Neuroprotective And Neurorestorative Signaling Mechanisms

我们已经确定了几个生长因子和细胞因子，可以保护神经元功能障碍和死亡的实验模型阿尔茨海默氏症，帕金森氏症和中风。这些营养因子激活刺激基因表达的信号通路，所述基因编码的蛋白质增加神经元对氧化和代谢应激的抗性。 BDNF的神经保护作用我们发现脑源性神经营养因子（BDNF）是帕金森病和亨廷顿病动物模型中饮食限制的神经保护作用的关键介质。 在其他研究中，我们发现热量限制减少了对多巴胺能神经元的损伤，并改善了非人灵长类帕金森病模型的功能结果。 CR的有益效果与BDNF和胶质细胞源性神经营养因子（GDNF）的量增加有关，GDNF是一种生长因子，目前正在帕金森病患者的早期临床试验中。 在相关研究中，我们发现抗抑郁药帕罗西汀可以通过增加BDNF的产生来抑制亨廷顿病小鼠模型中的神经元变性并改善运动功能和存活率。 此外，我们已经确定GLP-1（胰高血糖素样肽1）作为一种神经保护性神经肽，具有改善某些神经退行性疾病中神经元功能障碍和变性的潜力。 最近，我们已经证明了线粒体解偶联蛋白UCP 4的神经保护作用，它通过降低氧化应激水平发挥作用。 UCP 4的表达增加，响应饮食限制和BDNF治疗，提示UCP 4在饮食限制和神经营养因子的神经保护作用中的作用。 在临床前研究中，我们已经开发了尿酸和组氨酸的新型类似物作为中风小鼠模型的神经保护剂。 我们还表明，静脉注射免疫球蛋白和γ-分泌酶抑制剂通过抑制补体级联反应的机制改善小鼠中风后的预后。 此外，我们还开发了高通量筛选，以确定激活适应性细胞应激反应途径的化学物质，并从这些筛选中产生了几种新型神经保护剂。

We have identified several growth factors and cytokines that can protect neurons against dysfunction and death in experimental models of Alzheimers disease, Parkinsons disease and stroke. These trophic factors activate signaling pathways that stimulate the expression of genes whose encoded proteins increase resistance of neurons to oxidative and metabolic stress. Neuroprotective Actions of BDNF. We have found that brain-derived neurotrophic factor (BDNF) is a key mediator of the neuroprotective effects of dietary restriction in animal models of Parkinsons and Huntingtons diseases. In other studies we have found that caloric restriction reduces damage to dopaminergic neurons and improves functional outcome in a non-human primate model of Parkinsons disease. The beneficial effect of CR is associated with increased amounts of BDNF and glial cell line-derived neurotrophic factor (GDNF), a growth factor which is now in early clinical trials in patients with Parkinsons disease. In related studies we have found that the antidepressant paroxetine can suppress neuronal degeneration and improve motor function and survival in a mouse model of Hungtingtons disease by a mechanism involving increased production of BDNF. In addition, we have identified GLP-1 (glucagon-like peptide 1) as a neuroprotective neuropeptide with the potential to ameliorate neuronal dysfunction and degeneration in some neurodegenerative conditions. More recently, we have demonstrated a neuroprotective role for the mitochondrial uncoupling protein UCP4, which acts by reducing levels of oxidative stress. UCP4 expression increases in response to dietary restriction and BDNF treatment, suggesting a role for UCP4 in the neuroprotective effects of dietary restriction and neurotrophic factors. In preclinical studies we have developed novel analogs of uric acid and histidine as neuroprotective agents in a mouse model of stroke. We have also shown that intravenous immunoglobulin and gamma-secretase inhibitors improve outcome following a stroke in mice, by a mechanism involving inhibition of the complement cascade. In addition, we have developed high throughput screens to identify chemicals that activate adaptive cellular stress response pathways, with several novel neuroprotective agents emerging from these screens.