Thiothalidomides as neuroprotectant drugs for PD.

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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.