1-Methyl-4-phenylpyridinium

MPP+ (1-methyl-4-phenylpyridinium) is a positively charged organic molecule with the chemical formula C12H12N+. It is a neurotoxin that acts by interfering with oxidative phosphorylation in mitochondria by inhibiting complex I, leading to the depletion of ATP and eventual cell death. MPP+ (1-methyl-4-phenylpyridinium) is a positively charged organic molecule with the chemical formula C12H12N+. It is a neurotoxin that acts by interfering with oxidative phosphorylation in mitochondria by inhibiting complex I, leading to the depletion of ATP and eventual cell death. MPP+ arises in the body as the toxic metabolite of the closely related compound MPTP. MPTP is converted in the brain into MPP+ by the enzyme MAO-B, ultimately causing parkinsonism in primates by killing certain dopamine-producing neurons in the substantia nigra. The ability for MPP+ to induce Parkinson's disease has made it an important compound in Parkinson's research since this property was discovered in 1983. The chloride salt of MPP+ found use in the 1970s as an herbicide under the trade name cyperquat. Though no longer in use as an herbicide, cyperquat's closely related structural analog paraquat still finds widespread usage, raising some safety concerns. MPP+ has been known since at least the 1920s, with a synthesis of the compound being published in a German chemistry journal in 1923. Its neurotoxic effects, however, were not known until much later, with the first paper definitively identifying MPP+ as a Parkinson's-inducing poison being published in 1983. This paper followed a string of poisonings that took place in San Jose, California in 1982 in which users of an illicitly synthesized analog of meperidine were presenting to hospital emergency rooms with symptoms of Parkinson's. Since most of the patients were young and otherwise healthy and Parkinson's disease tends to afflict people at a much older age, researchers at the hospital began to scrutinize the illicitly synthesized opiates that the patients had ingested. The researchers discovered that the opiates were tainted with MPTP, which is the biological precursor to the neurotoxic MPP+. The MPTP was present in the illicitly synthesized meperidine analog as an impurity, which had a precedent in a 1976 case involving a chemistry graduate student synthesizing meperidine and injecting the resulting product into himself. The student came down with symptoms of Parkinson's disease, and his synthesized product was found to be heavily contaminated with MPTP. The discovery that MPP+ could reliably and irreversibly induce Parkinson's disease in mammals reignited interest in Parkinson's research, which had previously been dormant for decades. Following the revelation, MPP+ and MPTP sold out in virtually all chemical catalogs, reappearing months later with a 100-fold price increase. MPP+ can be readily synthesized in the laboratory, with Zhang and colleagues publishing a representative synthesis in 2017. The synthesis involves reacting 4-phenylpyridine with methyl iodide in acetonitrile solvent at reflux for 24 hours. An inert atmosphere is used to ensure a quantitative yield. The product is formed as the iodide salt, and the reaction proceeds via an SN2 pathway. The industrial synthesis of MPP+ for sale as the herbicide cyperquat used methyl chloride as the source of the methyl group. MPP+ is produced in vivo from the precursor MPTP. The process involves two successive oxidations of the molecule by monoamine oxidase B to form the final MPP+ product. This metabolic process occurs predominantly in astrocytes in the brain. MPP+ exhibits its toxicity mainly by promoting the formation of reactive free radicals in the mitochondria of dopaminergic neurons in the substantia nigra. MPP+ can siphon electrons from the mitochondrial electron transport chain at complex I and be reduced, in the process forming radical reactive oxygen species which go on to cause further, generalized cellular damage. In addition, the overall inhibition of the electron transport chain eventually leads to stunted ATP production and eventual death of the dopaminergic neurons, which ultimately displays itself clinically as symptoms of Parkinson's disease. MPP+ also displays toxicity by inhibiting the synthesis of catecholamines, reducing levels of dopamine and cardiac norepinephrine, and inactivating tyrosine hydroxylase.