Post on 22-Feb-2016
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New Emerging Team on Fetal Alcohol Syndrome:Oxidative Stress and Innovative Therapies
Leader: James F. Brien, Queen’s University
Canadian Institutes of Health Research
2BiomarkersB
Antioxidant Therapy
AOxidative Stress
C
CIHR NEW EMERGING TEAM ON FAS
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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 & Addictionresearch focus on :
Neurodevelopment and Early Life Events including FAS
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BiomarkersB I II IVAI II
Oxidative Stress
C I IIIII IV
Basic Biomedical (I)
Health Services & Systems (III)
Applied Clinical (II)
Population Health (IV)
A to C represent the Research Objectives.I to IV denote the four CIHR “Pillars”:
CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy
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Members of NET on FASAlan 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.
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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.
7FAS
Proposed Mechanisms of FAS
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Objective ATo determine whether oxidative stress is a mechanism
of the brain injury of FAS.
Definition of Oxidative StressOxygen radicals: highly reactive molecules generated
during cell metabolism.
Cell production
of O2 radicals
Cell degradation
of O2 radicals
Overabundance of O2 radicals/Oxidative Stress
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Proposed Mechanism of Brain Injury of FASMaternal Ingestion of Ethanol
Fetal Brain Exposure to Ethanol
Damage to Key Cell Molecules(DNA, Proteins, Membrane Phospholipids)
Fetal Brain Nerve Cell Death
Oxidative Stress / Increased Reactive Oxygen SpeciesH2O2 O2
– OH
Brain Injury of FAS
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Coronal Section of the Brain
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Measures of Oxidative Stress
Products of chemical reactionreactive oxygen + membrane
species phospholipids
2. Neuroimaging of brain:magnetic resonance imaging - structural changes.magnetic resonance spectroscopy - oxidative stress.
1. F2-isoprostanes:
lipid peroxidation
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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.
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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 reactionFatty acids + Ethanol in in body alcoholic beverages
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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.
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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)
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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.
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BiomarkersB I II IV
Prevention-Intervention
TrainingD
I IIIII IV
AI IIOxidative Stress
C I IIIII IV
Basic Biomedical (I)
Health Services & System s (III)
Applied Clinical (II)
Population Health (IV)
A to D represent the four Objectives.I to IV denote the four CIHR “Pillars”:
CIHR NEW EMERGING TEAM ON FAS
Antioxidant Therapy