在帕金森病病理模型中蛇床子素的神经保护作用机制研究

Parkinson's disease(PD)is a progressive neurodegenerative disease that is defined by pathological features including selective loss of dopaminergic neurons insubstantia nigra pars compacta and a subsequent decrease of dopamine levels in the striatum, which is the main target that is innervated by these neurons. PD is the second most common neurodegenerative disorder after Alzheimer's disease and primarily affects people of middle age and older. Although the etiopathogenesis of PD remains to be elucidated,the evidence strongly suggests that the disease is related to mitochondrial dysfunction, oxidative stress and inflammatory reaction. Oxidative stress and/or mitochondrial impairment are believed to culminate as the activation of an apoptotic cascade, which ultimately results in the loss of dopaminergic cells. Osthole, which is extracted from Cnidium monnieri and has been reported by world-wild researchers to have various pharmacological properties including anti-allergic, anti-inflammatory and anti-oxidative effects. Our prior works has showed that osthole is able to eliminate oxygen free radicals, inhibit mitochondrial dysfunction and ROS production in PC12 cells toxicity induced by the parkinsonian mimetic MPP+. Beside of this, we also confirmed that osthole had neuroprotective effect against ischemic injury in vitro, and the protection possibly was associated with prolonged activation of ERK1/2 and suppression of JNK activity. We hypothesized that osthole might exert neuroprotective effects as a natural antioxidants that can protect cells from oxidative damage by regulating ASK1-P38-MAPK pathway, and regulating IP3R calcium ion channels and chronic inflammation reactions when the neurons are damaged, but a further animal research followed by a serious of functional test as well as mechanism research of how it works need to be done. In this study,we plan to evaluate the protective effect of osthole in models of Parkinson's disease and put our focus on the mechanism. We think that this work will make our knowledge of neuroprotective potential of natural substances to move forward steps, and may be going to bring a new agent for the clinical practice of curing Parkinson's disease.

帕金森病（PD）是一种常见的神经元线粒体损伤为核心反应的退行性疾病，目前尚无有效治疗手段。蛇床子素是一种香豆素类化合物，近期研究表明它可调节细胞内钙通道，并具有抗炎作用。我们前期研究发现：在帕金森病细胞模型中，蛇床子素预处理可明显减少细胞的凋亡率，提高细胞活性，降低MPP+诱导产生的活性氧自由基的含量和Caspase3蛋白的活性，并在氧糖剥夺模型中对JNK有抑制作用，可能针对ASK1-P38 MAPK分子通路引起的线粒体损害和慢性炎症反应引起的神经元损害有抑制作用，并参与慢性损伤时神经细胞内IP3R钙通道的调节，但其具体的分子机制需要进一步实验证实。本课题是既往工作的延续，拟在帕金森病细胞模型和动物模型的基础上，以蛇床子素对受损神经元细胞所产生的保护作用及其分子机制为研究对象，探讨蛇床子素对帕金森病的神经保护作用和具体分子机制，有望为临床治疗或预防帕金森病提供新的治疗手段。