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New Emerging Team on Fetal Alcohol Syndrome: Oxidative Stress and Innovative Therapies

New Emerging Team on Fetal Alcohol Syndrome: Oxidative Stress and Innovative Therapies. Leader: James F. Brien, Queen’s University. Canadian Institutes of Health Research. CIHR NEW EMERGING TEAM ON FAS. Antioxidant Therapy. C. A. B. Biomarkers. Oxidative Stress. Rationale.

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New Emerging Team on Fetal Alcohol Syndrome: Oxidative Stress and Innovative Therapies

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  1. New Emerging Team on Fetal Alcohol Syndrome:Oxidative Stress and Innovative Therapies Leader: James F. Brien, Queen’s University Canadian Institutes of Health Research

  2. CIHR NEW EMERGING TEAM ON FAS Antioxidant Therapy C A B Biomarkers Oxidative Stress

  3. Rationale FAS is a NATIONAL RESEARCH PRIORITY. Speech from the Throne, January 30, 2001 CIHR Initiative for New Emerging Teams of Scientists in Focused Research Areas, July 2001 Institute of Neurosciences, Mental Health & Addiction research focus on : Neurodevelopment and Early Life Events including FAS

  4. CIHR NEW EMERGING TEAM ON FAS Antioxidant Therapy C I II III IV A to C represent the Research Objectives. I to IV denote the four CIHR “Pillars”: Basic Biomedical (I) Applied Clinical (II) Health Services & Systems (III) Population Health (IV) A B I II I II IV Biomarkers Oxidative Stress

  5. Members of NET on FAS Alan D. Bocking, obstetrics and maternal-fetal physiology, University of Western Ontario; James F. Brien,basic developmental pharmacology & toxicology, Queen’s University; Gideon Koren,pediatrics and clinical pharmacology & toxicology, Hospital for Sick Children, Toronto; Stephen G. Matthews,developmental neuro-endocrinology, University of Toronto; James N. Reynolds,developmental neuroscience, Queen’s University; Joanne Rovet,developmental neuropsychology, Hospital for Sick Children; Wendy J. Ungar,health economics and population health, Hospital for Sick Children.

  6. Research Objectives • To test the hypothesis that oxidative stress is an important mechanism of the brain injury of FAS; • To identify and validate reliable biomarkers for fetal ethanol exposure at critical periods of vulnerability during gestation and for the magnitude of fetal ethanol exposure; • To discover and develop innovative antioxidant treatment strategies for preventing or attenuating ethanol-induced oxidative stress in fetal life and decreasing its impact on brain function in postnatal life.

  7. Proposed Mechanisms of FAS FAS

  8. Objective A To determine whether oxidative stress is a mechanism of the brain injury of FAS. Definition of Oxidative Stress Oxygen radicals: highly reactive molecules generated during cell metabolism. Cell degradation of O2 radicals Cell production of O2 radicals Overabundance of O2 radicals/Oxidative Stress

  9. Oxidative Stress / Increased Reactive Oxygen Species H2O2 O2– OH  Proposed Mechanism of Brain Injury of FAS Maternal Ingestion of Ethanol Fetal Brain Exposure to Ethanol Damage to Key Cell Molecules (DNA, Proteins, Membrane Phospholipids) Fetal Brain Nerve Cell Death Brain Injury of FAS

  10. Coronal Section of the Brain

  11. Measures of Oxidative Stress 1. F2-isoprostanes: Products of chemical reaction reactive oxygen + membrane species phospholipids lipid peroxidation 2. Neuroimaging of brain: magnetic resonance imaging - structural changes. magnetic resonance spectroscopy - oxidative stress.

  12. Investigation of Occurrence of Oxidative Stress 1. Guinea pig study (fetus, neonate and juvenile) of key brain areas: F2-isoprostanes. 2. Human study of neonatal umbilical cord blood and amniotic fluid: F2-isoprostanes. 3. Study of FAS children: neuroimaging of brain for evidence of oxidative stress and relationship to structural changes.

  13. Objective B To identify biochemical markers in meconium (first stool passed by neonate) as measure of: gestational time and magnitude of fetal ethanol exposure resulting from maternal drinking. Fatty acid ethyl esters (FAEEs) (family of chemical compounds) Products of enzymatic reaction Fatty acids + Ethanol in in body alcoholic beverages

  14. Investigation of FAEEs as Biomarkers of Fetal Ethanol Exposure 1. Pregnant sheep study: identification of members of FAEEs family that constitute biomarkers of gestational time and magnitude of fetal ethanol exposure. 2. Human meconium lab study: validation of FAEEs as reliable biomarkers of fetal ethanol exposure. 3. Human meconium clinical study: elucidation of prevalence of alcohol consumption by pregnant women in Canada.

  15. Objective C To determine therapeutic efficacy and cost-effectiveness of antioxidant therapy for prevention/attentuation of brain injury of FAS Vitamin C + Vitamin E (pharmacological doses)

  16. Investigation of Antioxidant Therapy 1. Guinea pig study: evaluation of efficacy of vitamin C + vitamin E to prevent/attenuate brain injury produced by chronic fetal ethanol exposure. 2. Human study: evaluation of therapeutic efficacy and cost-effectiveness of vitamin C + vitamin E in preventing/attenuating brain injury of FAS.

  17. CIHR NEW EMERGING TEAM ON FAS Antioxidant Therapy

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