The Cerebellum

, Volume 7, Issue 3, pp 332–347 | Cite as

Mechanisms of ethanol-induced degeneration in the developing, mature, and aging cerebellum

  • Pia Jaatinen
  • Jyrki Rintala
Original Article


The adverse effects of acute and chronic ethanol exposure on cerebellar functions have been acknowledged for decades, in terms of impaired control of movement and balance. In addition to the motor impairment, cerebellar degeneration has recently been shown to contribute to distinct neuropsychological deficits in chronic alcoholics, as well as in children with prenatal ethanol exposure. The basic mechanisms underlying these ethanol-induced functional alterations and the related neuropathology in the cerebellum have mostly been clarified only recently. These mechanisms include: (i) excitotoxicity; (ii) dietary factors, especially thiamine depletion; (iii) glial abnormalities; (iv) changes in growth factors; (v) apoptotic mechanisms; (vi) oxidative stress; and (vii) compromised energy production. Although these mechanisms widely apply not only to the mature cerebellum, but also to the developing and the aging cerebella, the developing and the aged cerebellum have some special characteristics, which may make them even more vulnerable to ethanol-induced degeneration. These special instances will be discussed along with the general mechanisms of ethanol-induced cerebellar degeneration.

Key words

Ethanol cerebellum neuropathology 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Victor M, Adams R, Mancall EL. A restricted form of cerebellar cortical degeneration occurring in alcoholic patients. Arch Neurol. 1959;1:579–688.Google Scholar
  2. 2.
    Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome and related neurological disorders due to alcoholism and malnutrition. Philadelphia: FA Davis Co, 1989.Google Scholar
  3. 3.
    Mattson SM, Riley EP. A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin Exp Res. 1998;22:279–94.PubMedCrossRefGoogle Scholar
  4. 4.
    Roebuck TM, Mattson SN, Riley EP. A review of the neuroanatomical findings in children with fetal alcohol syndrome or prenatal exposure to alcohol. Alcohol Clin Exp Res. 1998;22:339–44.PubMedCrossRefGoogle Scholar
  5. 5.
    Sullivan EV. Compromized pontocerebellar and cerebellothalamo-cortical systems: Speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholics. Alcohol Clin Exp Res. 2003;27:1409–19.PubMedCrossRefGoogle Scholar
  6. 6.
    O’Hare ED, Kan E, Yoshii J, Mattson SN, Riley EP, Thompson PM, et al. Mapping cerebellar vermal morphology and cognitive correlates in prenatal alcohol exposure. Neuroreport. 2005;16:1285–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Pentney R. Alcohol toxicity in the cerebellum: Fundamental aspects. In: Manto M-U, Panfoldo M, editors. The cerebellum and its disorders. Cambridge: Cambridge University Press, 2001.Google Scholar
  8. 8.
    Manto M-U, Jacquy J. Alcohol toxicity in the cerebellum: Clinical aspects. In: Manto M-U, Panfoldo M, editors. The cerebellum and its disorders. Cambridge: Cambridge University Press, 2001.Google Scholar
  9. 9.
    West JR, Chen WJ, Pantazis NJ. Fetal alcohol syndrome: the vulnerability of the developing brain and possible mechanisms of damage. Metab Brain Dis. 1994;9:291–322.PubMedCrossRefGoogle Scholar
  10. 10.
    Guerri C. Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal ethanol exposure. Alcohol Clin Exp Res. 1998;22:304–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Goodlett CR, Horn KH. Mechanisms of alcohol-induced damage to the developing nervous system. Alc Res Health (NIAAA). 2001;25:175–84.Google Scholar
  12. 12.
    Hauser KF, Khurdayan VK, Goody RJ, Nath A, Saria A, Pauly JR. Selective vulnerability of cerebellar granule neuroblasts and their progeny to drugs with abuse liability. Cerebellum. 2003;2:184–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Green JT. The effects of ethanol on the developing cerebellum and eyeblink classical conditioning. Cerebellum. 2004;3:178–87.PubMedCrossRefGoogle Scholar
  14. 14.
