Institute of Biomedical Studies

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Browsing Institute of Biomedical Studies by Author "Bottiglieri, Teodoro, 1958-"

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    The effect of dietary folate deficiency and age on methylation metabolites, neurotransmitters, and behavior in mice.
    (2011-01-05T19:46:26Z) Wasek, Brandi Lynn.; Bottiglieri, Teodoro, 1958-; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.
    Severe folate deficiency caused by inborn errors of metabolism has profound deleterious effects in the CNS such as mental retardation, psychiatric disorders, seizures and myelopathy. Mild folate deficiency, due to dietary insufficiency, drugs, or a common mutation in the gene encoding methylenetetrahydrofolate reductase (MTHFR C677T), are associated with an increased risk for depression and dementia, especially in the aging population. The metabolism of folate is intimately linked with the synthesis of S-adenosylmethionine (SAM), the sole source of methyl groups required in methyltransferase reactions. S-adenosylhomocysteine (SAH), a product of methylation reactions, accumulates in folate deficiency due to increased conversion from homocysteine. Recent studies have linked hyperhomocysteinemia and hypomethylation to gene activity, as well as methylation dependent post-translational modification of proteins and neurotransmitter metabolism in depression and dementia. To better define the role of folate deficiency in CNS function, we fed young and old C57BL/6J mice folate deficient diets for 3 months and old heterozygous tg-MTHFR mice a low folate diet for 6 months. Mice were tested for grip strength, coordination, open field activity, and spatial memory. After treatment mice were sacrificed by CO2 asphyxiation or microwave radiation. Blood, peripheral and regional brain tissues were processed for the analysis of methylation and neurotransmitter metabolites. Age did not influence brain methylation metabolites in C57BL/6J mice. Low folate and folate deficient diets decreased the SAM/SAH ratio, an indicator of methylation status in most brain regions from C57BL/6J and heterozygous tg-MTHFR mice. Overall, the effects of folate deficiency were not exacerbated by age in C57BL/6J mice. Brain methylation metabolites differed significantly depending on the method of sacrifice. Specifically, folate deficiency decreased SAM in mice sacrificed by microwave radiation and increased SAH in mice sacrificed by asphyxiation. Folate deficiency reduced dopamine and serotonin turnover in several brain regions although the levels of the parent neurotransmitters were unaffected. Choline and acetylcholine levels were reduced by folate deficiency in the mid-brain. Folate deficiency impaired open field behavior, but did not have any significant effect on spatial memory. These studies help to further our understanding of the mechanisms involved in folate deficiency on CNS function in the aging brain.
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    Gamma Hydroxybutyrate (GHB): mechanisms of central nervous system toxicity.
    (2006-07-31T01:14:52Z) Lyng, Eric E.; Bottiglieri, Teodoro, 1958-; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.
    Gamma Hydroxybutyrate (GHB) is an endogenous metabolite of gamma-aminobutyric acid (GABA) and a putative neurotransmitter found in mammalian brain. The illicit use of GHB is a growing health care concern in the U.S. Low doses have euphoric and stimulatory effects while high doses act as a CNS depressant and can cause respiratory failure. In addition to fatalities and drug facilitated rape, in 2004 over 7000 GHB overdoses were reported in the U.S. Gamma Butyrolactone (GBL) and 1,4-Butanediol (1,4-BD), precursors of GHB, can cause similar effects after being converted to GHB in the body. While GHB is a Schedule I compound, recently it was given a Schedule III classification as a drug for treatment of cataplexy associated with narcolepsy. Individuals affected by the inherited disorder succinic semialdehyde dehydrogenase (SSADH) deficiency have significant elevation of GABA and GHB in body tissues, and a range of neurological complications. Currently there is no treatment option for a GHB overdose situation or for SSADH patients. GHB has been shown to inhibit striatal dopamine release leading to sedation and loss of locomotor activity in rodents. However, GHB’s mechanism of action is poorly understood. This dissertation investigated acute and chronic effects of GBL, a precursor to GHB, on locomotor function and monoamine neurotransmitter metabolism in mice. Dose response studies were performed to characterize the effects of GBL. Compounds aimed at increasing central dopaminergic activity or antagonism of GABAergic activity were tested for their ability to antagonize the locomotor effects induced by GBL. In total, eight different compounds were studied of which pergolide and nomifensine were successful at antagonizing the loss of locomotor activity when administered either prior to or after GBL. Chronic administration of GBL over the course of 14 days was evaluated in mice using a rotarod system. These studies did not reveal any long term detrimental effect of GBL on locomotor function. This dissertation is the first report showing the ability of pergolide and nomifensine to antagonize the loss of locomotor activity induced by GBL. These studies provide insight into treatment options for GHB toxicity or overdose as well as for patients with SSADH deficiency.
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    Metabolomic analysis in Parkinson’s and Alzheimer’s disease.
    (May 2023) Kalecký, Karel, 1991-; Bottiglieri, Teodoro, 1958-
    Parkinson’s disease (PD) and Alzheimer’s disease (AD) are two most prevalent forms of neurodegeneration with progressively disabling symptoms and no cure, leading to a high burden to caregivers and society in general. The underlying disease mechanisms remain unclear and more research is required to develop novel therapies. Metabolomics is a scientific area, which explores biochemical processes happening inside an organism by measuring their intermediates. Thus, metabolomics studies the high-level functioning as also influenced by external factors including nutrition, environment, and microorganisms, directly reflecting the final phenotype. Recent technological advancements have enabled performing accurate metabolomic measurements across many pathways of metabolism simultaneously. Here, we present a series of metabolomic experiments that allows new insights into the disease mechanisms in PD and AD. Specifically, we searched for disease-related metabolic differences via case-control association studies. We focused on human brain frontal cortex and putamen, the direct location of the pathologies, combining broad investigation across many metabolic pathways with detailed analysis focused on one-carbon metabolism. Other experiments were conducted with human plasma to search for potential diagnostic biomarkers in AD and PD. Additionally, we included a mouse model of PD to compare its metabolic changes with real disease in human. The majority of experiments were targeted using liquid chromatography and flow injection analysis coupled to tandem mass spectrometry. Untargeted analysis was based on comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry. Furthermore, we emphasize the importance of data processing and analysis, for which we have developed several new methods. Our results are summarized in individual chapters. The most fascinating finding implicates the anti-parkinsonian medication levodopa as a direct contributor to dementia in susceptible individuals through the accumulation of homocysteine. The susceptibility is largely explained by low amounts of betaine (trimethylglycine) and B vitamins that act as enzymatic cofactors in one-carbon metabolism, combined with specific genetic polymorphisms. Similar changes were observed in AD. The risk of developing dementia, especially in PD, could thus be potentially reduced by low-cost nutritional intervention. Collectively, our work represents a systematic effort in metabolomics in PD and AD, and constitutes a major scientific contribution in biomedical research of these diseases.