Prolonged alcohol abuse causes brain damage, but the mechanisms remain uncertain. From studies with adult rats in vivo and rat brain slice cultures, we know that chronic binge alcohol (ethanol) exposure and withdrawal ("alcoholic" levels, 70-120 mM) cause hippocampal/cortical neurodegeneration that (a) is not typically excitotoxic;(b) entails brain edema (diuretics prevent the edema and neurodamage);(c) involves oxidative stress (antioxidants neuroprotect);and (d) requires phospholipase A2 (PLA2) activation, which mobilizes (JO-6 arachidonic acid (AA), a free radical source (PLA2 inhibitors reduce neurodamage). Notably, u)-3 fatty acid docosahexaenoic acid (DHA) suppresses AA release and provides neuroprotection. Meanwhile, research by H.Y. Kim, NIAAA intramural investigator and DHA/alcohol research pioneer, indicates a related "lipid-based" mechanism of alcohol-induced apoptotic neurodamage involving depletion of DHA-containing phosphatidylserine (PS) and reduced pro-survival signaling that are also prevented by DHA supplementation. With Dr. Kim's collaboration, this U01 application explores functional connections between these two neurodegenerative mechanisms, and how DHA protection is realized. We propose to research three aims, posed here as questions, using adult-age (as opposed to usual adolescent) rat organotypic hippocampal/ entorhinal cortical slice cultures chronically exposed to binge alcohol/ withdrawal;techniques include biolistic transfection, antisense oligos and HPLC/MS analysis.
Aim I : Are alcohol-induced reductions of membrane PS, DHA content and downstream pro-survival kinase (Akt, raf-1) activities causative events in subsequent neurodegeneration/apoptosis? Aim 2: Are alcohol-induced edema, PLA2 activation, AA mobilization and oxidative stress leading to neurodegeneration coupled to alcohol-induced changes in membrane aminophospholipids and survival kinase activities? and Aim 3: Does DHA-supplemented neuroprotection during binge alcohol entail DHA incorporation into/ potentiation of membrane PS, increased pro-survival signaling, reduced PLA2 activity and diminished AA release/oxidative stress? The lipid analyses in Aims 1 &3 are accomplished in Dr. Kim's NIAAA laboratory;all other research is at Loyola University.

Public Health Relevance

This U01 collaborative study of chronic binge alcohol's potential neuroinflammatory, lipid-based mechanisms of brain toxicity and DHA neuroprotection holds the promise of yielding nutritional and other insights that can be therapeutically valuable in reducing neurodegeneration and brain dysfunction in alcohol abuse and withdrawal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA018279-04
Application #
8317642
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Regunathan, Soundar
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$333,342
Indirect Cost
$110,371
Name
Loyola University Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Collins, Michael A; Tajuddin, Nuzhath; Moon, Kwan-Hoon et al. (2014) Alcohol, phospholipase A2-associated neuroinflammation, and ?3 docosahexaenoic acid protection. Mol Neurobiol 50:239-45
Moon, Kwan-Hoon; Tajuddin, Nuzhath; Brown 3rd, James et al. (2014) Phospholipase A2, oxidative stress, and neurodegeneration in binge ethanol-treated organotypic slice cultures of developing rat brain. Alcohol Clin Exp Res 38:161-9
Collins, Michael A; Moon, Kwan-Hoon; Tajuddin, Nuzhath et al. (2013) Docosahexaenoic acid (DHA) prevents binge ethanol-dependent aquaporin-4 elevations while inhibiting neurodegeneration: experiments in rat adult-age entorhino-hippocampal slice cultures. Neurotox Res 23:105-10
Tajuddin, Nuzhath F; Przybycien-Szymanska, Magdalena M; Pak, Toni R et al. (2013) Effect of repetitive daily ethanol intoxication on adult rat brain: significant changes in phospholipase A2 enzyme levels in association with increased PARP-1 indicate neuroinflammatory pathway activation. Alcohol 47:39-45
Collins, Michael A; Neafsey, Edward J (2012) Ethanol and adult CNS neurodamage: oxidative stress, but possibly not excitotoxicity. Front Biosci (Elite Ed) 4:1358-67
Collins, Michael A; Neafsey, Edward J (2012) Neuroinflammatory pathways in binge alcohol-induced neuronal degeneration: oxidative stress cascade involving aquaporin, brain edema, and phospholipase A2 activation. Neurotox Res 21:70-8