    Phillips SC, Harper CG, Kril J. A quantitative histological study of the cerebellar vermis in alcoholic patients. Brain. 1987;110:301–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Torvik A, Torp S. The prevalence of alcoholic cerebellar atrophy. A morphometric and histological study of an autopsy material. J Neurol Sci. 1986;75:43–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Baker KG, Harding AJ, Halliday GM, Kril JJ, Harper CG. Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke’s encephalopathy. Neuroscience. 1999;91:429–38.PubMedCrossRefGoogle Scholar
  17. 17.
    Allsop J, Turner B. Cerebellar degeneration associated with chronic alcoholism. J Neurol Sci. 1966;3:238–58.PubMedCrossRefGoogle Scholar
  18. 18.
    Andersen BB. Reduction of Purkinje cell volume in cerebellum of alcoholics. Brain Res. 2004;1007:10–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Karhunen PJ, Erkinjuntti T, Laippala P. Moderate alcohol consumption and loss of cerebellar Purkinje cells. Br Med J. 1994;308:1663–7.Google Scholar
  20. 20.
    Ferrer I, Fabreques I, Pineda M, Gracia I, Ribalta T. A Golgi study of cerebellar atrophy in human chronic alcoholism. Neuropathol Appl Neurobiol. 1984;10:245–53.PubMedCrossRefGoogle Scholar
  21. 21.
    Pentney RJ. Quantitative analysis of ethanol effects on the Purkinje cell dendritic tree. Brain Res. 1982;249:397–401.PubMedCrossRefGoogle Scholar
  22. 22.
    Tavares MA, Paula-Barbosa MM, Gray EG. A morphometric Golgi analysis of the Purkinje cell dendritic tree after long-term alcohol consumption in the adult rat. J Neurocytol. 1983;12:939–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Pentney RJ, Dlugos CA. Cerebellar Purkinje neurons with altered terminal dendritic segments are present in all lobules of the cerebellar vermis of aging, ethanol-fed F344 rats. Alcohol Alcohol. 2000;35:35–43.PubMedGoogle Scholar
  24. 24.
    Tavares MA, Paula-Barbosa MM. Alcohol-induced granule cell loss in the cerebellar cortex of the adult rat. Exp Neurol. 1982;78:574–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Tavares MA, Paula-Barbosa MM, Cadete-Leite A. Chronic alcohol consumption reduces the cortical layer volumes and the number of neurons of the rat cerebellar cortex. Alcohol Clin Exp Res. 1987;11:315–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Tabbaa S, Dlugos C, Pentney R. The number of granule cells and spine density on Purkinje-cells in aged, ethanol-fed rats. Alcohol. 1999;17:253–60.PubMedCrossRefGoogle Scholar
  27. 27.
    Pentney RJ, Mullan BA, Felong AM, Dlugos CA. The total numbers of cerebellar granule neurons in young and aged Fischer 344 and Wistar-Kyoto rats do not change as a result of lengthy ethanol treatment. Cerebellum. 2002;1:79–89.PubMedCrossRefGoogle Scholar
  28. 28.
    Green JT, Tran T, Steinmetz JE, Goodlett CR. Neonatal ethanol produces cerebellar deep nuclear cell loss and correlated disruption of eyeblink conditioning in adult rats. Brain Res. 2002;956:302–11.PubMedCrossRefGoogle Scholar
  29. 29.
    Green JT, Arenos JD, Dillon CJ. The effects of moderate neonatal ethanol exposure on eyeblink conditioning and deep cerebellar nuclei neuron numbers in the rat. Alcohol. 2006;39:135–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Jones KL, Smith DW, Ullelend CN, Streissguth AP. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet. 1973;1:1267–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Conry J. Neuropsychological deficits in fetal alcohol syndrome and fetal alcohol effects. Alcohol Clin Exp Res. 1990;14:650–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Clarren SK, Alvord EC, Sumi SM, Streissguth AP, Smith DW. Brain malformations related to prenatal exposure to ethanol. J Pediatr. 1978;92:64–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Wisniewski K, Dambska M, Sher JH, Qazi Q. A clinical neuropathological study of the fetal alcohol syndrome. Neuropediatrics. 1983;14:197–201.PubMedGoogle Scholar
  34. 34.
