Biochemical evaluation of the neurotoxicity of MPTP and MPP⁺ in embryonic and newborn mice

Abstract

-One of the toxicities caused by 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is damage to dopaminergic neurons. When injected into C57BL/6J mice, MPTP penetrates into the brain and is converted to 1-methyl-4-phenylpyridinium (MPP + ) by monoamine oxidase (MAO)-B in astrocytes. MPP + has high affinity for the dopamine transporter (DAT) on dopaminergic neurons, and is taken up into the cell to cause cell death. There have been relatively few researches on the acute MPTP toxicity to embryonic or newborn mice. In the present study, we attempted to evaluate the influence of MPTP and MPP + on embryonic and newborn mice by measuring sequential changes in major indexes of MPTP toxicity and MPTP metabolism; levels of Tyrosine Hydroxylase (TH), DAT, MAO-A and MAO-B. In addition, we measured the levels of dopamine and its metabolites, 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA), in the brain of newborn mice. A single injection of MPTP and MPP + reduced the levels of dopamine and its metabolites, DOPAC and HVA, in the brain of newborn mice about 6-12 hr after the injection. Similarly the levels of mRNAs and proteins of DAT and TH were lowered in the brain of embryonic and newborn mice as well. The levels of these indexes were generally recovered at 24 hr after injection, indicating that the neurotoxicity induced by a single injection of MPTP or MPP + is temporary and recoverable in embryonic and newborn mice. By contrast, no significant changes in the expression levels of MAO-A and MAO-B were observed in either MPTP-or MPP + -treated mice.

Comprehensive Perspectives on Experimental Models for Parkinson’s Disease

“…SIRT3 protects a rotenone-induced PD cell model on SH-SY5Y via activation of the liver kinase B1-AMP-activated protein kinase-mTOR pathway [21]. DAT plays an important role in the neurotoxic process [42], and MPP⁺exhibits high affinity to DAT on dopaminergic neurons [18]; thus, MPTP-induced models are most widely used in Parkinsonism research or neuronal protective drug screening among these three neurotoxins. A novel study indicated that silencing PGC-1 alpha in MPTP-treated SH-SY5Y improved cell viability and mitochondrial function [20], presenting a potential therapeutic target in PD drug discovery.…”

Sulfide:quinone oxidoreductase ameliorates neurodegeneration in a murine model of Parkinson's disease

“…1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that inhibits mitochondrial ETC complex I. Following systemic administration, MPTP crosses the blood brain barrier and is converted (in astrocytes) to 1-methyl-4-phenylpyridinium ion (MPP + ) by monoamine oxidase-B [ [9] , [10] , [11] ]. MPP + binds to dopamine transporters on dopaminergic neurons with high affinity, facilitating cellular uptake and resulting in inhibition of ETC complex I, impairment of ATP production and increased oxidative stress and cell death [ [12] , [13] , [14] , [15] ].…”

Behavioral characterization in MPTP/p mouse model of Parkinson’s disease

“…Upon uptake in the brain, MPTP is transformed to its active metabolite, 1-methyl-4-phenylpyridinium (MPP + ), by astrocytic monoamine oxidase-B. MPP + has a strong specificity for the dopamine transporter on dopaminergic neurons, where it is taken up and induces cell death [5]. Administration of the toxin MPTP results in nigrostriatal dopaminergic (DA) cell loss of varying degrees that depend on the regimen used [6].…”