Funded Studies
Objective/Rationale:
Our objective is to test the in vivo pharmacokinetic profile, mode of action and efficacy of two novel and highly selective JNK inhibitors in the MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) preclinical model of Parkinson’s disease (PD). These include BI78D3 that binds with high affinity to the D-domain of JIP1 (JNK-interacting protein 1) but not the ATP-binding site and BI87G9 which binds to both the D-domain of JIP1 and the ATP-binding site to block JNK signaling.
Project Description:
This project will study two novel JNK inhibitors (BI78D3 and BI87G9) for their pharmacokinetics, mechanism of action and neuroprotective efficacy in blocking PD in preclinical models following MPTP administration. The pharmacokinetic properties of the JNK inhibitors will be studied to determine the optimal dose(s) and route of administration providing pharmacologically meaningful levels of drugs in vivo. Using the optimal pharmacological dose(s) of the JNK inhibitors we will perform neuroprotective studies using acute and chronic MPTP models of PD. Specifically effects on striatal dopamine and metabolites, numbers of tyrosine hydroxylase immunoreactive neurons of substantia nigra, markers of oxidative damage, inflammation, and impact on JNK signaling in substantia nigra will be studied with and without MPTP at various doses of these drugs.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Activation of JNK signaling has long been implicated in pathogenesis of PD. Preliminary studies using BI78D3 and BI87G9 showed efficacy against liver damage and insulin sensitivity in type II diabetes in mice by blocking JNK signaling. Proposed studies to determine the pharmacokinetics, mode of action, and their efficacy in the MPTP preclinical model of PD will provide crucial data for future testing and use of these drugs to stop the progression of PD in humans.
Anticipated Outcome:
It is anticipated that the proposed studies will provide key information for the development of BI78D3 and BI87G9 as a potential candidate drug(s) to slow the progression of PD in patients. Our studies will identify the optimal neuroprotective dose and the mode of action in vivo of BI78D3 and BI87G9 in attenuating MPTP neurotoxicity in preclinical models. This is a crucial step in moving these JNK inhibitors from the laboratory to clinical settings.