MINOCYCLINE AND CREATINE IN SUBJECTS WITH EARLY UNTREATED PARKINSON'S DISEASE

米诺环素和肌酸在早期未经治疗的帕金森病患者中的应用

• 批准号: 7379100
• 负责人: JOANNE M WOJCIESZEK
• 金额: $ 0.12万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379100
• 关键词: MINOCYCLINE; CREATINE; SUBJECTS; EARLY; UNTREATED

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major goal of the neuroscience community is to develop neuroprotective treatment strategies that will slow or forestall the progression of chronic neurodegenerative disease. Parkinson's disease ((PD) is one of the most common adult-onset neurodegenerative disorders, affecting approximately 1 million people in North America that is characterized chronically by tremor, rigidity, bradykinesia and postural instability. The clinical features of PD usually emerge in mid to late adulthood with tremor and bradykinesia being the most obvious initial manifestations. Illness and disability progressively advance despite treatments that temporarily ameliorate the signs and symptoms of PD. Many patients have deterioration in cognitive performance and disorders mood and behavior in addition to the progressive impairment of motor function. Eventually PD leads to profound functional disability in the areas of employability, ambulation and self-care. Although the advent of levodpa therapy has been associated with a prolongation of survival in RD, there is still substantial functional disability associated with advancing PD {Hoehn et al. 1976; Uitti, et al. 1993; Diamond, et al., 1987; Rajput, et al., 1984; Clarke, et al., 1995}. No treatment has been definitively identified to slow the progression of PD. Current dopaminergic therapies in PD are symptomatic (relieve signs and symptoms), but there are both short-term (motor fluctuations) and long-term (possible hastening of disease progression) concerns about these medications that warrant a reassessment of therapeutic strategies. The pathology of PD is characterized by the loss of pigmented neurons in the brainstem, particularly dopaminergic neurons in the substantia nigra pars compacta and neuroadenergic neurons in the locus ceruleus. The loss of nigral neurons is associated with the presence of intracytoplasimic eosinophilic inclusions (Lewy bodies). The cause of neuronal dysfunction and death, and the nature of intracytoplasmic inclusions remain largely obscure, although the latter are consistently immunostained with antibodies to alpha-synuclein and ubiquitin.These neuropathologic changes are associated with neurochemical abnormalities including diminished striatal levels of dopamine and its metabolites. Although the pathogenesis of PD has not been fully elucidated, there are important clues as to potential mechanisms. The identification of a large familial cluster of PF with a mutation in the alpha synuclein and ubiquitin. These neuropathologic changes are associated with neuropathologic changes are associated with neurochemical abnormalities including diminished striatal levels of dopamine and its metabolites. Although the pathogenesis of PD has not been fully elucidated, there are important clues as to potential mechanisms. The