MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) is an extremely selective and species-specific neurotoxin (see NEUROTOXINS). Its toxic effects are almost exclusively limited to the dopaminergic neurons of the SUBSTANTIA NIGRA of PRIMATES. MPTP-induced loss of nigral dopamine neurons results in an irreversible Parkinsonian condition which is virtually identical to the IDIOPATHIC condition. The discovery of the toxic effects of MPTP has had a pronounced effect on research into PARKINSON’S DISEASE. It has both enabled the development of an excellent animal model of the condition and given insights into the mechanisms which may cause the degeneration of nigral dopaminergic neurons.
The cardinal symptoms of Parkinson’s disease are BRADYKINESIA, RIGIDITY and TREMOR. The disease is progressive and typically affects the aged. The condition results from degeneration of DOPAMINE cells in the substantia nigra which consequently results in loss of dopamine within the STRIATUM. As the disease progresses dopaminergic neurons in the VENTRAL TEGMENTAL AREA may also degenerate along with NORADRENERGIC neurons in the LOCUS COERULEUS. In general, the symptoms can be alleviated in a dose-dependent manner by the
Human Movement Disorders
Location
Dysfunction
Description
Spinal cord
Paraplegia
Loss of sensation and movement in lower torso and legs
Paralysis
Loss of movement
Paresis
Some loss of movement (either general low grade
loss or total loss but in a restricted area of the body)
Cerebellum
Ataxia
Loss of control of posture, balance and gait (fine movements preserved)
Primary motor cortex
Hemiplegia
Loss of movement on one side only (movement control is lateralized, therefore will only get paraplegia with a bilateral lesion)
Secondary and/or tertiary motor cortex
Apraxia
Loss of purposeful movements (such as movements on command or copying)
Neglect
Loss of directed to movements to parts of space
Basal ganglia
Athetosis
Chorea
Dyskinesia
Akinesia
Bradykinesia
Writhing movement
Involuntary jerky movement
Disordered movement
Absence of movement initiation
Slow execution of movement
systemic administration of dopaminergic agents such as L-DOPA. Parkinson’s disease typically occurs in the absence of obvious precipitating factors hence the term idiopathic Parkinson’s disease. A single, relatively small dose of MPTP is sufficient to induce a profound, irreversible Parkinsonian condition in humans which is virtually identical to the idiopathic condition in terms of its symptomology, pathology and response to treatment. The toxic effects of the compound were discovered by chance when drug abusers self-administered MPTP as a contaminant in a batch of a synthetically produced ‘designer drug’. There are however subtle differences between MPTP-induced Parkinsonism and Parkinson’s disease. MPTP patients can be much younger and their response to dopamine agonist therapy more problematic. There is a tendency for these patients to experience severe side-effects to dopamine agonists much sooner than idiopathic patients. These side-effects include ‘end of dose deterioration’, DYSKINESIA at peak effect and psychiatric complications. It is also debatable whether LEWY BODIES, that is inclusion bodies which are characteristic of the degenerating substantia nigra in the brains of idiopathic Parkinsonian patients, are seen following MPTP-induced neurotoxicity.
MPTP shows remarkable species specific toxicity. It is extremely toxic to humans and certain species of monkey. The macaque monkeys, Macaca fascicularis, are particularly susceptible to the toxic effects of MPTP, doses in the range of 1 mg/kg being sufficient to induce a marked Parkinsonian syndrome. This syndrome is virtually identical to the idiopathic human condition with the exception of resting tremor which is not always observed. The drug is far less toxic to marmosets where it tends to induce a milder syndrome which is reversible to some extent. In contrast, MPTP has virtually no toxic effects in rats and guinea pigs though certain strains of mice, for example C57 black mice, are susceptible to large doses of the drug. There is anecdotal evidence to suggest that older monkeys are more vulnerable to the toxic effects of MPTP than young ones. Degeneration of dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus have been reported following the administration of large doses of MPTP to aged macaques. However, it appears that the full behavioural syndrome can be elicited following MPTP doses which result in selective degeneration of nigral dopaminergic neurons and where striatal dopamine depletions are limited to the CAUDATE NUCLEUS and the PUTAMEN.
MPTP itself is a relatively harmless compound. Its toxic properties arise from its conversion into the highly toxic compound MPP+. MPTP is a small lipid soluble molecule which can penetrate the BLOOD-BRAIN BARRIER with ease. Once in the brain it is thought to be oxidized to MPP+, the reaction being catalysed by the enzyme MONOAMINE OXIDASE-B (MAO-B), which is found in the MITOCHONDRIA of GLIAL CELLS. This proposed mechanism is supported by the observation that DEPRENYL, a selective inhibitor of MAO-B, can protect experimental animals from the toxic effects of MPTP. This observation has led to clinical trials where MAO-B inhibitors have been administered in attempts to slow the progression of the idiopathic human condition on the assumption that the degeneration that occurs in Parkinson’s disease is mediated by an MPTP-like compound. Results to date remain contentious. MPP+, once formed, is thought to enter dopaminergic neurons via the dopamine REUPTAKE system. This hypothesis is supported by the observation that blockers of the dopamine transporter reduce the toxic effects of MPP+ on cultured dopaminergic neurons. The species specific nature of MPTP-induced toxicity may reflect an action of neuromelanin. This pigment tends to be present in nigral neurons of species which are susceptible to MPTP. It is thought that neuromelanin may actively bind MPP+ and thus act as a depot for it. The precise manner in which MPP+ kills nigral neurons is unclear but it is assumed that the compound interferes with mitochondrial functioning.
