http://www.ncbi.nlm....st_uids=9247319Life Sci. 1997;61(5):495-502. Related Articles,Links
Depletion of nigrostriatal and forebrain tyrosine hydroxylase by S-adenosylmethionine: a model that may explain the occurrence of depression in Parkinson's disease.
Charlton CG.
College of Pharmacy, Florida A and M University, Tallahassee 32307, USA.
The loss of nigrostriatal tyrosine hydroxylase (TH), dopamine and dopaminergic neurons are the major pathology of Parkinson's disease (PD). These catecholaminergic changes are responsible for the symptoms of tremor, hypokinesia and rigidity. Depression is also a major symptom in PD, but the cause is unknown. The impairments of catecholaminergic fibers in the frontal lobe may be involved, because the frontal lobe of the cerebrum is involved in the regulation of mood, and decreased catecholaminergic activity in the frontal lobe is related to behavioral depression. The changes that damage the nigrostriatal dopamine system and induce motor impairments may also damage the forebrain catecholamine fibers and induce depression. It means that manipulations that damage the nigrostriatum (NS) and induce parkinsonism may also deplete TH in the frontal cortex. Such an effect would suggests a basis for the depression seen in PD. The injection of S-adenosyl-L-methionine (SAM), the biological methyl donor, into the brain of rats damaged the NS, depleted TH and caused tremor and hypokinesia. SAM may interfere also with the forebrain TH, which may help to explain the occurrence of depression in PD. Experiments were designed to test such a hypothesis. The results showed that SAM caused a loss of immunoreactive nerve fibers and it decreased the intensity of TH-immunoreactivity (IR) in the frontal cortex. These changes were accompanied with the loss of cells and the depletion of TH-IR from nerve fibers in the SN and the caudate nucleus. Other studies showed that SAM depletes DA and since SAM induces PD-like changes the results may be relevant to the co-occurrence of PD symptoms and depression. A single biological manipulation may impair the nigrostriatal dopaminergic neurons as well as the frontal cortex catecholaminergic fibers.
http://www.ncbi.nlm....st_uids=7888091Mol Neurobiol. 1994 Aug-Dec;9(1-3):149-61. Related Articles,Links
Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain. Support for an excess methylation hypothesis for parkinsonism.
Charlton CG, Mack J.
Department of Pharmacology, Meharry Medical College, Nashville, TN 37208.
The major symptoms of Parkinson's disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal dopaminergic terminals. Norepinephrine, serotonin, and melanin pigments are also decreased and cholinergic activity is increased. The cause of PD is unknown. Increased methylation reactions may play a role in the etiology of PD, because it has been observed recently that the CNS administration of S-adenosyl-L-methionine (SAM), the methyl donor, caused tremors, hypokinesia, and rigidity; symptoms that resemble those that occur in PD. Furthermore, many of the biochemical changes seen in PD resemble changes that could occur if SAM-dependent methylation reactions are increased in the brain, and interestingly, L-DOPA, the most effective drug used to treat PD, reacts avidly with SAM. So methylation may be important in PD; an idea that is of particular interest because methylation reactions increase in aging, the symptoms of PD are strikingly similar to the neurological and functional changes seen in advanced aging, and PD is age-related. For methylation to be regarded as important in PD it means that, along with its biochemical reactions and behavioral effects, increased methylation should also cause specific neuronal degeneration. To know this, the effects of an increase in methylation in the brain were studied by injecting SAM into the lateral ventricle of rats. The injection of SAM caused neuronal degeneration, noted by a loss of neurons, gliosis, and increased silver reactive fibers in the SN. The degeneration was accompanied with a decrease in SN tyrosine hydroxylase (TH) immunoreactivity, and degeneration of TH-containing fibers. At the injection site in the lateral ventricle it appears that SAM caused a weakening or dissolution of the intercellular substances; observed as a disruption of the ependymal cell layer and the adjacent caudate tissues. SAM may also cause brain atrophy; evidenced by the dilation of the cerebral ventricle. Most of the SAM-induced anatomical changes that were observed in the rat model are similar to the changes that occur in PD, which further support a role of SAM-dependent increased methylation in PD.
http://www.ncbi.nlm....st_uids=8503824Behav Neural Biol. 1993 May;59(3):186-93. Related Articles,Links
S-adenosyl-L-methionine decreases motor activity in the rat: similarity to Parkinson's disease-like symptoms.
Crowell BG Jr, Benson R, Shockley D, Charlton CG.
Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37221.
S-Adenosyl-L-methionine has been shown to cause Parkinson's disease-like effects that include hypokinesia, tremor, rigidity, and abnormal posture. S-Adenosyl-L-methionine is the rate-limiting endogenous methyl donor. Its biochemical role, which includes the metabolism of dopamine and the synthesis of acetylcholine, also resembles the changes that occur in Parkinson's disease. Therefore, S-adenosyl-L-methionine may play a role in Parkinson's disease-like motor impairments. In this study we manipulated the levels of S-adenosyl-L-methionine in the brain of rats and quantified the changes in hypokinetic type motor activity that seems to occur also in Parkinsonism. Male Sprague-Dawley rats were anesthetized with chloral hydrate (400 mg/kg/rat), cannulated, injected into the lateral ventricle with S-adenosyl-L-methionine or saline, and their motor activity was measured in a Digiscan Animal Activity Monitor. Other behaviors were also observed. S-Adenosyl-L-methionine caused hypokinesia, tremor, rigidity, and abnormal posture in rats. Motor activity was significantly decreased within 2 min postinjection. The hypokinesia was maximal at 60 min, at which time a 65, 75, and 90% decrease for total distance, number of movements, and the ratio of total distance to the number of movements occurred, respectively. The hypokinetic effect of S-adenosyl-L-methionine was dose dependent. A 65.0 and 51.3% decrease in total distance and number of movements, respectively, were observed following 9.38 x 10(-9) mol. The 5.0 x 10(- mol caused a reduction of 73.42 and 57.66% and 4.0 x 10(-7) mol/rat caused a 94.9 and 78.43% decrease, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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