    Konovalov HV, Kovetsky NS, Bobryshev YV, Ashwell KWS. Disorders of brain development in the progeny of mothers who used alcohol during pregnancy. Early Human Dev. 1997;48:153–66.CrossRefGoogle Scholar
  35. 35.
    Sowell ER, Jernigan TL, Mattson SN, Riley EP, Sobel DF, Jones KL. Abnormal development of the cerebellar vermis in children prenatally exposed to alcohol: Size reduction in lobules I through V. Alcohol Clin Exp Res. 1996;20:31–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Archibald SL, Fennema-Notestine C, Gamst A, Riley EP, Mattson SN, Jernigan TL. Brain dysmorphology in individuals with severe prenatal alcohol exposure. Dev Med Child Neurol. 2001;43:148–54.PubMedCrossRefGoogle Scholar
  37. 37.
    Autti-Ramo I, Autti T, Korkman M, Kettunen S, Salonen O, Valanne L. MRI findings in children with school problems who had been exposed prenatally to ethanol. Dev Med Child Neurol. 2002;44:98–106.PubMedCrossRefGoogle Scholar
  38. 38.
    Pfeiffer J, Majewski F, Fischbach H, Bierich JR, Volk B. Alcohol embryo- and fetopathy. J Neurol Sci. 1979;41:125–37.CrossRefGoogle Scholar
  39. 39.
    Rosett HL, Weiner L. Alcohol and the fetus. New York: Oxford University Press, 1984.Google Scholar
  40. 40.
    Streissguth AP, Barr HM, Sampson PD. Moderate prenatal alcohol exposure: Effects on child IQ and learning problems at 7 1/2 years. Alcohol Clin Exp Res. 1990;14:662–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Altman J, Bayer SA. Development of the cerebellar system. New York: CRC Press, 1997.Google Scholar
  42. 42.
    McKay BE, Turner RW. Physiological and morphological development of the rat cerebellar Purkinje cell. J Physiol. 2005;567:829–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Goodlett CR, Marcussen BL, West JR. A single day of alcohol exposure during brain growth spurt induces brain weight restriction and cerebellar Purkinje cell loss. Alcohol. 1990;7:107–14.PubMedCrossRefGoogle Scholar
  44. 44.
    Goodlett CR, Eilers AT. Alcohol-induced Purkinje cell loss with a single binge exposure in neonatal rats: A stereological study of temporal windows of vulnerability. Alcohol Clin Exp Res. 1997;21:738–44.PubMedGoogle Scholar
  45. 45.
    Hamre KM, West JR. The effects of the timing of ethanol exposure during the brain growth spurt on the number of cerebellar Purkinje and granule cell nuclear profiles. Alcohol Clin Exp Res. 1993;17:610–22.PubMedCrossRefGoogle Scholar
  46. 46.
    Pauli J, Wilce P, Bedi KS. Acute exposure to alcohol during early postnatal life causes a deficit in the total number of cerebellar Purkinje cells. J Comp Neurol. 1995;360:506–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Thomas JD, Goodlett CR, West JR. Alcohol-induced Purkinje cell loss depends on developmental timing of alcohol exposure and correlates with motor performance. Dev Brain Res. 1998;105:159–66.CrossRefGoogle Scholar
  48. 48.
    Marcussen BL, Goodlett CR, Mahoney JC, West JR. Developing rat Purkinje cells are more vulnerable to alcohol-induced depletion during differentiation than during neurogenesis. Alcohol. 1994;11:147–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Napper RMA, West JR. Permanent neuronal cell loss in the cerebellum of rats exposed to continuous low blood alcohol levels during the brain growth spurt: A stereological investigation. J Comp Neurol. 1995;362:283–92.PubMedCrossRefGoogle Scholar
  50. 50.
