Posted by raybakes on October 16, 2004, at 7:29:48
In reply to Re: brain fog and creatine/methylation » raybakes, posted by Larry Hoover on October 15, 2004, at 13:29:22
Hi Lar,
came across these two abstracts - the first one seems to suggest that dopamine degradation via the quinone pathway (monoamine oxidase?) is neurotoxic, but methylation of dopamine via COMT, bypasses that pathway.
Int J Mol Med. 2004 Mar;13(3):343-53. Related Articles, Links
CNS dopamine oxidation and catechol-O-methyltransferase: importance in the etiology, pharmacotherapy, and dietary prevention of Parkinson's disease.Zhu BT.
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. BTZhu@cop.sc.edu
In this article, a particular emphasis has been placed on the conceptual development and understanding of the unique pathogenic changes that are indigenous to the striatal dopaminergic neurons as an important etiological factor in human Parkinson's disease (PD) as well as on the understanding of their clinical implications. Specifically, I have discussed the etiological roles of central nervous system dopamine oxidation in PD, along with a critical review of the available evidence in support of the proposed hypotheses. The chemically-reactive dopamine quinone/semiquinone intermediates are known to be highly neurotoxic and potentially genotoxic. There is considerable evidence for the suggestion that the long-term use of levodopa accelerates the progression of PD. In comparison, centrally-acting non-catechol dopamine receptor agonists would be an excellent alternative to levodopa for the treatment of PD (particularly for late-stage PD) because these agents would not undergo redox cycling to cause oxidative neuronal damage. Catechol-O-methyltransferase (COMT)-mediated methylation metabolism of catecholamine neurotransmitters is a crucial first-line detoxification pathway, and its role in the causation and prevention of PD is also discussed. On the basis of the modulation of COMT-mediated methylation of catecholamines, it is mechanistically explained that hyperhomocysteinemia would be a pathogenic factor in PD whereas vitamins B6, B12, and folate would be a protective factor. Lastly, according to the mechanistic understanding developed here, a novel dietary strategy is proposed that is specifically tailored toward lowering the risk of human PD, which includes eating a nutritionally-balanced diet that contains adequate (but not excessive) amounts of fruits and vegetables, along with adequate dietary supplementation of S-adenosyl-L-methionine, vitamins C, B6, B12, and folate. It is believed that these conceptual developments would also aid in our better understanding of other age-related neurodegenerative disorders, such as Alzheimer's and Huntington's diseases.
The second one talks about biopterin and it's precursor possibly acting as anti-oxidants in dopaminergenic neurons..
J Neurochem. 2003 Apr;85(1):214-23. Related Articles, Links
Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures.Madsen JT, Jansen P, Hesslinger C, Meyer M, Zimmer J, Gramsbergen JB.
Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, Odense, Denmark.
Complex-I inhibition and oxidative processes have been implicated in the loss of nigral dopamine neurones in Parkinson's disease and the toxicity of MPTP and its metabolite MPP+. Tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase, may act as an antioxidant in dopaminergic neurones and protects against the toxic consequences of glutathione depletion. Here we studied the effects of manipulating tetrahydrobiopterin levels on MPP+ toxicity in organotypic, rat ventral mesencephalic slice cultures. In cultures exposed to 30 micro m MPP+ for 2 days, followed by 8 days 'recovery' in control medium, we measured dopamine and its metabolites in the tissue and culture medium by HPLC, lactate dehydrogenase release to the culture medium, cellular uptake of propidium iodide and counted the tyrosine hydroxylase-immunoreactive neurones. Inhibition of tetrahydrobiopterin synthesis by 2,4-diamino-6-hydroxypyrimidine had no significant synergistic effect on MPP+ toxicity. In contrast, the tetrahydrobiopterin precursor l-sepiapterin attenuated the MPP+-induced dopamine depletion and loss of tyrosine hydroxylase-positive cells in a dose-dependent manner with 40 micro m l-sepiapterin providing maximal protection. Accordingly, increasing intracellular tetrahydrobiopterin levels may protect against oxidative stress by complex-I inhibition
poster:raybakes
thread:402926
URL: http://www.dr-bob.org/babble/alter/20040928/msgs/403760.html