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（由申请人提供）：该 1 期 SBIR 提案的目标是从肿瘤坏死因子 a (TNF-a) 抑制化合物库中鉴定用于治疗进行性帕金森病 (PD) 的候选药物。 ，神经性运动障碍，其特征是黑质致密部（SN）内大量多巴胺能神经元丢失，导致纹状体多巴胺（DA）水平降低，从而导致异常运动行为。最近的研究表明，神经炎症细胞因子 TNF-a 是 PD 相关神经退行性病理学的关键介质。研究表明：1) 黑质纹状体和脑脊液中的 TNF-a 水平升高了 4 至 10 倍。 PD 患者和 PD 动物模型，以及 2) 抑制 TNF-a 合成或基因敲除 TNF-a 受体可阻止 PD 小鼠纹状体 DA 消耗。 TNF-α 是治疗 PD 的可行药物靶标，在 PD 小鼠模型研究中，沙利度胺通过阻断 TNF-α 介导的纹状体 DA 水平消耗而显示出抗 PD 活性，但沙利度胺的致畸和抗血管生成作用已得到充分证实。 P2D, Inc. 最近从专有库中确定了四种主要 TNF-a 抑制剂，将其开发为 PD 治疗药物。抑制剂是硫代羰基化沙利度胺类似物（硫代沙利度胺）。初步研究表明，四种硫代沙利度胺：1) 与母体化合物沙利度胺相比，在体外的 TNF-a 合成抑制剂的效力强 18-66 倍，2) 降低血清 TNF-a 水平。在脂多糖诱导的炎症大鼠模型中高达 91%，3) 较小且亲脂，允许与沙利度胺相比，其具有更高的血脑屏障（BBB）渗透性，4）表现出较弱的抗血管生成性，并且，5）具有较低的细胞毒性。最近的数据还表明，四种硫沙利度胺中的任何一种的长期外周给药都不会导致血管生成。成年小鼠的全身毒性和神经或运动损伤综合起来，这些数据表明硫沙利度胺是打破 TNF-a 驱动的纹状体 DA 自我繁殖循环的优秀候选药物。给予神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的小鼠长期以来一直作为 PD 药物疗效研究的稳健模型。 P2D 的四种硫代沙利度胺先导化合物（PD-2015、-2016、-2019 和 -2024）在 MPTP 治疗的小鼠中的具体目标是：具体目标 1：确定硫沙利度胺对 MPTP 治疗的 PD 小鼠运动活性和 Rotarod 运动性能的影响 具体目标 2：确定硫沙利度胺对血清 TNF-a 水平、黑质纹状体 TNF-a、IL-1a、IL- 的影响。 1?? MPTP 治疗的帕金森病 (PD) 小鼠中，IFN-α、IL-2、-4、-6、-8 和 -10 以及 iNOS 水平，最后是纹状体 DA 及其代谢物。影响美国数百万人的神经性运动障碍。现有的帕金森病药物疗效不佳，并且在长期使用过程中会产生有害的副作用，因此，初步研究表明，硫沙利度胺可能是一种有效的药物。是治疗PD的优良药物。