WT)小鼠的脑血流和中风损伤，并测试HO1-/-小鼠是否减少了这些影响。并且，我们将确定白藜芦醇是否诱导HO1表达的变化，从而导致这些小鼠的神经元培养中铁稳态和细胞存活率的变化。为了进一步阐明可能的细胞作用机制，培养的神经元将被用来测试它们在白藜芦醇预处理后对血红素毒性(HO底物)的敏感性，并测定铁的外流。我们将检验这一新假设，即白藜芦醇的一些有益作用，如增加脑血流量和减少缺血损伤，可能归因于HO1诱导本身及其生物学作用。这些结果将首次表明，预适应是否足以提供神经保护，以及这种效果是否受血红素加氧酶活性的调节。它将提供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)和慢性神经退行性疾病(如年龄/血管相关痴呆和AD)中提供大脑抵抗。

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).