    Pierce DR, Williams K, Light KE. Purkinje cell vulnerability to developmental ethanol exposure in the rat cerebellum. Alcohol Clin Exp Res. 1999;23:1650–9.PubMedGoogle Scholar
  51. 51.
    Pierce DR, Goodlett CR, West JR. Differential neuronal loss following early postnatal alcohol exposure. Teratology. 1989;40:113–26.PubMedCrossRefGoogle Scholar
  52. 52.
    Bonthius DJ, West JR. Permanent neuronal deficits in rats exposed to alcohol during the brain growth spurt. Teratology. 1991;44:147–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Bonthius DJ, Bonthius NE, Napper RM, Astley SJ, Clarren SK, West JR. Purkinje cell deficits in nonhuman privates following weekly exposure to ethanol during gestation. Teratology. 1996;53:230–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Maier SE, West JR. Regional differences in cell loss associated with binge-like alcohol exposure during the first two trimesters equivalent in the rat. Alcohol. 2001;23:49–57.PubMedCrossRefGoogle Scholar
  55. 55.
    Bauer-Moffett C, Altman J. The effect of ethanol chronically administered to preweanling rats on cerebellar development: A morphological study. Brain Res. 1977;119:249–68.PubMedCrossRefGoogle Scholar
  56. 56.
    Vaudry D, Rousselle C, Basille M, Falluel-Morel A, Pamantung TF, Fontaine M, et al. Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death. Proc Natl Acad Sci. 2002;99:6398–403.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen S, Hillman DE. Regulation of granule cell number by a pre-determined number of Purkinje cells in development. Dev Brain Res. 1989;45:137–7.CrossRefGoogle Scholar
  58. 58.
    Heaton MB, Paiva M, Madorsky I, Siler-Marsiglio K, Shaw G. Effect of bax deletion on ethanol sensitivity in the neonatal rat cerebellum. J Neurobiol. 2006;66:95–101.PubMedCrossRefGoogle Scholar
  59. 59.
    Tran TD, Jackson HD, Horn KH, Goodlett CR. Vitamin E does not protect against neonatal ethanol-induced cerebellar damage or deficits in eyeblink classical conditioning in rats. Alcohol Clin Exp Res. 2005;29:117–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Dikranian K, Qin YQ, Labruyere J, Nemmers B, Olney JW. Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures. Brain Res Dev Brain Res. 2005;155:1–13.PubMedCrossRefGoogle Scholar
  61. 61.
    Sullivan EV, Deshmukh A, Desmond JE, Lim KO, Pfefferbaum A. Cerebellar volume decline in normal aging, alcoholism, and Korsakoff’s syndrome: relation to ataxia. Neuropsychology. 2000;14:341–52.PubMedCrossRefGoogle Scholar
  62. 62.
    Torvik A, Torp S, Lindboe CF. Atrophy of the cerebellar vermis in aging: A morphologic and histologic study. J Neurol Sci. 1986;76:283–94.PubMedCrossRefGoogle Scholar
  63. 63.
    Khutoryan BM. Quantitative characterization of the cellular elements of human cerebellar nuclei at different ages. Neurosci Behav Physiol. 2005;35:5–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Duckett S, Schoedler S. Nutritional disorders and alcoholism. In: Duckett S, editor. The pathology of the aging human nervous system. Philadelphia: Lea & Febiger, 1991.Google Scholar
  65. 65.
    Courville C. Effects of alcohol on the nervous system of man. Los Angeles: San Lucas Press, 1955.Google Scholar
  66. 66.
    Sullivan EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A. Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcohol Clin Exp Res. 1995;19:110–29.PubMedCrossRefGoogle Scholar
  67. 67.
    Pfefferbaum A, Sullivan E, Mathalon DH, Lim KO. Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics. Alcohol Clin Exp Res. 1997;21:521–9.PubMedGoogle Scholar
  68. 68.
