MPTP

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animal studies. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animal studies. While MPTP itself has no psychoactive effects, the compound may be accidentally produced during the manufacture of MPPP, a synthetic opioid drug with effects similar to those of morphine and pethidine (meperidine). The Parkinson-inducing effects of MPTP were first discovered following accidental injection as a result of contaminated MPPP. Injection of MPTP causes rapid onset of Parkinsonism, hence users of MPPP contaminated with MPTP will develop these symptoms. MPTP itself is not toxic, and as a lipophilic compound can cross the blood–brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme monoamine oxidase B (MAO-B) of glial cells, specifically astrocytes. MPP+ kills primarily dopamine-producing neurons in a part of the brain called the pars compacta of the substantia nigra. MPP+ interferes with complex I of the electron transport chain, a component of mitochondrial metabolism, which leads to cell death and causes the buildup of free radicals, toxic molecules that contribute further to cell destruction. Because MPTP itself is not directly harmful, toxic effects of acute MPTP poisoning can be mitigated by the administration of monoamine oxidase inhibitors (MAOIs) such as selegiline. MAOIs prevent the metabolism of MPTP to MPP+ by inhibiting the action of MAO-B, minimizing toxicity and preventing neural death. Dopaminergic neurons are selectively vulnerable to MPP+ because DA neurons exhibit dopamine reuptake which is mediated by DAT which also has high-affinity for MPP+. dopamine transporter scavenge for excessive dopamine at the synaptic spaces and transports them back into the cell. Even though this property is exhibited by both VTA and SNc neurons, VTA neurons are protective against MPP+ insult due to the expression of calbindin. Calbindin regulates the availability of Ca2+ within the cell, which is not the case in SNc neurons due to their high-calcium dependent autonomous pacemaker activity. The resulting gross depletion of dopaminergic neurons has severe implications on cortical control of complex movements. The direction of complex movement is based from the substantia nigra to the putamen and caudate nucleus, which then relay signals to the rest of the brain. This pathway is controlled via dopamine-using neurons, which MPTP selectively destroys, resulting over time in parkinsonism. MPTP causes Parkinsonism in primates including humans. Rodents are much less susceptible. Rats are almost immune to the adverse effects of MPTP. Mice were thought to only suffer from cell death in the substantia nigra (to differing degree according to the strain of mice used) but do not show Parkinsonian symptoms; however, most of the recent studies indicate that MPTP can result in Parkinsonism-like syndromes in mice (especially chronic syndromes). It is believed that the lower levels of MAO-B in the rodent brain's capillaries may be responsible for this. The neurotoxicity of MPTP was hinted at in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in Maryland, US, synthesized MPPP with MPTP as a major impurity, and self-injected the result. Within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health found traces of MPTP and other pethidine analogs in his lab. They tested the substances on rats, but due to rodents' tolerance for this type of neurotoxin nothing was observed. Kidston's Parkinsonism was treated with levodopa but he died 18 months later from a cocaine overdose. Upon autopsy, Lewy bodies and destruction of dopaminergic neurons in the substantia nigra were discovered.