CURRENT OPINION

MPTP AND PARKINSON'S DISEASE

T.S. HARIHARAN

Professor of  Phrmacologist

Medical College, Trichur.
 Paralysis agitans or Parkinson's disease was first descrided by James Parkinsone in 1817. This neurologic disorder is termed  as idiopathic, since no concrete evidence is available even this day as to the possible role of any etiological factor. The disease does not to bear any relation to any known disease process such as atherosclerosis, trauma, or intoxication, even though Parkinsinism can occur secondary to drugs like neuroleptics, toxins like manganese and carbonmonoxide and to vascular infarcts.
IMPORTANT MILESTONES IN PERKINSON'S DISEASE
 1817- James parkinson-First described the disease
 1912- Lewy- Demonstrated intraneuronal eosinophilic inclusion bodies.
 1919- Tretiakoff- Duggested the possible neuropathology. loss of melanin containing neurons in substantia nigra.
 1957- Carlsson - Suggested the neurophysiologica basis. dopamine deficiancy in the brain.
 1959- Bartler, Bosengreen and  Carlsson-Found out that 80% of dopamine in human brains in concentrated in basal ganglia, especially the corpus striatum.
1960- Hornykiewikz- Dopamine deficiancy in CNS was demonstrated directly in patients.
1968- Cotzias- Established Levodopa therapy in patients with Parkinson's disease
  Further studies on Parkinson's disease got stuck up mainly because of a major problem, namely the absence of a fully satisfactory animal model. This state of affairs was to continue for long until 1982 when there was a dramatic turn around for the better. In what has to be admitted as sensational, the story of MPTP induced Parkinsonism atarted unfolding.
MPTP- INDUCED PARKINSONISM THE STORY BEGINS
  It all started suddenly when the attention of J.W. Langstone and J.W. Tetrud was drawn to a few drug abusers haiking from North California who presented with a full blown Parkinsonian syndrome developed overnight. The irony of the episode was that all the seven individual affected were young men of around 35 years. Initial investigations revealed a clear link between heroin abuse and the onset of Parkinsonism. Subsequent analysis of samples from affected individuals led to the identification of a chemical named MPTP (Methyl Phenyl Tetrahydro Pyridine) as the real culprit.
  Later on, the source of the heroin sample was traced to an illicit chemist of North California. Tempted by a desire to reap enormous profit, he attempted to make 'synthetic heroin' and succeeded in synthesising a chemical known as MPPP a revers ester of Pethidine (Methyl Phenyl Propionoxy Piperidine). Since MPPP sould be manufactured easily and was not a controlled substance, it was freely sold in streets North California. The chemist never imagined that NPTP could present as an impurity in the sample sold, causing Parkinsonism like features.
  Further studies by Langston and coworkers reveald that MPTP could produce Parkinsonian features in the monkeys too. Histological studies in these animals also showed selective destruction of pars compacta of substantia nigra whereas the locus coeruleus neurons were not affected. In the words of Langston "We are in a rather unusual position of having not only an animal model for a human disease. but also have a human model of the animal model of the disease".
CLINICAL CHARACTERISTICS OF MPTP INDUCED PARKINSONISM
1) All the patients numbering seven were young with an average age of 33
2) symptoms and signs were remarkable in their similarly to Parkinson's disease in its advanced form (indistinguishable from Idiopathic Parkinsonism)- They comprise the classical traid of bradykinesia, rigidity and tremor as well as subtle features like hypomimia, Micrographia, postural instability, shuffling gait and drooling. Dementia however was not a feature.
3) All the patients responded to levodopa therapy dramatically. But, Bromocripyine had to be added later for satisfactory control.
4) Spinal fluid analysis showed a selective depression of HVA, the dopamine metabolite, whereas the metabolite for norepinephrine was slightly elevated.
5) It is thus a pure hypodopaminergic state with the lesions restricted to substantia nigra (Afferent Parkinsonism).
6) Most of the problems expected during management of a typical Parkinsonian patient were encountered in these patient also. These included end-of dose-wearing off. peak-dose dyskinesias and levodopa induced hallucinations. In fact all these complications arose quite early in the treatment.
EARLY PARKINSONISM INDUCED BY MPTP
  Will MPTP produce anything other than an advanced form if Parkinsonism? To answer the question, more than 400 individuals in North California were identified to have probably been exposed to MPTP. Miled Parkinsonism was noted in about 50 persons, the clinical profile quite comparable to early Parkinsonism. The only differences were that the disease was more symmetric and resting tremor was noted only in 28% of persons.
  While recent studies strongly preculde a genetic origin of Parkinson's diseas, the newly found MPTP induced Parkinsonism has focussed attention on the strong possibility of an enviornmental toxin such as MPTP as a cause of the diseas. A working hypothesis toward the etiopathogenesis was put forward by Calne and Langstone after a detailed analysis of the MPTP induced Parkinsonism in humans involving a combination of environmental factors and ageing. At present such a hypothesis seems to be most acceptable and feasible
IDIOPATHIC PARKINSONISM POSSIBLE ETIOLOGY
1) Environmental Factors
  Individuals in their early adult life may suffer an insult to the substantia nigra either from exposure to a neurotoxin like MPTP or from infection or head trauma. Most of them ramain a symptomatic, since more than 80% of striatal neurons have to be lost before clinical features could appear.
2) Ageing
