Molecular Neurobiology

, Volume 41, Issue 2–3, pp 420–425 | Cite as

Moderate Ethanol Preconditioning of Rat Brain Cultures Engenders Neuroprotection Against Dementia-Inducing Neuroinflammatory Proteins: Possible Signaling Mechanisms

  • Michael A. CollinsEmail author
  • Edward J. Neafsey
  • Kewei Wang
  • Nicholas J. Achille
  • Robert M. Mitchell
  • Sreevidya Sivaswamy


There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer’s disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol “preconditioning” phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20–30 mM ethanol) of rat brain cultures prevents neurodegeneration due to β-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca+2]i and proinflammatory mediators—e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor → transducer → effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in “effector” heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning-like suppression of ongoing neuroinflammation related to amyloidogenic protein accumulation.


Moderate ethanol preconditioning Alzheimer’s disease Neuroinflammatory proteins 



central nervous system


moderate ethanol preconditioning


hippocampal–entorhinal cortical


human immunodeficiency virus


protein kinase C


focal adhesion kinase


N-methyl-d-aspartate receptor


adenosine1 receptor



The research was supported by National Institutes of Health RO1 AA013568, Loyola University Alcohol Research Program Training Grant T32 AA013527, Loyola Neuroscience Institute, a Loyola Schmitt fellowship to S. Sivaswamy, and an Illinois Department of Public Health Alzheimer’s Research award to R.M. Mitchell.


