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Alcohol, Phospholipase A2-associated Neuroinflammation, and ω3 Docosahexaenoic Acid Protection

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Abstract

Chronic alcohol (ethanol) abuse causes neuroinflammation and brain damage that can give rise to alcoholic dementia. Insightfully, Dr. Albert Sun was an early proponent of oxidative stress as a key factor in alcoholism-related brain deterioration. In fact, oxidative stress has proven to be critical to the hippocampal and temporal cortical neurodamage resulting from repetitive “binge” alcohol exposure in adult rat models. Although the underlying mechanisms are uncertain, our immunoelectrophoretic and related assays in binge alcohol experiments in vivo (adult male rats) and in vitro (rat organotypic hippocampal-entorhinal cortical slice cultures) have implicated phospholipase A2 (PLA2)-activated neuroinflammatory pathways, release of pro-oxidative arachidonic acid (20:4 ω6), and elevated oxidative stress adducts (i.e., 4-hydroxynonenal-protein adducts). Also, significantly increased by the binge alcohol treatments was aquaporin-4 (AQP4), a water channel enriched in astrocytes that, when augmented, may trigger brain (esp. cellular) edema and neuroinflammation; of relevance, glial swelling is known to provoke increased PLA2 activities or levels. Concomitant with PLA2 activation, the results have further implicated binge alcohol-elevated poly (ADP-ribose) polymerase-1 (PARP-1), an oxidative stress-responsive DNA repair enzyme linked to parthanatos, a necrotic-like neuronal death process. Importantly, supplementation of the brain slice cultures with docosahexaenoic acid (22:6 ω3) exerted potent suppression of the induced changes in PLA2 isoforms, AQP4, PARP-1 and oxidative stress footprints, and prevention of the binge alcohol neurotoxicity, by as yet unknown mechanisms. These neuroinflammatory findings from our binge alcohol studies and supportive rat binge studies in the literature are reviewed.

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Abbreviations

AQP4:

Aquaporin-4

ARA:

Arachidonic acid

ATZ:

Acetazolamide

DHA:

Docosahexaenoic acid

PARP-1:

Poly (ADP-ribose) polymerase-1

PLA2 :

Phospholipase A2

ROS:

Reactive oxygen species

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Acknowledgments

The research was supported by the National Institutes of Health U01AA018279, R01AA0016959, and T32DA016176 and Loyola University Chicago Research Funding Committee and the Alcohol Research Program. The technical support of Dr. S. Alex Marshall is acknowledged. Dr. Toni Pak and Dr. Magdalena Szymanska, Department of Physiology at Loyola University Medical Center, are recognized for providing brain regions from alcohol-binged young adult rats that generated in their neuroendocrine studies [51].

Conflict of Interests

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, 60153, USA

    Michael A. Collins, Nuzhath Tajuddin, Kwan-Hoon Moon & Edward J. Neafsey

  2. Laboratory of Molecular Signaling, NIAAA, National Institutes of Health, Bethesda, MD, 20892, USA

    Hee-Yong Kim

  3. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536, USA

    Kimberly Nixon

Authors
  1. Michael A. Collins
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  2. Nuzhath Tajuddin
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  3. Kwan-Hoon Moon
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  4. Hee-Yong Kim
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  5. Kimberly Nixon
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  6. Edward J. Neafsey
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Corresponding author

Correspondence to Michael A. Collins.

Additional information

Based on the Albert Y. Sun Memorial Lecture by MAC at the ISN-ASN satellite symposium: ‘Unveiling the Significance of Lipid Signaling in Neurodegeneration and Neuroprotection’ Cancun MX, April 2013.

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Collins, M.A., Tajuddin, N., Moon, KH. et al. Alcohol, Phospholipase A2-associated Neuroinflammation, and ω3 Docosahexaenoic Acid Protection. Mol Neurobiol 50, 239–245 (2014). https://doi.org/10.1007/s12035-014-8690-0

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  • DOI: https://doi.org/10.1007/s12035-014-8690-0

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