  Parkinsonism typically manifests itself 40 years of age. With ageing, there is slow and gradual decline in the population of dopamine neurons which may add to the already existing dopamine deficiency. In other words, the environmental factors set the stage for the disease, while the ageing process administers the "coup de grace".
3)  The initial nigral cell loss may lead to hyperactivity of the remaining dopamine neurons resulting in enhanced synthesis and release of dopamine, with increased oxidative deamination of dopamine. More and more peroxides and free oxygen radicals are generated which further accentuate cell death. A classical vicious cycle is thereby set.
CAN WE PREDICT THE OCCURRENCE OF PARKINSON'S DISEAS?
  It is well known that Parkinson's disease is characterised by a gradual onset and slow progression. The indicates that there is a progressive destruction of the nigral neurons that manifests itself clinically when more than 80% of the dopaminergic neuronal population is lost. Natuarally a state of preclinical hypodopaminergic state should possibly exist.If so, is there any way to detect this state of preclinical Parkinsonism sufficiently early and thereby to predict the future occurence of disease?
 Studies conducted on the hapless victims of MPTP  exposure in North California  point to such a distinct posibility and hope. In this connection a few of the individuala, who evidently got 'exposed' to the neurotoxin but did'nt manifest the disease, were subjected for PET scanning technique. The study revealed a significant depletion of dopamine in the straitum, an observaton which for thr first time indicated the existence of a preclinical hypodopaminergic state (Preclinical Parkinsonism). This study also raises the possibility of predicting the future occurrence of Parkinsonism  in persons at high risk (over the age of 50.)
  Well, one might be tempted to ask at this juncture, and with a certain degree of sarcasm-'what is the fun in predicting the futuredevolopments of a disease, when we don't know how to health progression'. It may be of real interest to know that the revolutionary substance, MPTP has already kindled sufficient hope and intence research is on in this direction. The exact mechanism by which MPTP induced Parkinsonism would help us understand the basis for such a hope of preventing the disease.
MECHANISM OF MPTP ACTION
  MPTP having a chemical structure of 1-Methyl 4- Phynyl Tetrahydro Pyridine, has been subjected to extensive studies in both primates as well as humans. The mechanism of action has thus been clearly identified as :
1) MPTP itself is not the actual neurotoxic agent, rather it needs to be converted to an active metabolite in the brain.
2) MPTP is highly lipophilic. after oral ingestion it crosses the blood brain barrier and it transforms into MPP (Methyl Phenyl Pyridiminum). MPP appears to act on neuron itself resulting in cell destruction.
3) Conversion of MPTP to MPP is catalysed by the enzyme monoamoneoxidase (B), and this occurs probably in the glial tissue of the brain.
4) MPP Is transported selectively into the neuronal cells of the substantia nigral by the dopamine uptake system, and it causes direct cell destruction.
INFLUENCE OF MAO INHIBITION MPTP ACTION
  In experiments conducted on primates exposed to MPTP, inhibition of monoamineoxidase enzyme by drugs or chemicals could completely prevent the neuronal cell destruction and thereby the devolopment of Parkinsonism. In consonance with this observation, there are reports from clinical studies that patients receiving Selegiline (Deprenyl), a selective inhibitor of MAO-B, along with levodopa, exhibited a survival period longer than those who received levodopa alone. It would therefore be quite logical to surmise that inhibition of monoamineoxidase enzyme could favourably alter the course of Parkinsonism.
  The benefit of combining levodopa with an inhibitor of MAO-B as reported above could very well be extended to the actual management of Idiopathic Parkinsonism too. We had already seen how an initial destruction of a small propertion of dopaminergic neurons could set up a vicious cycle resulting in progressively increasing neuronal loss because of peroxides and free oxygen radicals. MAO-B plays a crucial role in this generation of oxidant activity. Thus administration of MAO inhibitors in Parkinson's  disease could prove to be of significant benefit on slowing the progression of the disease process.
  Based on the cocept, clinical trials have already been undertaken to establish the efficacy of selegiline in early Parkinsonism. The results of two such trials are already available and are promosing. In both trials patients with early Parkinsonism maintained on Selegiline alone in a dose of 10 mg a day. such a regimen could significantly lengthen the period necessary for introduction of levodopa into therapy, possibly implying a slowing down of disease progression.
  It is worth mentioning in this connection that yet another drug has also been drawing the attention of investigators, namely, Vitamin E (Tocopherol). Tocopherol is an established antioxidant and hence could also help to retard disease progression in patients with early Parkinsonism by blocking neuronal destruction produced by free oxygen radicals, superoxide and Hydrogen peroxide.
CONCLUSION
  MPTP, a chemical discovered chance, as a contaminant of illicit drugs, has ushered in an exciting era in Parkinsonism research. It has provided us with the most-sought-after animal model for Parkinsonism (not to speak of the "Unfortunate" human model). The substance has also revealed that environmental toxins can produce selective damage to dopaminergic neurons of the brain and can initiate the disease process in Parkinsonism. More over MPTP has for the first time, instilled new hopes of delaying the progression of the lesion in patients with Parkinsonism.