  1. 1.
    Dirnagl U, Simon RP, Hallenbeck JM (2003) Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26:248–254CrossRefPubMedGoogle Scholar
  2. 2.
    Gidday JM (2006) Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7:437–448CrossRefPubMedGoogle Scholar
  3. 3.
    Chopp M, Chen H, Ho KL, Dereski MO, Brown E, Hetzel FW, Welch KM, Chopp M, Chen H, Ho KL, Dereski MO, Brown E, Hetzel FW, Welch KM (1989) Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat. Neurology 39:1396–1398PubMedGoogle Scholar
  4. 4.
    Kitagawa K, Matsumoto M, Kuwabara K, Tagaya M, Ohtsuki T, Hata R, Ueda H, Handa N, Kimura K, Kamada T (1991) ‘Ischemic tolerance’ phenomenon detected in various brain regions. Brain Res 561:203–211CrossRefPubMedGoogle Scholar
  5. 5.
    Agarwal DP (2002) Cardioprotective effects of light-moderate consumption of alcohol: a review of putative mechanisms. Alcohol Alcohol 37:409–415PubMedGoogle Scholar
  6. 6.
    Sato M, Fraga C, Das DK (2004) Induction of the expression of cardioprotective proteins after mild-to-moderate consumption of alcohol. Pathophysiology 10:139–145CrossRefPubMedGoogle Scholar
  7. 7.
    Collins MA, Neafsey EJ, Mukamal KJ, Gray MO, Parks DA, Das DK, Korthuis RJ (2009) Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 33:206–219CrossRefPubMedGoogle Scholar
  8. 8.
    Peters R, Peters J, Warner J, Beckett N, Bulpitt C (2008) Alcohol, dementia and cognitive decline in the elderly: a systematic review. Age Ageing 37:505–512CrossRefPubMedGoogle Scholar
  9. 9.
    Anstey KJ, Mack HA, Cherbuin N (2009) Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am J Geriatr Psychiatry 17:542–555CrossRefPubMedGoogle Scholar
  10. 10.
    Wang Q, Sun AY, Simonyi A, Kalogeris TJ, Miller DK, Sun GY, Korthuis RJ (2007) Ethanol preconditioning protects against ischemia/reperfusion-induced brain damage: role of NADPH oxidase-derived ROS. Free Radic Biol Med 43:1048–1060CrossRefPubMedGoogle Scholar
  11. 11.
    Diekmann S, Nitsch R, Ohm TG (1994) The organotypic entorhinal-hippocampal complex slice culture of adolescent rats. A model to study transcellular changes in a circuit particularly vulnerable in neurodegenerative disorders. J Neural Transm Suppl 44:61–71PubMedGoogle Scholar
  12. 12.
    Kaul M, Lipton SA (2006) Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res 4:307–318CrossRefPubMedGoogle Scholar
  13. 13.
    Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB, Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB (1988) Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335:639–642CrossRefPubMedGoogle Scholar
  14. 14.
    Aggoun-Zouaoui D, Charriaut-Marlangue C, Rivera S, Jorquera I, Ben-Ari Y, Represa A, Aggoun-Zouaoui D, Charriaut-Marlangue C, Rivera S, Jorquera I, Ben-Ari Y, Represa A (1996) The HIV-1 envelope protein gp120 induces neuronal apoptosis in hippocampal slices. NeuroReport 7:433–436CrossRefPubMedGoogle Scholar
  15. 15.
    Collins MA, Neafsey EJ, Zou JY (2000) HIV-1 gp120 neurotoxicity in brain cultures is prevented by moderate ethanol pretreatment. NeuroReport 11:1219–1222CrossRefPubMedGoogle Scholar
  16. 16.
    Belmadani A, Zou JY, Schipma MJ, Neafsey EJ, Collins MA (2001) Ethanol pre-exposure suppresses HIV-1 glycoprotein 120-induced neuronal degeneration by abrogating endogenous glutamate/Ca2+-mediated neurotoxicity. Neuroscience 104:769–781CrossRefPubMedGoogle Scholar
  17. 17.
    Belmadani A, Kumar S, Schipma M, Collins MA, Neafsey EJ (2004) Inhibition of amyloid-beta-induced neurotoxicity and apoptosis by moderate ethanol preconditioning. NeuroReport 15:2093–2096CrossRefPubMedGoogle Scholar
  18. 18.
    Carmel JB, Kakinohana O, Mestril R, Young W, Marsala M, Hart RP (2004) Mediators of ischemic preconditioning identified by microarray analysis of rat spinal cord. Exp Neurol 185:81–96CrossRefPubMedGoogle Scholar
  19. 19.
    Collins MA, Wang K, Achille N, Neafsey EJ (2005) Moderate ethanol preconditioning of the brain as a neuroprotective strategy: role for selective heat shock protein induction? Alcohol Clin Exp Res 29:121ACrossRefGoogle Scholar
  20. 20.
    Valentim LM, Rodnight R, Geyer AB, Horn AP, Tavares A, Cimarosti H, Netto CA, Salbego CG (2003) Changes in heat shock protein 27 phosphorylation and immunocontent in response to preconditioning to oxygen and glucose deprivation in organotypic hippocampal cultures. Neuroscience 118:379–386CrossRefPubMedGoogle Scholar
  21. 21.
    Sivaswamy S, Neafsey EJ, Collins MA (2008) PKC and Focal Adhesion Kinase (FAK): possible transducer roles in ethanol preconditioning-induced neuroprotection from HIV-1 gp120. J Neurochem 104:32Google Scholar
  22. 22.
    Wei H, Campbell W, Vander Heide RS (2006) Heat shock-induced cardioprotection activates cytoskeletal-based cell survival pathways. Am J Physiol Heart Circ Physiol 291:H638–H647CrossRefPubMedGoogle Scholar
  23. 23.
    Larsson C (2006) Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal 18:276–284CrossRefPubMedGoogle Scholar
  24. 24.
    Mitchell RM, Neafsey EJ, Collins MA (2009) Essential involvement of the NMDA receptor in ethanol preconditioning-dependent neuroprotection from amyloid-beta in vitro. J Neurochem 111:580–588CrossRefPubMedGoogle Scholar
  25. 25.
    Maler JM, Esselmann H, Wiltfang J, Kunz N, Lewczuk P, Reulbach U, Bleich S, Ruther E, Kornhuber J (2005) Memantine inhibits ethanol-induced NMDA receptor up-regulation in rat hippocampal neurons. Brain Res 1052:156–162CrossRefPubMedGoogle Scholar
  26. 26.
    Goebel-Goody SM, Davies KD, Alvestad Linger RM, Freund RK, Browning MD (2009) Phospho-regulation of synaptic and extrasynaptic N-methyl-d-aspartate receptors in adult hippocampal slices. Neuroscience 158:1446–1459CrossRefPubMedGoogle Scholar
  27. 27.
    Leveille F, El Gaamouch F, Gouix E, Lecocq M, Lobner D, Nicole O, Buisson A (2008) Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 22:4258–4271CrossRefPubMedGoogle Scholar
  28. 28.
    Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yankner BA, Wyllie DJ, Ikonomidou C, Hardingham GE (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 11:476–487CrossRefPubMedGoogle Scholar
  29. 29.
    Prendergast MA, Harris BR, Blanchard JA 2nd, Mayer S, Gibson DA, Littleton JM (2000) In vitro effects of ethanol withdrawal and spermidine on viability of hippocampus from male and female rat. Alcohol Clin Exp Res 24:1855–1861CrossRefPubMedGoogle Scholar
  30. 30.
    Collins MA, Zou JY, Neafsey EJ (1998) Brain damage due to episodic alcohol exposure in vivo and in vitro: furosemide neuroprotection implicates edema-based mechanism. FASEB J 12:221–230PubMedGoogle Scholar
  31. 31.
    Collins MA, Corso TD, Neafsey EJ (1996) Neuronal degeneration in rat cerebrocortical and olfactory regions during subchronic "binge" intoxication with ethanol: possible explanation for olfactory deficits in alcoholics. Alcohol Clin Exp Res 20:284–292CrossRefPubMedGoogle Scholar
  32. 32.
    Nagy J (2008) Alcohol related changes in regulation of NMDA receptor functions. Curr Neuropharmacol 6:39–54CrossRefPubMedGoogle Scholar
  33. 33.
    Michaelis ML, Seyb KI, Ansar S (2005) Cytoskeletal integrity as a drug target. Curr Alzheimer Res 2:227–229CrossRefPubMedGoogle Scholar
  34. 34.
    Edelstein SL, Kritz-Silverstein D, Barrett-Connor E (1998) Prospective association of smoking and alcohol use with cognitive function in an elderly cohort. J Womens Health 7:1271–1281CrossRefPubMedGoogle Scholar
  35. 35.
    Luchsinger JA, Tang MX, Siddiqui M, Shea S, Mayeux R (2004) Alcohol intake and risk of dementia. J Am Geriatr Soc 52:540–546CrossRefPubMedGoogle Scholar
  36. 36.
    Tanaka N, Asada T, Kinoshita T, Yamashita F, Uno M (2002) Alcohol consumption and risk of dementia. Lancet 360:491CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Michael A. Collins
    • 1
    Email author
  • Edward J. Neafsey
    • 1
  • Kewei Wang
    • 2
  • Nicholas J. Achille
    • 3
  • Robert M. Mitchell
    • 4
  • Sreevidya Sivaswamy
    • 1
  1. 1.Biochemistry Division, Department of PharmacologyLoyola University Medical SchoolMaywoodUSA
  2. 2.Department of AnesthesiaUniversity of ChicagoChicagoUSA
  3. 3.Oncology InstituteLoyola Medical CenterMaywoodUSA
  4. 4.Ph.D. Program in Molecular & Cellular BiochemistryLoyola UniversityMaywoodUSA

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