Thiothalidomides as neuroprotectant drugs for PD.

描述（由申请人提供）：该1期SBIR申请的目标是从肿瘤坏死因子a （TNF-a）抑制化合物文库中鉴定用于治疗帕金森病（PD）的候选药物。PD是一种进行性神经运动障碍，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，导致异常运动行为。对有效的帕金森病药物存在着巨大而迫切的需求。最近的研究暗示神经炎症细胞因子TNF-a是pd相关神经退行性病理的关键介质。研究表明：1)PD患者和PD动物模型中黑质纹状体和脑脊液TNF-a水平升高4 - 10倍；2)抑制TNF-a合成或基因敲除TNF-a受体可阻断PD小鼠纹状体DA消耗。总的来说，这些研究表明TNF-a是治疗PD的可行药物靶点。在PD小鼠模型研究中，沙利度胺通过阻断tnf -a介导的纹状体DA水平的消耗显示出抗PD活性。然而，沙利度胺的充分证明致畸和抗血管生成作用使其不适合长期临床使用。P2D, Inc.最近从专有文库中确定了四种主要的TNF-a抑制剂，用于PD治疗。这些TNF-a抑制剂是硫代羰基化的沙利度胺类似物（thiothalidomides）。初步研究表明，这四种硫代沙利度胺：1)与母体化合物沙利度胺相比，在体外是18- 66倍的TNF-a合成抑制剂，2)在脂多糖诱导炎症大鼠模型中降低血清TNF-a水平高达91%，3)体积小且亲脂，允许更大的血脑屏障（BBB）渗透性，4)与沙利度胺相比表现出较弱的抗血管生成能力，5)具有低细胞毒性。最近的数据还表明，慢性外周给药四种硫沙利度胺中的任何一种都不会导致成年小鼠的全身毒性和神经或运动损伤。综上所述，这些数据表明，硫沙利度胺是打破PD中由TNF-a驱动的纹状体DA丢失的自我繁殖循环的优秀候选药物。长期以来，给小鼠注射神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）一直被用作PD药物疗效研究的稳健模型。拟议的研究将评估P2D的四种硫沙利度胺先导化合物（PD-2015、-2016、-2019和-2024）在MPTP治疗小鼠中的疗效。目的1：确定硫萨力度胺对mptp治疗的PD小鼠的运动活动和Rotarod运动性能的影响。特异性目标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-1¿、IFN-？， IL-2, -4, -6， -8和- 10，以及iNOS水平，最后是mptp处理的PD小鼠纹状体DA及其代谢物。帕金森氏症（PD）是一种进行性神经运动障碍，影响着美国数百万人。目前的PD药物在长期使用中疗效较差，且存在不良的副作用。因此，迫切需要有效的PD药物。初步研究表明，硫沙利度胺可作为治疗帕金森病的优良药物。

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.