A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson's disease

Yuki Kishimoto; Joshua Johnson; William Fang; Joshua Halpern; Krisztina Marosi; Dong Liu; John G Geisler; Mark P Mattson

doi:10.1016/j.neurobiolaging.2019.09.011

A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson's disease

Neurobiol Aging. 2020 Jan:85:123-130. doi: 10.1016/j.neurobiolaging.2019.09.011. Epub 2019 Sep 26.

Authors

Yuki Kishimoto¹, Joshua Johnson¹, William Fang¹, Joshua Halpern¹, Krisztina Marosi¹, Dong Liu¹, John G Geisler², Mark P Mattson³

Affiliations

¹ Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
² Mitochon Pharmaceuticals, Inc., Blue Bell, PA, USA.
³ Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: mmattso2@jhmi.edu.

PMID: 31718928
DOI: 10.1016/j.neurobiolaging.2019.09.011

Abstract

Dopaminergic neuronal cell loss in the substantia nigra is responsible for the motor symptoms that are the clinical hallmark of Parkinson's disease (PD). As of yet there are no treatments that slow or prevent the degeneration of dopaminergic neurons in PD patients. Here we tested the hypothesis that dopaminergic neurons can be protected by treatment with the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) and the novel DNP prodrug MP201. We found that mice treated with low doses of DNP and MP201 were protected against motor dysfunction and dopamine neuron loss in the 6-hydroxydopamine PD model, with MP201 being more efficacious than DNP. Amelioration of motor deficits and dopamine neuron loss by MP201 treatment was associated with reductions in microglial and astrocyte activation and neuroinflammation. These preclinical findings suggest the potential application of mitochondrial uncoupling agents such as MP201 as disease-modifying therapies for PD.

Keywords: 6-Hydroxydopamine; MP201; Microglia; Mitochondria; Motor dysfunction; Parkinson’s disease.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

2,4-Dinitrophenol / analogs & derivatives*
2,4-Dinitrophenol / pharmacology
2,4-Dinitrophenol / therapeutic use*
Animals
Cell Death / drug effects
Disease Models, Animal
Dopaminergic Neurons / pathology*
Mice, Inbred C57BL
Oxidopamine / pharmacology
Parkinson Disease / drug therapy*
Parkinson Disease / pathology
Prodrugs / pharmacology
Prodrugs / therapeutic use*

Substances

Prodrugs
mp201 compound
Oxidopamine
2,4-Dinitrophenol