Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of mental retardation in the USA. Ethanol impairs neuronal survival and function by two major mechanisms: 1) it inhibits insulin signaling required for viability, metabolism, synapse formation, and acetylcholine production;and 2) it functions as a neurotoxicant, causing oxidative stress, DNA damage and mitochondrial dysfunction. Ethanol inhibition of insulin signaling is mediated at the insulin receptor (IR), and caused by impaired binding and attendant reductions in the transmission of survival signals. In addition, increased activation of phosphatases that reverse IR tyrosine kinase and PI3 K activities, exacerbates ethanol?s inhibitory effects on neuronal survival. In contrast, the neurotoxicant effects of ethanol promote DNA damage, and are likely caused by DNA adduct formation through production and accumulation of acetaldehyde, a major metabolite of ethanol. Therefore, chronic in utero ethanol exposure produces a dual state of CNS insulin resistance and oxidative stress. Preliminary studies showed that: 1) genetic or chemical depletion of CNS IR causes FASD-like morphologic, biochemical, and molecular defects; 2) CNS insulin resistance-related impairments can be reduced by treatment with insulin-sensitizers i.e. PPAR agonists;and 3) FASD-associated CNS abnormalities may persist or progress leading to functional deficits in adolescents. In this competing renewal application, experiments proposed in 3 specific aims will characterize the long-term consequences of chronic gestational exposure to ethanol, focusing on early and late adolescence, and determine the degrees and mechanisms in which PPAR agonist treatments prevent or reduce long-term CNS abnormalities caused by chronic in utero exposure to ethanol.
Aim #1 will characterize the long-term consequences of brain insulin resistance in early and late adolescent rats following chronic in utero exposure to ethanol.
Aim #2 will utilize an in vitro model of primary cerebellar neuron cultures generated from control and ethanol-exposed rat pups to characterize the effects of PPAR agonists on neuronal survival and function.
Aim #3 will take advantage of information gained in Aim #2 to optimize an in vivo approach for PPAR agonist therapeutic rescue of the long-term adverse effects of chronic in utero ethanol exposure in relation to CNS neuronal survival and function in early and late adolescence. Graded in utero ethanol exposures will be used to determine if the therapeutic effectiveness of PPAR agonists varies with ethanol dose. In addition, experiments will address the role of gender in relation to the nature and severity of ethanol-induced CNS abnormalities and responsiveness to PPAR agonists. The experimental design is translational because it utilizes a therapeutic strategy that realistically could be applied to humans.

Public Health Relevance

We have linked fetal alcohol spectrum disorder-associated brain abnormalities to insulin resistance and oxidative stress in neurons. Preliminary data suggest that prenatal alcohol exposure may cause persistent or progressive neuronal injury in adolescent brains, and therefore, we now propose to characterize the degree to which pre-natal alcohol exposure causes long-lasting adverse effects on brain function. Our second goal is to evaluate treatments that target the underlying causes of ethanol-mediated brain abnormalities and assess their effectiveness in preventing structural and functional impairments in adolescent brains following chronic prenatal alcohol exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012908-10
Application #
8401171
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2003-02-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2013
Total Cost
$291,313
Indirect Cost
$102,149
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
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Tong, Ming; Longato, Lisa; Ramirez, Teresa et al. (2014) Therapeutic reversal of chronic alcohol-related steatohepatitis with the ceramide inhibitor myriocin. Int J Exp Pathol 95:49-63
de la Monte, Suzanne M (2014) Relationships between diabetes and cognitive impairment. Endocrinol Metab Clin North Am 43:245-67
de la Monte, Suzanne M; Kril, Jillian J (2014) Human alcohol-related neuropathology. Acta Neuropathol 127:71-90
Ramirez, Teresa; Longato, Lisa; Dostalek, Miroslav et al. (2013) Insulin resistance, ceramide accumulation and endoplasmic reticulum stress in experimental chronic alcohol-induced steatohepatitis. Alcohol Alcohol 48:39-52
Lizarazo, Diana; Zabala, Valerie; Tong, Ming et al. (2013) Ceramide inhibitor myriocin restores insulin/insulin growth factor signaling for liver remodeling in experimental alcohol-related steatohepatitis. J Gastroenterol Hepatol 28:1660-8
Mellion, Michelle L; Nguyen, Vananh; Tong, Ming et al. (2013) Experimental model of alcohol-related peripheral neuropathy. Muscle Nerve 48:204-11
de la Monte, Suzanne M (2012) Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease. Front Biosci (Elite Ed) 4:1582-605
de la Monte, Suzanne; Derdak, Zoltan; Wands, Jack R (2012) Alcohol, insulin resistance and the liver-brain axis. J Gastroenterol Hepatol 27 Suppl 2:33-41
de la Monte, Suzanne M (2012) Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease. Drugs 72:49-66

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