Small molecule TNF-alpha inhibitors as neuroprotectant drugs for PD

Several preclinical and clinical studies implicate the neuroinflammatory cytokine TNF-alpha as a key mediator in PD-associated neurodegenerative pathology. P2D, Inc. has recently identified four lead TNF-alpha inhibitors to be developed as PD therapeutics. These TNF-alpha inhibitors: 1) are potent TNF-alpha synthesis inhibitors in vitro, 2) reduce serum TNF-alpha levels up to 91 percent in a rat neuroinflammation model, 3) are small and lipophilic allowing potentially greater blood brain barrier penetrability and thus better CNS activity, 4) demonstrate no signs of systemic toxicity or behavioral impairment following chronic administration to rodents. Overall, our small molecular weight TNF-alpha inhibitors are excellent drug candidates that may break the self-propagating cycle of TNF-alpha-driven striatal dopamine loss in PD. The proposed studies will evaluate the efficacy of our four lead TNF-alpha inhibitors in the 6-hydroxydopamine rodent PD model by employing motor behavior and biochemical measures.