Thiothalidomides as neuroprotectant drugs for PD.

硫沙利度胺作为 PD 的神经保护药物。

• 批准号: 7331541
• 负责人: SOMASUNDAR PRASAD GABBITA
• 金额: $ 35.82万
• 依托单位: P2D, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331541
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adult; Adverse effects; Affect; Analysis of Variance; Animal Model; Animals; Behavior; Biochemical; Blood - brain barrier anatomy; Chronic; Clinical; Clinical Treatment; Control Groups; Corpus striatum structure; Data; Disease model; Dopamine; Dose; Drug Delivery Systems; Drug vehicle; Enzyme-Linked Immunosorbent Assay; Exhibits; Goals; High Pressure Liquid Chromatography; Hour; IL8 gene; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Interferons; Interleukin-1; Interleukin-10; Interleukin-4; Interleukin-6; Intervention; Knock-out; Lead; Libraries; Lipopolysaccharides; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Motor; Motor Activity; Movement Disorders; Mus; Nerve Degeneration; Neuro-Oncological Ventral Antigen 2; Neurologic; Neuroprotective Agents; Neurotoxins; Parents; Parkinson Disease; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phase; Proteins; Rattus; Regression Analysis; Replacement Therapy; Reverse Transcriptase Polymerase Chain Reaction; Saline; Serum; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Substantia nigra structure; TNF gene; Testing; Thalidomide; Therapeutic; Time; Toxic effect; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; analog; cohort; cytokine; cytotoxicity; day; dopaminergic neuron; drug efficacy; human TNF protein; inhibitor/antagonist; motor impairment; mouse model; neuroinflammation; neuron loss; pars compacta; receptor; research study; thiothalidomide

DESCRIPTION (provided by applicant): The goal of this Phase 1 SBIR proposal is to identify drug candidate(s) from a tumor necrosis factor a (TNF-a) inhibiting library of compounds for treating Parkinson's disease (PD). PD is a progressive, neurological movement disorder characterized by massive dopaminergic neuron loss within the substantia nigra pars compacta (SN) that results in diminished striatal dopamine (DA) levels causing abnormal motor behavior. A large and critical need exists for effective PD drugs. Recent studies implicate the neuroinflammatory cytokine TNF-a as a key mediator in PD-associated neurodegenerative pathology. Studies demonstrate that: 1) nigrostriatal and CSF TNF-a levels are elevated four to ten-fold in PD patients and in animal models of PD, and 2) inhibiting TNF-a synthesis or genetically knocking out the TNF-a receptor blocks striatal DA depletion in PD mice. Overall, these studies suggest that TNF-a is a viable drug target for treating PD. Thalidomide demonstrates anti-PD activity by blocking TNF-a-mediated depletion of striatal DA levels in a PD mouse model study. However, thalidomide's well-documented teratogenic and anti- angiogenic effects make it unsuitable for long-term clinical use. P2D, Inc. has recently identified four lead TNF-a inhibitors from a proprietary library to be developed as PD therapeutics. These TNF-a inhibitors are thiocarbonylated thalidomide analogs (thiothalidomides). Preliminary Studies demonstrate that the four thiothalidomides: 1) are 18- 66-fold more potent TNF-a synthesis inhibitors compared to the parent compound thalidomide in vitro, 2) reduce serum TNF-a levels up to 91 % in an lipopolysaccharide-induced inflammation rat model, 3) are small and lipophilic allowing greater blood- brain-barrier (BBB) penetrability, 4) exhibit weak anti-angiogenicity compared to thalidomide and, 5) possess low cytotoxicity. Recent data also indicates that chronic, peripheral administration of any of the four thiothalidomides does not result in systemic toxicity and neurological or motor impairment in adult mice. Taken together, these data suggest that thiothalidomides are excellent drug candidates to break the self-propagating cycle of TNF-a driven striatal DA loss in PD. Mice administered the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have long-served as a robust model for PD drug efficacy studies. The proposed studies will evaluate the efficacy of P2D's four thiothalidomide lead compounds (PD-2015, -2016, -2019, and -2024) in MPTP- treated mice. The Specific Aims are: Specific Aim 1: Determine the effect of thiothalidomides on locomotor activity and Rotarod motor performance in MPTP-treated PD mice. Specific Aim 2: Determine the effect of thiothalidomides on serum TNF-a levels, nigrostriatal TNF-a, IL-1a, IL-1¿, IFN-?, IL-2, -4, -6, -8, and- 10, and iNOS levels and, finally, striatal DA and its metabolites in MPTP-treated PD mice. Parkinson's disease (PD) is a progressive, neurological movement disorder that affects millions in the US. Present PD drugs demonstrate poor efficacy and cause deleterious side effects during long-term use. Thus, a critical need exists for effective PD drugs. Preliminary studies indicate that thiothalidomides may serve as excellent drugs in treating PD.

