Authors
Charlton CG. Crowell B Jr.
Institution
Department of Physiology, Meharry Medical College, Nashville, TN 37208.
Title
Parkinson's disease-like effects of S-adenosyl-L-methionine: effects of
L-dopa.
Source
Pharmacology, Biochemistry & Behavior. 43(2):423-31, 1992 Oct.
Abstract
The major symptoms of Parkinson's disease (PD) are due to degeneration of the
nigrostriatal pathway and depletion of dopamine (DA). Tyrosine hydroxylase
(TH), norepinephrine (NE), serotonin (5-HT), and melanin pigments are also
decreased and acetylcholinergic activity increased. Biochemically, increased
methylation can cause the depletion of DA, NE, 5-HT, and melanin pigments and
also an increase of acetylcholine; thus, increased methylation can present a
biochemical picture that resembles the biochemical changes that occur in PD.
During the therapy of PD with L-dopa, it is well known that L-dopa reacts
avidly with S-adenosyl-L-methionine (SAM), the biologic methyl donor, to
produce 3-O-methyl-dopa. Correspondingly, L-dopa has been shown to deplete
the concentration of SAM, and SAM has been found to induce PD-like motor
impairments in rodents; therefore, an excess of SAM-dependent methylation may
be associated with Parkinsonism. To further study the effects of methylation,
SAM was injected into the lateral ventricle of rats. SAM caused tremors,
rigidity, abnormal posture, and dose-related hypokinesia. Doses of 9.38, 50,
and 400 nM/rat caused 61.9, 73.4, and 94.8% reduction, respectively, of motor
activity. A 200-mg/kg IP dose of L-dopa, given before 50 nM SAM, blocked the
SAM-induced hypokinesia. SAM also caused a decrease in TH immunoreactivity,
apparent degeneration of TH-containing fibers, loss of neurons, and the
accumulation of phagocytic cells in the substantia nigra. These results
showed that excess SAM in the brain, probably due to its ability to increase
methylation, can induce symptoms that resemble some of the changes that occur
in PD.