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Review
. 2021 Aug 1;21(4):422-433.
doi: 10.17305/bjbms.2020.5181.

MPTP-induced mouse model of Parkinson's disease: A promising direction of therapeutic strategies

Musa Mustapha  1 , Che Norma Mat Taib  2
Affiliations
Review

MPTP-induced mouse model of Parkinson's disease: A promising direction of therapeutic strategies

Musa Mustapha et al. Bosn J Basic Med Sci. .

Abstract

Among the popular animal models of Parkinson's disease (PD) commonly used in research are those that employ neurotoxins, especially 1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). This neurotoxin exerts it neurotoxicity by causing a barrage of insults, such as oxidative stress, mitochondrial apoptosis, inflammation, excitotoxicity, and formation of inclusion bodies acting singly and in concert, ultimately leading to dopaminergic neuronal damage in the substantia nigra pars compacta and striatum. The selective neurotoxicity induced by MPTP in the nigrostriatal dopaminergic neurons of the mouse brain has led to new perspectives on PD. For decades, the MPTP-induced mouse model of PD has been the gold standard in PD research even though it does not fully recapitulate PD symptomatology, but it does have the advantages of simplicity, practicability, affordability, and fewer ethical considerations and greater clinical correlation than those of other toxin models of PD. The model has rejuvenated PD research and opened new frontiers in the quest for more novel therapeutic and adjuvant agents for PD. Hence, this review summarizes the role of MPTP in producing Parkinson-like symptoms in mice and the experimental role of the MPTP-induced mouse model. We discussed recent developments of more promising PD therapeutics to enrich our existing knowledge about this neurotoxin using this model.

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Conflict of interest statement

Conflict of interest statement: The authors declare no conflict of interests.

Figures

FIGURE 1
FIGURE 1
Structure, pharmacokinetics and pharmacodynamics of MPTP in the CNS. Upon injection of MPTP, it crosses the BBB and is converted to the toxic metabolite MPP+ by MAO-B. This metabolite is transported into the dopaminergic neuron by DAT. In the cytoplasm, MPP+ is further transported into vesicles by VMAT. Consequently, further concentration of MPP+ in the cytoplasm leads to a cascade of reactions that results in cell death. BBB: blood-brain barrier; CNS: central nervous system; DAT: dopamine transporter; MAO-B: monoamine oxidase type B; MPDP+: 1-methyl-4-phenyl-2, 3-dihydropyridine; MPP+: 1-methyl-4-phenylpyridinum; MPTP: 1-methyl-4- phenyl-1, 2, 3, 6-tetrahydropyridine; VMAT: vesicular monoamine transporter type 2.
FIGURE 2
FIGURE 2
Summary of the neurotoxic pathways of MPTP. MPP+ causes inhibition of COMPLEX-1 in the mitochondria which leads to the opening of transitional pores and then release of cytochrome C which causes a cascade of reactions that leads to cell death (Mitochondrial apoptotic pathway). Inhibition of COMPLEX 1 also causes an increase in ROS which leads to cell damage and eventually cell death (Oxidative stress pathway). Further excessive production of ROS leads to formation of AS monomers, and the monomers then form toxic oligomers which then inhibits UPS and ATGS and eventually leads to cell death (Alpha synuclein pathway). MPP+ causes excessive binding of glutamate at the synaptic cleft. This causes Ca influx that leads to excessive production of ROS, which damages the cell and cell death occurs finally (Glutamatergic pathway). MPP+ activates microglia cell and induces release of proinflamatory cytokines/enzymes leading to excessive ROS production, then cell damage and eventually cell death (Inflammation pathway). APAF-1: apoptosis protease activating factor 1; AS: Alpha synuclien; ATGS: autophagy system; iNOS: Inducible nitric oxide synthase; LB: Lewy body; MPP+: 1-methyl-4-phenylpyridinium; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Mt: Mitochondria; ROS: Reactive oxygen species; UPS: ubiquitin-proteasome system; (-): downregulates; (+): upregulates; (↑): Activates.
FIGURE 3
FIGURE 3
Schematic diagram of the commonest MPTP dosing regimen and route.
See this image and copyright information in PMC

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