描述（由适用提供）：该阶段1 SBIR提案的目的是从肿瘤坏死因子A（TNF-A）抑制用于治疗帕金森氏病（PD）的化合物库中的候选药物。 PD是一种进行性的，神经系统运动障碍，其特征是在质体Nigra pars compacta（SN）内大量多巴胺能神经元丧失（SN），导致纹状体多巴胺（DA）水平降低，导致异常运动行为。存在有效的PD药物的巨大和批判性需求。最近的研究暗示了神经炎性细胞因子TNF-A作为PD相关神经退行性病理学的关键介体。研究表明：1）PD患者和PD的动物模型中的黑质纹状体和CSF TNF-A水平升高了四到十倍，2）抑制TNF-A合成或遗传敲除TNF-A受体阻滞的PD小鼠中的DA DEPTIONTION。总体而言，这些研究表明TNF-A是治疗PD的可行药物靶标。沙利度胺通过在PD小鼠模型研究中阻止TNF-A介导的纹状体DA水平的部署来证明抗PD活性。然而，沙利度胺有据可查的致畸和抗血管生成作用使其不适合长期临床使用。 P2D，Inc。最近确定了从专有文库中的四个铅TNF-A抑制剂作为PD疗法开发。这些TNF-A抑制剂是硫代苯甲酸的硫乙酰胺类似物（硫代胺）。初步研究表明，与父母在体外相比，与父母化合物丘脂相比，四种硫代硫化剂：1）在脂肪型诱发的大鼠模型中，降低血清TNF-A水平高达91％，是少量和lip）允许血液，3）降低血清TNF-A水平高达91％，3）降低血清TNF-A水平高达91％，3）是允许血液的brining brain，3）与沙利度胺相比，暴露的弱抗血管生成性和5）具有低细胞毒性。最近的数据还表明，慢性，外周三四个硫代胺胺中的任何一个不会导致全身毒性，成年小鼠的神经系统障碍或运动障碍。综上所述，这些数据表明，硫代脂蛋白是最好的候选药物，可以打破PD中TNF-A驱动的纹状体DA损失的自传播周期。施用神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的小鼠长期以来作为PD药物效率研究的强大模型。拟议的研究将评估P2D的四种硫硫代胺铅化合物（PD -2015，-2016，-2019和-2024）在MPTP处理的小鼠中的有效性。具体目的是：具体目标1：确定硫代替象代码对MPTP处理的PD小鼠运动运动和旋风运动性能的影响。具体目标2：确定硫代脂蛋白对血清TNF-A水平，鼻叶纹状体TNF-A，IL-1A，IL-1？，IFN-？,, IL-2，-4，-6，-6，-8和-10，以及INOS级别以及最终的MPTPPP-PD-PD pd pd pd pd mptp-pd pd米的代谢物。帕金森氏病（PD）是一种进步的神经运动障碍，影响了美国数百万。目前的PD药物表现出较差的有效性，并在长期使用过程中引起有害的副作用。这是有效的PD药物的关键需求。初步研究表明，硫代胺可以用作治疗PD的优秀药物。