Neuroprotective And Neurorestorative Signaling Mechanisms

我们已经在阿尔茨海默病、帕金森病和中风的实验模型中发现了几种可以保护神经元免受功能障碍和死亡的生长因子和细胞因子。这些营养因子激活信号通路，刺激基因的表达，这些基因编码的蛋白质增加神经元对氧化和代谢应激的抵抗力。BDNF的神经保护作用。我们发现脑源性神经营养因子（BDNF）是饮食限制对帕金森病和亨廷顿病动物模型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多巴胺能神经元的损伤，并改善了帕金森病的非人类灵长类动物模型的功能结果。CR的有益作用与BDNF和胶质细胞系衍生神经营养因子（GDNF）的增加有关，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的神经元变性，改善运动功能和生存率。此外，我们已经确定GLP-1（胰高血糖素样肽1）是一种神经保护神经肽，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UCP4的神经保护作用，它通过降低氧化应激水平起作用。UCP4在饮食限制和BDNF治疗后表达增加，提示UCP4在饮食限制和神经营养因子的神经保护作用中起作用。在临床前研究中，我们开发了尿酸和组氨酸作为中风小鼠模型神经保护剂的新型类似物。我们还表明，静脉注射免疫球蛋白和γ分泌酶抑制剂可以通过抑制补体级联的机制改善小鼠中风后的预后。此外，我们已经开发了高通量筛选来识别激活适应性细胞应激反应途径的化学物质，从这些筛选中出现了几种新的神经保护剂。此外，我们已经证明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、帕金森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, Parkinson's disease and Alzheimer's disease.