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BH4 - a bad actor?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by adreno, Apr 27, 2012.

  1. adreno

    adreno 3% neanderthal

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    Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: implications for Parkinson's disease.

    Choi HJ, et al. Show all

    Neurochem Int. 2006 Mar;48(4):255-62. Epub 2005 Dec 15.

    Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-ku, Seoul 138-736, South Korea.

    Abstract Parkinson's disease (PD) is a neurodegenerative disorder associated with a selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of PD is not clearly understood, oxidative stress and mitochondrial dysfunction are thought to play a role. We have previously suggested tetrahydrobiopterin (BH4), an obligatory cofactor for the dopamine synthesis enzyme tyrosine hydroxylase and present selectively in monoaminergic neurons in the brain, as an endogenous molecule that contributes to the dopaminergic neurodegeneration. In the present study, we show that BH4 leads to inhibition of activities of complexes I and IV of the electron transport chain (ETC) and reduction of mitochondrial membrane potential. BH4 appears to be different from rotenone and MPP(+), the synthetic compounds used to generate Parkinson models, in its effect on complex IV. BH4 also induces the release of mitochondrial cytochrome c. Pretreatment with the sulfhydryl antioxidant N-acetylcysteine or the quinone reductase inducer dimethyl fumarate prevents the ETC inhibition and cytochrome c release following BH4 exposure, suggesting the involvement of quinone products. Together with our previous observation that BH4 leads to generation of oxidative stress and selective dopaminergic neurodegeneration both in vitro and in vivo via inducing apoptosis, the mitochondrial involvement in BH4 toxicity further suggests possible relevance of this endogenous molecule to pathogenesis of PD.

    PMID 16343695
  2. adreno

    adreno 3% neanderthal

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    Particular vulnerability of rat mesencephalic dopaminergic neurons to tetrahydrobiopterin: Relevance to Parkinson's disease.

    Lee SY, et al. Show all

    Neurobiol Dis. 2007 Jan;25(1):112-20. Epub 2006 Oct 16.

    Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-ku, Seoul, 138-736, Korea.

    Abstract We determined whether tetrahydrobiopterin(BH4), an endogenous cofactor for dopamine(DA) synthesis, causes preferential damage to DArgic neurons among primary cultured rat mesencephalic neurons and whether the death mechanism has relevance to Parkinson's disease (PD). DArgic neurons were more vulnerable to BH4 than non-DArgic neurons, exhibiting sensitivity at lower concentrations, evident by morphological and neurotransmitter uptake studies. BH4-exposed DArgic neurons showed (1) increased TUNEL staining and activated caspase-3 immunoreactivity, indicative of apoptotic death; (2) mitochondrial membrane potential loss and increased cytosolic cytochrome c, suggesting mitochondrial dysfunction; (3) increased level of oxidized proteins and protection by antioxidants, indicative of oxidative stress; and (4) increased ubiquitin immunoreactivity, suggesting alteration of protein degradation pattern. Percent of cells positive for these parameters were much higher for DArgic neurons, demonstrating preferential vulnerability. Therefore, the DArgic neuronal damage induced by BH4, the molecule synthesized and readily upregulated in DArgic neurons and activated microglia, suggests physiological relevance to the pathogenesis of PD.

    PMID 17049260
  3. nanonug

    nanonug Senior Member

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    These studies are very interesting and confusing. For example, from "Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures", one reads:

    "Accordingly, increasing intracellular tetrahydrobiopterin levels may protect against oxidative stress by complex-I inhibition."

    My gut reaction is that it's maybe oxidized BH4 that is causing the problems in the above two studies but I would definitely would like to see more evidence either way.
  4. adreno

    adreno 3% neanderthal

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  5. nanonug

    nanonug Senior Member

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    All these studies are coming from the same group of people, including the ones you originally posted. I'd like to see stuff from different people/groups to make sure we are not dealing with bias resulting from emotional investment.
  6. adreno

    adreno 3% neanderthal

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    Right. Here's a study with the opposite viewpoint (not from the same group):

    Abstract

    Within the central nervous system, tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis. In addition, BH4 is now established to be an essential cofactor for all isoforms of nitric oxide synthase (NOS). Inborn errors of metabolism affecting BH4 availability are well documented and the clinical presentation can be attributed to a paucity of dopamine, serotonin, and nitric oxide (NO) generation. In this article, we have focussed upon the sensitivity of BH4 to oxidative catabolism and the observation that when BH4 is limiting some cellular sources of NOS may generate superoxide whilst other BH4 saturated NOS enzymes may be generating NO. Such a scenario could favor peroxynitrite generation. If peroxynitrite is not scavenged, e.g., by antioxidants such as reduced glutathione, irreversible damage to critical cellular enzymes could ensue. Such targets include components of the mitochondrial electron transport chain, alpha ketoglutarate dehydrogenase and possibly pyruvate dehydrogenase. Such a cascade of events is hypothesized, in this article, to occur in neurodegerative conditions such as Parkinsons and Alzheimers disease.

    http://www.springerlink.com/content/r0j4u6437613155m/
  7. nanonug

    nanonug Senior Member

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    At the end of the day, it seems to me that it is very important to minimize peroxynitrite production. Even on the first abstract you posted, it says: "Pretreatment with the sulfhydryl antioxidant N-acetylcysteine or the quinone reductase inducer dimethyl fumarate prevents the ETC inhibition and cytochrome c release following BH4 exposure".

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