Methylphenyltetrahydropyridine

MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) is a chemical that is related to the opioid analgesic drugs. MPTP itself does not have any opioid effect, but it may be produced accidentally during illicit manufacture of MPPP, a synthetic opioid with effects similar to those of heroin and morphine.

MPTP causes Parkinsonian side-effects, hence some users of MPPP develop these symptoms. This happens when MPTP is metabolized into MPP+ (by MAO-B), which kills neurons in a part of the brain called 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.

MPTP has quite selective abilities to effect neuronal death in dopaminergic cells, apparently through a high-affinity uptake process in nerve terminals normally used to reuptake dopamine after it has been released into the synaptic cleft. Such effects lead to gross depletion of dopaminergic neurons which 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.

The neurotoxicity of MPTP was discovered in 1976 after Barry Kidston, a 23-year-old chemistry graduate student in Maryland, synthesized MPPP incorrectly and injected the result. It was contaminated with MPTP, and within three days he began exhibiting symptoms of Parkinson's disease. The National Institute of Mental Health found traces of MPTP in his lab and eventually discovered its effects by testing the chemical on rats.

In 1982, seven people in Santa Clara County, California were diagnosed with Parkinson's after using MPPP contaminated with MPTP. J. William Langston, then a neurologist at Santa Clara Valley Medical Center and faculty member at Stanford Medical School, tracked down MPTP as the cause, researched its effects on primates, and was eventually able to successfully treat motor symptoms of three of the seven patients with neural grafts of fetal stem cells from aborted human fetuses in collaboration with neuroscientists from Lund University Hospital in Sweden. This experience was documented in a book he authored, The Case of the Frozen Addict (ISBN 0-679-42465-2), about his quest for a cure, which was later featured in two NOVA productions by Public Broadcasting Service.

Contribution of MPTP to research into Parkinson's disease
Langston et al.(1984) found that, injections of MPTP in squirrel monkeys resulted in parkinsonism, symptoms of which were subsequently reduced by Levo-dopa, a precursor for the neurotransmitter dopamine, currently the drug-of-choice in treatment of Parkinson's. The symptoms and brain structures of MPTP-induced Parkinson's are fairly indistinguishable to the point that MPTP may be used to simulate the disease in order that science may study Parkinson's physiology and possible treatments within the laboratory.

Based on this, it has been postulated that Parkinson's disease may be caused by minute amounts of MPP+ like compounds from ingestion or exogenously through repeated exposure and that these substances are too minute to be detected significantly by epidemiological studies. Nevertheless, knowledge of MPTP and its use in reliably recreating Parkinson's disease in experimental models has inspired scientists to investigate the possibilities of surgically replacing neuron loss through fetal tissue implants, subthalamic electrical stimulation and stem cell research, all of which have demonstrated initial, provisional successes.