Abstract Details

Title Evaluation Of Additive Neuroprotective Effect of Combination Therapy For Parkinson's Disease Using in Vitro Models

Topic Movement Disorders

Presentation(s) S4 - Movement Disorders: Basic Science (1:48 PM-2:00 PM)

Poster/Presentation
Number 005

Background All the cellular processes leading to neurodegeneration cannot be addressed with just one medication. Therefore, combinations of medications targeting different disease mechanisms simultaneously may show additive or synergistic efficacy in slowing Parkinson’s Disease progression.

Objective This was a drug-repurposing study aimed to evaluate different combinations of nine drugs and food supplements for potential additive or synergistic neuroprotective effect using in-vitro Parkinson’s Disease models.

Design/Methods We evaluated 44 combinations of the nine medications and supplements (sodium phenylbutyrate, terazosin, exenatide, ambroxol, deferiprone, coenzyme-Q10, creatine, dasatinib and tauroursodeoxycholic acid), chosen for their effect on different targets, that had shown neuroprotective effects in preclinical models of Parkinson’s Disease. Wild type induced pluripotent stem cells-derived human dopaminergic neurons treated with 1-methyl-4-phenylpyridinium (MPP⁺) were used for initial screening. The most promising combinations were re-tested using idiopathic Parkinson’s Disease patient-derived induced pluripotent stem cells line and alpha-synuclein triplication line. Anti-neuroinflammatory effects were assessed using iPSC-derived activated human microglia cells. As metrics, we evaluated neurite length, number of branch points per mm², the number of live neurons, neuronal network density using intracellular neurofilament heavy chain (NFH) and pro-inflammatory cytokines.

Results We have identified four combinations of two to three drugs that showed an additive protective effect in neurite length, number of branch points and pro-inflammatory cytokines. Only one combination of sodium phenylbutyrate, exenatide and tauroursodeoxycholic acid also showed improvement in cytolysis in MPP⁺-treated wild type cell line. A combination of supplements tauroursodeoxycholic acid, Creatine and coenzyme-Q10 showed an increase in NFH and reduction in proinflammatory cytokines.

Conclusions We demonstrated that some of the medications and food supplements, used in combination, can exert an additive neuroprotective effect in in-vitro models of Parkinson’s Disease that is superior to each of the compounds individually. This preliminary data should be replicated and confirmed in other preclinical models of Parkinson’s Disease and ultimately in clinical trials.

Authors/Disclosures
Alexander Shtilbans, MD, PhD, FAAN (Hospital for Special Surgery) PRESENTER	Dr. Shtilbans has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Kyowa Kirin. Dr. Shtilbans has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amneal Pharmaceuticals. The institution of Dr. Shtilbans has received research support from NIH. The institution of Dr. Shtilbans has received research support from Praxis Precision Medicines.
Elise Esneault, PhD	Dr. Esneault has received personal compensation for serving as an employee of Porsolt.
Florian Simon, MSc	Mr. SIMON has nothing to disclose.
Joe Mazzulli, PhD	Dr. Mazzulli has stock in Lysosomal Therapeutics Inc.
Drew Quiriconi	Mr. Quiriconi has nothing to disclose.
Dror M. Rom	Dr. Rom has nothing to disclose.
Wolfgang Reintsch, PhD	Mr. Reintsch has nothing to disclose.
Valerio E. Piscopo, PhD	Dr. Piscopo has nothing to disclose.
Andrea Krahn	Ms. Krahn has nothing to disclose.
Thomas M. Durcan, PhD	Dr. Durcan has nothing to disclose.

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