identification of a large familial cluster of PD with a mutation in the alpha-synuclein gene [Polymeropoulos, et al., 1997], the identification of mutations in the parkingene [Kitada, et al., 2998] and evidence for familiar aggregation of PD in Iceland are epidemiologic studies [Gorell, et al., 2998; Seidler, et al., 1996] suggesting that environmental factors may contribute to the development of PD. Currently the relative contribution and importance of these factors are unknown. Based on accumulated observations in animal models, there appear to be several classes of agents that may be useful as neuroprotective strategies. These classes include NOS inhibitors, anti-apoptotic agents such as JNK inhibitors and potentially MAP-B inhibitors (via the mechanism of bcl-2 upregulation), neuroimmunophilin compounds, glutamate antagonists (including amantadine and riluzole), D2 receptor agonists including pramipexole antioxidant agents including Coenzyme Q10 and acetyl-levo-carnitine, and anti-inflammatory agents including sodium salicylate, acetylsalicylic acid and cyclo-oxygenase 2 inhibitors. In addition to having demonstrated efficacy in preclinical models of PD, several of these compounds have been tested in humans, including dosage ranging tolerability studies. The impact of inhibitors on disease progression has also been reported. Minocycline is a semisynthetic second-generation tetracycline antibiotic that has neuroprotective properties that are distinct from its anti-microbial action. Minocycline is FDA approved for the treatment of a variety of infections including brain and meningeal infections and has been well tolerated when used chronically for diverse conditions such as acne and rheumatoid arthritis. Minocycline is highly lipid soluble and has been shown to have good brain penetration and bioavailability (Saivin 1988). The toxicities of Minocycline are similar to other tetracyclines and it is contraindicated in pregnancy and during childhood. Minocycline is protective in a broad range of models of CNS injury and degeneration including MPTP and 6 hydroxydopamine models of PD (Wu, et al., 2002) and excitotoxicity (Tikka, et al., 2001). With respect to PD, the main actions of Minocycline are twofold: its ability to inhibit microglial activation and microglial derived mediators of cytotoxic damage such as interleukin-1beta, NADPH-oxidase, and inducible nitric oxide synthase (iNOS) and interrupt apoptosis via inhibition of caspase 1 and 3 (Du, et al., 2001; Chen, et al., 2000). Creatine is a natural derivative of the amino acids arginine and glycine. In humans it is synthesized primarily in the liver, kidney and pancreas and can be supplied endogenously through the diet. The primary food sources are animal protein including meat and fish. Cells primarily use creatine in the intermediate form of phosphocreatine that serves as as a phosphate donor to generate AT from ADP. Creatine supplementation by humans has generally been used for improving performance in athletes. Oral supplementation of creatine leads to increased plasma free creatine, increased muscle and brain creatine and