The degeneration of the nigrostriatal pathway and depletion of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and melanin pigments, and increases in acetylcholine (Ach) activity are some of the biochemical aberrations in Parkinson's disease (PD) that are associated with the symptoms of tremors, hypokinesia and muscular rigidity. An increase in biological methylation, relative to the synthesis of the biogenicamines, should decrease DA, NE, melanin and 5-HT, increase Ach, and should produce metabolites that are known hypokinetic and cytotoxic agents that conceivably could account for part of the symptoms and the neuronal degeneration in parkinsonism. Preliminary studies showed that the injection of S-adenosyl-L-methionine (SAM), the methyl donor, into the brain caused parkinsonian-type of motor impairments, namely; tremor, rigidity and hypokinesia that were inhibited by 1-dopa, the major therapy for PD, but not d-dopa, the inactive stereoisomer. Following the repeated injections of SAM neuronal degeneration and tyrosine hydroxylase (TH) depletion in the basal ganglia were also detected, so SAM may be of importance in PD. This project will further study the parkinsonian-types of motor impairments caused by SAM in the rat. In particular, the dose spectrum, acute versus the chronic, and the effects of specific pharmacological agents will be examined. Correlation will be made with changes in DA, NE, 5-HT and their methylated metabolites, as well as choline and Ach. The activities of TH and choline acetyl transferase and neuronal degeneration, morphological and population changes will also be studied. The challenges will help us understand the mechanism of action of SAM in inducing the motor and neuronal aberrations and will screen for potential synergists and antagonists. The information generated will contribute to our knowledge of the CNS pharmacology and toxicology of SAM and show whether increased methylation will produce imbalances that resemble the symptoms of PD. The studies may help in the development of a model for parkinsonism, and in the longer terms, it might turn out that an excess of methylation may be found to be associated with PD; may be as a secondary factor. The data will allow us to develop strategy for both basic and clinical studies. The role of SAM is extensive and profound, affecting the metabolism of, not only, neurotransmitters but also RNA, DNA, membranes proteins and lipids. As a rate limiting factor in methylation, whose activities increased with aging the pathological role of SAM is also likely to be profound; although at present very under-rated.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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Meharry Medical College
Schools of Medicine
United States
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