NUCLEAR MICROSCOPIC INVESTIGATIONS INTO THE ELEMENTAL CHANGES IN THE SUBSTANTIA-NIGRA OF UNILATERALLY MPTP-LESIONED PARKINSONIAN MONKEYS

Various transition metals, particularly iron, have been implicated in the aetiology of the neurodegenerative disease, Parkinson's disease, i n which there is a characteristic loss of cells in the substantia nigr a (SN) region of the brain. In this study, monkeys were unilaterally l esioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyrid ine (MPTP) to obtain primate models of parkinsonism, with the non-lesi oned side of the brain serving as controls. The monkeys were sacrifice d at one day, one week, two weeks, one month and one year after lesion ing to investigate the time dependent elemental changes in the parkins onian SN. Sections of the brain encompassing both the lesioned and non -lesioned SNs were analysed using the National University of Singapore nuclear microscope. Adjacent sections were tyrosine hydroxylase (TH) immunohistochemically stained to provide complementary information on dopaminergic cell loss and to facilitate definition of the SN boundari es during data analysis. In one-day and one-week monkeys (representing early stages of the disease), there were no changes in elemental conc entrations within experimental errors and the adjacent TH-stained sect ions did not show apparent cell loss in the SN. At two weeks, cell los s was seen in the lesioned SN compared to the control SN. Although the re was no bulk increase in SN iron, localised accumulation of iron in granules containing up to 15% by weight iron was observed in the lesio ned SN of one of the two-week monkeys. An average 15% increase in nigr al iron, significant at the 90% confidence level (p < 0.1), was seen i n the one-month monkeys. TH-stained sections for the one-month monkeys showed cell loss in the lesioned SN. In one-year samples (representin g the advanced stage of the disease) there was a significant (p < 0.05 ) 56% increase in iron, 14% increase in phosphorous and a 20% decrease in copper. Here an almost complete loss of cells in the lesioned SN w as apparent from the adjacent TH-stained sections. These preliminary r esults suggest that while bulk increase in iron may seem to follow cel l death, localised accumulation of SN iron in the early stages of the disease may play an important role in initiating and/or accelerating n igral cell death. (C) 1997 Elsevier Science B.V.