    Pentney RJ, Quigley PJ. Morphometric parameters of Purkinje dendritic networks after ethanol treatment during aging. Alcohol Clin Exp Res. 1987;11:536–40.PubMedCrossRefGoogle Scholar
  69. 69.
    Rintala J, Jaatinen P, Kiianmaa K, Riikonen J, Kemppainen O, Sarviharju M, Hervonen A. Dosedependent decrease in glial fibrillary acidic proteinimmunoreactivity in rat cerebellum after lifelong ethanol consumption. Alcohol. 2001;23:1–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Cadete-Leite A, Alves MC, Tavares M, Paula-Barbosa MM. Effects of chronic alcohol intake and withdrawal on the prefrontal neurons and synapses. Alcohol. 1990;7:145–52.PubMedCrossRefGoogle Scholar
  71. 71.
    Goodlett CR, Peterson SD, Lundahl KR, Pearlman AD. Binge-like alcohol exposure of neonatal rats via intragastric intubation induces both Purkinje cell loss and cortical astrogliosis. Alcohol Clin Exp Res. 1997;21:1010–7.PubMedGoogle Scholar
  72. 72.
    Lundqvist C, Alling C, Knoth R, Volk B. Intermittent ethanol exposure of adult rats: Hippocampal cell loss after one month of treatment. Alcohol Alcohol. 1995;30:737–48.PubMedGoogle Scholar
  73. 73.
    Phillips SC, Cragg BG. Alcohol withdrawal causes a loss of cerebellar Purkinje cells in mice. J Stud Alcohol. 1984;45:475–80.PubMedGoogle Scholar
  74. 74.
    Riikonen J, Jaatinen P, Karjala K, Rintala J, Pörsti I, Wu X, Eriksson CJP, Hervonen A. Effects of continuous versus intermittent ethanol exposure on rat sympathetic neurons. Alcohol Clin Exp Res. 1999;23:1245–50.PubMedCrossRefGoogle Scholar
  75. 75.
    Bonthius DJ, West JR. Alcohol-induced neuronal loss in developing rats: Increased brain damage with binge exposure. Alcohol Clin Exp Res. 1990;14:107–18.PubMedCrossRefGoogle Scholar
  76. 76.
    Hunt WA. Are binge drinkers more at risk of developing brain damage? Alcohol. 1993;10:559–61.PubMedCrossRefGoogle Scholar
  77. 77.
    Obernier JA, Bouldin TW, Crews FT. Binge ethanol exposure in adult rats causes necrotic cell death. Alcohol Clin Exp Res. 2002;26:547–57.PubMedCrossRefGoogle Scholar
  78. 78.
    Lovinger DM. Excitotoxicity and alcohol-related brain damage. Alcohol Clin Exp Res. 1993;17:19–27.PubMedCrossRefGoogle Scholar
  79. 79.
    Hoffman PL, Iorio KR, Snell LD, Tabakoff B. Attenuation of glutamate-induced neurotoxicity in chronically ethanolexposed cerebellar granule cells by NMDA receptor antagonists and ganglioside GM1. Alcohol Clin Exp Res. 1995;19:721–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Wegelius K, Korpi ER. Ethanol inhibits NMDA-induced toxicity and trophism in cultured cerebellar granule cells. Acta Physiol Scand. 1995;154:25–34.PubMedCrossRefGoogle Scholar
  81. 81.
    Iorio KR, Reinlib L, Tabakoff B, Hoffman PL. Chronic exposure of cerebellar granule cells to ethanol results in increased N-methyl-D-aspartate receptor function. Mol Pharmacol. 1992;41:1142–8.PubMedGoogle Scholar
  82. 82.
    Iorio KR, Tabakoff B, Hoffman PL. Glutamate-induced neurotoxicity is increased in cerebellar granule cells exposed chronically to ethanol. Eur J Pharmacol. 1993;248:209–12.PubMedGoogle Scholar
  83. 83.
