MPTP and Its Role in Toxic Parkinsonism

0 Comment

The degeneration of the substantia nigra of the basal ganglia coupled with intracytoplasmic inclusions known as Lewy bodies is the pathological characteristic seen in patients afflicted with PD. "The primary biochemical defect is the loss of striatal dopamine" which is the neurotransmitter produced by the neurons in the pars compacta of the substantia nigra (Braddom, 1164). The basal ganglia "assist in the regulation of voluntary movement and the learning of motor skills" (Snell, 320). It also functions in the initiation of movements. It is because of this that patients present primarily
with motor affectations with the cardinal signs for PD which include bradykinesia (characterized by a slowness and sudden pause in movement), resting tremors (uncontrolled shaking or movement), muscular rigidity (stiffness) and postural instability.
The specific cause for Parkinson’s disease is still unknown. Genetic factors such as defects in or mutations of several genes are known to cause PD, but these mutations actually result in only a very small number of cases of PD, in as little as 5% of the total number of PD cases. The two most important genes are "called parkin (autosomal recessive) and LRRK2 (autosomal dominant). Other genes that, when mutated, are known to cause PD include alpha-synuclein, DJ-1, PINK-1, and UCHL-1" (American Parkinson Disease Association). Envirionmental factors, such as exposure to toxins like pesticides/herbicides, industrial chemicals, trace metals, cyanide and carbon monoxide, are also thought to be a likely cause of Parkinson’s Disease. ‘The most compelling evidence for an environmental factor in PD relates to the toxin 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP)" (Olanow &amp. Tatton, 124). In the late 1940’s, MPTP was first tested for its possible therapeutic use tested as a possible anti-parkinsonian agent. Conversely, the drug was abandoned soon after the 6 humans given the drug developed PD symptoms and 2 of them died ( The surge in the numbers of the MPTP-induced Parkinsonism came in the 1980’s when it was being sold in the streets as synthetic heroin. The case study done by (Ballard, Tetrud &amp. Langston, 949) wherein the subjects, seven patients in total, developed permanent chronic and severe parkinsonism after repeatedly injecting MPTP intravenously. MPTP is able to cross the blood-brain barrier and react with the enzyme monoamine oxidase (MAO) (Hauser The interactions of MPTP with monoamine oxidase (MAO) was studied by Singer, Salach, Castagnoli &amp. Trevort in 1986. (785)
(Last Name) 3
l-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic. The nigrostriatal toxicity is not due to MPTP itself but to one or amore oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A