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MPTP's Mechanism of Causing Parkinsons Disease
by Jay M. Gorell, M.D.
Excerpted from: Parkinson.org

Jay M Gorell, M.D.
William T. Gossett Chair in Neurology
Head, Division of Movement Disorders
Department of Neurology
Henry Ford Health System

The MPTP Model of Parkinsons Disease

MPTP, a pro-toxin formed in impure preparations of meperidine (Demerol), when injected intravenously in gram quantities, enters the brain. It is converted to MPP+ by monoamine oxidase B (MAO-B) in astrocytes. This toxin enters dopaminergic nerve terminals and is then concentrated in mitochondria, where it inhibits Complex I of the oxidative phosphorylation cascade. This action is associated with reduced ATP formation, as well as with the formation of free radicals. Eventually, the mitochondrial permeability transition pore's electrochemical gradient is abolished and apoptosis (programmed cell death) is induced. MPP+'s action is blocked by MAO-B inhibitors (e.g., selegilene), nitric oxide synthase inhibitors (reducing the peroxynitrite radical), and by salicylates (inhibiting a variety of free radicals), suggesting the involvement of these biochemical pathways in the pathogenesis of cell death.

MPTP parkinsonism produces a clinical phenocopy of PD, though, pathologically, it destroys nigrostriatal neurons throughout the nigra indiscriminantly, and typical Lewy bodies are not produced. Nonetheless, it is the best model of PD to date, and a great deal has been learned from it, in no small measure because of similarities of its neurochemical pathology with that of PD.

MPTP parkinsonism produces a mitochondriopathy (Complex I deficiency), placing the neurochemical pathology at the crossroads of the phases of commitment and execution of apoptosis. Recall that there are triggering factors of apoptosis (e.g., DNA damage, cell cycle perturbations, metabolic-toxic insults, growth factor deprivation), commitment factors (chiefly associated with the BCL-2 system), and an execution phase, associated with caspase activation. Despite these intriguing issues, there are conflicting studies regarding whether apoptosis is present in PD brain postmortem, and larger studies using carefully defined criteria will be necessary to settle the question.