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CELLULAR AND SUBCELLULAR DAMAGE IN PARKINSON'S DISEASE AND IN MPTP - INDUCED PARKINSONISM

Objective


The study shows that when marmosets are chronically exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a progressive parkinsonian syndrome occurs. The low doses, which are required for the chronic regimen, do not bring about the acute pharmacological effects, which commonly appear when repeated maximal doses of MPTP are administered. In addition to behavioural signs, chronic administration of MPTP also produced biochemical morphological alternations. The first consisted in a depletion of dopamine, DOPAC and homovanillic acid (HVA) in the neostriatum. This depletion was reversible, since 8 months after discontinuance of MPTP all the biochemical values were back to normal. Morphological abnormalities lasted longer than biochemical alterations. A swelling of dopaminergic neurons was the first detectable morphological lesion; this occurred at a time when dopaminergic terminals located in the neostriatum were depleted. 8 months after discountinuance of MPTP, dopaminergic perikarya were still swollen and, in addition, a significant percentage of them did not stain for thyrotropic hormone (TH).

The lack of staining for a metabolic marker does not necessarily imply that nonstained neurons are not viable. Indeed, the derangement from a normal metabolic balance is reversible to a large extent. Therefore, it may be the case that a loss of TH staining in the midbrain of marmosets treated chronically with MPTP may be due to biochemical alterations brought about by the uptake (and, possibly, build up of toxic compounds into such neurons.

In monkeys of group A treated chronically with MPTP the depletion of dopamine and of its metabolites occurred both in the caudate nucleus and in the putamen. This observation is in keeping with earlier observations showing that in idiopathic Parkinson's disease the putamen is more severely affected than the caudate nucleus, while in MPTP treated monkeys the 2 anatomical components of the neostriatum are equally affected. The da ta further show that this equal distribution of biochemical depletion does not depend on the acute regimen of MPTP administration. This makes it clear that the pathophysiology of Parkinson's diseases and that of MPTP induced parkinsonism (either from acute or from chronic exposure) differ with reference to the distribution of dopamine depletion in the neostriatum.
Aim of this project is the identification of pathogenic mechanisms of parkinsonism. Experiments will be mainly performed on monkeys treated with MPTP and on autopsy speciments of patients affected by Parkinson's disease. The working hypothesis to be tested is based on earlier data collected by the applicants; it assumes that retrograde damage of perikarya occurs after lesion of the terminals, in dopaminergic neurones. An interdisciplinary approach will be used, which takes advantage of different, but complementary, expertise available in the three laboratories involved.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Università Cattolica del Sacro Cuore
Address
Largo Agostino Gemelli 8
00168 Roma
Italy

Participants (2)

KING'S COLLEGE LONDON
United Kingdom
Address
Strand
WC2R 2LS London
Università degli Studi di Cagliari
Italy
Address
Via Dei Genovesi
09100 Cagliari