Neuroprotective And Neurorestorative Signaling Mechanisms

我们已经确定了几种生长因子和细胞因子，它们可以在阿尔茨海默病、帕金森氏病和中风的实验模型中保护神经元免受功能障碍和死亡的影响。这些营养因子激活信号通路，刺激基因的表达，这些基因的编码蛋白增加了神经元对氧化和代谢应激的抵抗力。脑源性神经营养因子的神经保护作用。我们发现，在帕金森病和亨廷顿病的动物模型中，脑源性神经营养因子(BDNF)是限制饮食所产生的神经保护作用的关键介质。在其他研究中，我们发现，在帕金森氏病的非人类灵长类动物模型中，热量限制减少了对多巴胺能神经元的损害，并改善了功能结果。CR的有益效果与BDNF和胶质细胞系衍生神经营养因子(GDNF)的数量增加有关，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，我们发现抗抑郁剂帕罗西汀通过增加脑源性神经营养因子的产生来抑制神经元变性，改善运动功能，提高小鼠的存活率。此外，我们还发现GLP-1(胰升糖素样肽1)是一种神经保护性多肽，在某些神经退行性疾病中具有改善神经元功能障碍和变性的潜力。最近，我们展示了线粒体解偶联蛋白UCP4的神经保护作用，它通过降低氧化应激水平发挥作用。在饮食限制和BDNF治疗下，UCP4的表达增加，提示UCP4在饮食限制和神经营养因子的神经保护作用中发挥作用。在临床前研究中，我们开发了尿酸和组氨酸的新类似物，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伽马分泌酶抑制剂可以通过抑制补体级联反应来改善小鼠中风后的预后。此外，我们还开发了高通量筛选，以识别激活适应性细胞应激反应途径的化学物质，并从这些筛选中涌现出几种新型神经保护剂。此外，我们还证明了exendin-4，一种用于治疗糖尿病的GLP-1类似物，能够改善中风、亨廷顿病和阿尔茨海默病动物模型的神经功能缺陷。

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. Moreover, we have demonstrated the ability of exendin-4, a GLP-1 analog used to treat diabetes, to ameliorate neurological deficits in animal models of stroke, Huntington's disease and Alzheimer's disease.