MPTP a neurotoxin research model of Parkinson’s Disease

The toxin 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP), causes irreversible Parkinson’s disease symptoms (Parkinsonism) through the destruction of dopaminergic neurons in the substantia nigra of the brain (Sian et al., 1999). MPP+ is a prodrug to the neurotoxin 1-methyl-4-phenylprinidium which has been used for various animal testing experiments to study disease, inducing the effects of Parkinson’s.

The discovery

When searching for a less addictive drug than morphine, scientists synthesised the opioid analgesic, desmethylprodine (MPPP).  MPPP was found to simulate the central nervous system. However, after showing no more effect than pethidine (a morphine-like synthetic opioid), MPPP never reached the market.

In 1976, Barry Kidston, a chemistry graduate, successfully re-synthesized MPPP. It produced the same effects of pethidine without the legal restrictions (MPPP never having been brought to market). Taking the drug recreationally for several months, Kidston was suddenly taken ill and hospitalized, presenting symptoms of Parkinson’s disease. Although confused by the rarity of Parkinson’s in someone so young, physicians treated Kidston with the standard addition of dopamine; the key component, which when absent causes the well-known characteristics seen in Parkinson’s Disease.

Further cases followed, with many young people presenting the symptoms of Parkinson’s disease. The cause puzzled physicians and after many more tests, it was subsequently discovered that the self-administered recreational drug, MPPP, was the common underlying factor in all patients. Eventually, it was revealed that the actual cause was the development of a movement disorder, closely resembling Parkinson’s disease in the drug abusing patients (Sian et al., 1999). Following research from the National Institute of Mental Health, it was concluded that in the synthesis of MPPP, MPTP was an impurity which had been unknowingly taken by the drug users. Although successfully treated with dopamine, Kidston was later found dead from a cocaine overdose. From his autopsy, the destructive effects of MPTP on the dopaminergic neurons in the substantia nigra of the brain were discovered.

Where and how?

MPTP readily penetrates the blood-brain barrier, where it is then trapped in the cells surrounding the neurons of the brain. Although not psychoactive itself, the precursor MPTP is transformed to MPP+, a far more toxic compound. The resulting ion is actively transported into the dopaminergic neurons of the brain, where it is sequestered. Here, MPP+ undergoes a series of complex metabolic reactions, leading to production of reactive oxygen species and eventually, cell death. It is these key events are believed to be the cause of Parkinson’s disease, and have been revealed all thanks to the discovery of MPTP.

Contribution to Parkinson’s treatments

Many papers have studied the exact mechanisms of neurons and their responses to MPTP in detail. Dopaminergic neurons in brain cells have been found to be sensitive to MPTP. Scientists have developed systems to inhibit the activation of MPTP to the more toxic MPP+ using the metabolic inhibitor, quinidine. Further study looking into the transport of MPP+ into neurons has shown this is via the dopamine (DA) transporter. Thus, the treatment of Parkinson’s with DA-antagonists has been found to protect against neurotoxicity. Through discovery of MPTP’s potential mechanisms of action, effective treatments are now being developed against Parkinson’s disease.

Over the years there have been various other toxicants which also cause Parkinson’s symptoms, however MPTP has become the dominant model. This is because MPTP causes these symptoms in both humans and monkeys, with induced symptoms in monkey’s being the gold-standard for preclinical testing of new Parkinson’s disease therapies (Jackson-Lewis et al., 2007). Also the use and study of MPTP and its effects in other animal models such as mice has also made great contributions towards treatments for Parkinson’s disease in humans, with many successful Parkinson’s treatments emerging from murine models.

The discovery of MPTP and investigation into its neurodegenerative effects have so far contributed to a magnitude of research regarding Parkinson’s disease, with many new potential therapies under development from the research surrounding MPTP.