Mechanism of the neurotoxicity of MPTP

Abstract

This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.Monoamine oxidase; MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); Neurotoxin; NADH dehydrogenase

Generation of reactive oxygen species in 1-methyl-4-phenylpyridinium (MPP+) treated dopaminergic neurons occurs as an NADPH oxidase-dependent two-wave cascade

“…MPTP is converted to MPP+ in astrocytes by monoamine oxidase B [45]. Specific uptake of MPP+ released from astrocytes into dopaminergic neurons occurs via a cell membrane dopamine transporter (DAT).…”

“…To generate ROS in N27 cell cultures, we treated N27 cells for upto 24 hours with a range of concentrations of MPP+, a metabolite of MPTP. The mechanism by which MPTP exerts toxicity in vivo requires its conversion in astrocytes via monoamine oxidase B to MPP+ (reviewed in [45]). Since the N27 cultures lack astrocytes to perform this conversion, we have treated N27 cells with MPP+ itself.…”

Atractylenolide-I Protects Human SH-SY5Y Cells from 1-Methyl-4-Phenylpyridinium-Induced Apoptotic Cell Death

“…MPP + is the active metabolite of MPTP, which accumulates within dopaminergic neurons up to millimolar concentration in the mitochondria, and selectively inhibits nicotinamide adenine dinucleotide coenzyme (NADH Co) Q1 reductase (complex I) of the mitochondrial electron transport chain [8]. Inhibition of complex-I increases the shunting of electrons through complex-II, which generates 5–7 times more ROS [9].…”

Cx43 Mediates Resistance against MPP+-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells via Modulating the Mitochondrial Apoptosis Pathway

“…It has been reported that environmental factors can increase the risk of PD development, including rural living, well water use, and exposure to chemicals (pesticides, herbicides, industrial chemicals, and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)) [6]. To study neural degeneration in PD, neurotoxin 1-methyl-4-phenylpyridinium (MPP + ), the active metabolite of MPTP, has been widely used because it causes a severe Parkinsonian-like syndrome with loss of dopaminergic cells through selectively and potently inhibiting complex I of the mitochondrial electron transport chain in both cellular and animal models [7,8,9]. …”