phosphocreatine and can lead to enhanced athletic performance (Williams, et al., 1998; Gordon, et al., 1995; and Earnest, et al., 1995). There have been no major safety or tolerability problems with oral supplementation of creatine in dosages as high as 20 grams per day for short periods in normal healthy individuals. The main reasons for using creatine in PD is its potential to support and stabilize mitochondrial function by serving as an energy buffer. Evidence of mitochondrial dysfunction and oxidative stress has been shown in experimental models of PD and in tissue from PD patients. Creatine could support or augment mitochondrial function by acting as an energy buffer, by acting indirectly as an antioxidant, and by antagonizing mitochondrial permeability (Tarnopolsky et al., 1999). Creatine is protective in animal models of PD (Mathews, et al., 1999) and other neurodegenerative disorders including HD (Andreassen, et al., 2001), and ALS (Klivenyi, et al., 1999).

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。神经科学界的主要目标是制定神经保护治疗策略，以减慢或阻止慢性神经退行性疾病的进展。帕金森氏病（（PD）是最常见的成年神经退行性疾病之一，在北美影响约100万人，其特征是震颤，僵化，僵硬，胸肌和姿势性不稳定。尽管在震颤和促进疾病中，PD的临床特征通常会逐渐逐渐出现，但促进了最初的疾病。改善PD的症状和症状在认知表现中，情绪和行为以及PD的逐步降低，最终会导致功能性残疾。 Al。 Rajput等，1984； Clarke等，1995}。尚未确定尚未确定降低PD的进展。 PD中当前的多巴胺能疗法是有症状的（减轻体征和症状），但是对于这些药物，既有短期（运动波动）和长期（可能加剧疾病进展的）关注，这些药物需要重新评估治疗策略。 PD的病理的特征是脑干中有色神经元的丧失，尤其是在ceruleus骨中的Nigra pars compacta和神经腺能神经元中的多巴胺能神经元。 ni骨神经元的丧失与内囊中嗜酸性粒细胞内夹杂物（Lewy身体）的存在有关。神经元功能障碍和死亡的原因以及胞质内夹杂物的性质在很大程度上仍然是晦涩的，尽管后者始终用抗α-突触核蛋白和泛素抗体的抗体进行免疫染色。这些神经病态病态变化与包括隔坐式隔坐式的神经化学异常级别有关，这些神经性异常含量与神经化学异常水平相关联。尽管PD的发病机理尚未完全阐明，但对于潜在机制还是有重要的线索。在α突触核蛋白和泛素中具有突变的大家族性PF的鉴定。这些神经病理学的变化与神经病理学的变化有关，与神经化学异常有关，包括纹状体水平降低的多巴胺及其代谢产物。尽管PD的发病机理尚未完全阐明，但对于潜在机制还是有重要的线索。在α-核蛋白基因中具有突变的大型家族性PD的鉴定[Polymeropoulos等，1997]，驻停车场的突变[Kitada等，2998]和冰岛熟悉的PD聚集的证据是流行性的研究[Gorell等[Gorell等[GORELL等[2]。 Seidler等，1996]提出环境因素可能有助于PD的发展。目前，这些因素的相对贡献和重要性尚不清楚。基于动物模型中的累积观察结果，似乎有几种可能作为神经保护策略有用的药物。这些类别包括NOS抑制剂，抗凋亡剂，例如JNK抑制剂和潜在的MAP-B抑制剂（通过Bcl-2上调的机制），神经免疫性素化合物，谷氨酸拮抗剂，包括氨甲磺酸盐和riluzole，包括D2受体毒Agonist剂，包括PRAMIPECENISTENTENTENT，包括PRAMIPECENISTENTENTERS，包括PRAMIPECENISTENTENTENTERS，以及乙酰基路 - 肉碱和抗炎剂，包括水杨酸钠，乙酰基盐酸酸和环氧酶2抑制剂。除了在PD的临床前模型中证明了功效外，其中几种化合物已经在人类中进行了测试，包括耐受性研究的剂量。还报道了抑制剂对疾病进展的影响。 Minocycline是一种半合成第二代四环素抗生素，具有神经保护特性，与其抗微生物作用不同。 Minocycline已获得FDA批准用于治疗包括脑和脑膜感染在内的各种感染，并且在长期用于多种疾病（例如痤疮和类风湿关节炎）时，已耐受耐受性。米诺环素是高度脂溶性的，已被证明具有良好的脑穿透性和生物利用度（Saivin 1988）。米诺环素的毒性与其他四环素类似，在怀孕和童年时期是禁忌的。米诺环素在CNS损伤和变性的广泛模型中具有保护性，包括MPTP和6种PD的羟基多巴胺模型（Wu等，2002）和兴奋性毒性（Tikka等人，等等，2001）。关于PD，米诺环素的主要作用是双重的：它抑制细胞毒性损伤的小胶质激活和小胶质细胞衍生的介体，例如介导蛋白毒性损伤，例如白介素-1Beta，NADPH-氧化酶，诱导型氮氧化物合成酶（Inos）（Inos）和Intrabise in Intrabise and and and and and epase 1（du）。 Al。，2000）。肌酸是氨基酸精氨酸和甘氨酸的天然衍生物。在人类中，它主要是在肝脏，肾脏和胰腺中合成的，可以通过饮食内源性。主要食物是动物蛋白，包括肉和鱼。细胞主要在磷酸磷酸酯的中间形式中使用肌酸，作为磷酸盐供体，可从ADP产生。人类补充肌酸的补充通常用于改善运动员的表现。口服肌酸的补充会导致不含血浆的肌酸增加，肌肉和脑肌酸和磷酸蛋白质增加，并可以提高运动性能（Williams等，1998; Gordon等，1995; Earnest等，等等，1995）。在正常健康个体中，短期每天以高达20克的剂量来补充肌酸的口服肌酸，没有重大的安全性或耐受性问题。在PD中使用肌酸的主要原因是其通过用作能量缓冲液来支持和稳定线粒体功能的潜力。在PD患者的PD和组织中，已经显示了线粒体功能障碍和氧化应激的证据。肌酸可以通过充当能量缓冲，通过间接充当抗氧化剂并拮抗线粒体通透性来支持或增强线粒体功能（Tarnopolsky等，1999）。肌酸在PD的动物模型（Mathews等，1999）和其他神经退行性疾病中具有保护性，包括HD（Andreassen等，2001）和ALS（Klivenyi等，1999）。