    Dawson TM, Snyder SH. Gases as biological messengers: Nitric oxide and carbon monoxide in the brain. J Neurosci. 1994;14:5147–59.PubMedGoogle Scholar
  84. 84.
    Manto M, Laute M, Pandolfo M. Depression of extracellular GABA and increase of NMDA-induced nitric oxide following acute intra-nuclear administration of alcohol in the cerebellar nuclei of the rat. Cerebellum. 2005;4:230–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Netzeband JG, Trotter C, Caguioa JN, Gruoi DK. Chronic ethanol exposure enhances AMPA-elicited Ca2+ signals in the somatic and dendritic regions of cerebellar Purkinje neurons. Neurochem Int. 1999;35:163–74.PubMedCrossRefGoogle Scholar
  86. 86.
    Rewal M, Wen Y, Simpkins JW, Jung ME. Ethanol withdrawal reduces cerebellar parvalbumin expression in a manner reversed by estrogens. Neurosci Lett. 2005;377:44–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Kumar S, Fleming RL, Morrow L. Ethanol regulation of caminobutyric acidA receptors: genomic and nongenomic mechanisms. Pharmacol Ther. 2004;101:211–26.PubMedCrossRefGoogle Scholar
  88. 88.
    Valenzuela CR, Harris RA. Alcohol: Neurobiology. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG, editors. Substance abuse: A comprehensive textbook. Baltimore, MD: Williams & Wilkins, 1997. 119–42.Google Scholar
  89. 89.
    Korpi ER, Koikkalainen P, Vekovischeva OY, Mäkelä R, Kleinz R, Uusi-Oukari M, Wisden W. Cerebellar granulecell-specific GABAA receptors attenuate benzodiazepineinduced ataxia: evidence from (6-subunit-deficient mice. Eur J Neurosci. 1999;11:233–40.PubMedCrossRefGoogle Scholar
  90. 90.
    Boehm SL, Ponomarev I, Jennings AW, Whiting PJ, Rosahl TW, Garrett EM, et al. γ-aminobutyric acid A receptor subunit mutant mice: New perspectives on alcohol actions. Biochem Pharmacol. 2004;68:1581–602.PubMedCrossRefGoogle Scholar
  91. 91.
    Schmid G, Bonanno G, Raiteri L, Sarviharju M, Korpi ER, Raiteri M. Enhanced benzodiazepine and ethanol actions on cerebellar GABAA receptors mediating glutamate release in an alcohol-sensitive rat line. Neuropharmacology. 1999;38:1273–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M. Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity. Nature Neurosci. 2005;8:339–45.PubMedCrossRefGoogle Scholar
  93. 93.
    Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science. 2000;287:1056–60.PubMedCrossRefGoogle Scholar
  94. 94.
    Balazs R, Jorgensen OS, Hack N. N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture. Neuroscience. 1988;27:437–51.PubMedCrossRefGoogle Scholar
  95. 95.
    Pantazis NJ, Dohrman DP, Luo J, Thomas JD, Goodlett CR, West JR. NMDA prevents alcohol-induced neuronal cell death of cerebellar granule cells in culture. Alcohol Clin Exp Res. 1995;19:846–53.PubMedCrossRefGoogle Scholar
  96. 96.
    Bhave SV, Hoffmann PL. Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA. J Neurochem. 1997;68:578–86.PubMedGoogle Scholar
  97. 97.
    Altman J. Morphological development of the rat cerebellum and a source of its mechanism. In: Chan Palay V, Palay S, editors. The cerebellum: New vistas. Berlin: Springer-Verlag, 1982. pp 8–49.Google Scholar
  98. 98.
    Liskow BI, Rinck C, Campbell J, De Souza C. Alcohol withdrawal in the elderly. J Stud Alcohol. 1989;50:414–21.PubMedGoogle Scholar
  99. 99.
    Brower KJ, Mudd S, Blow FC, Young JP, Hill EM. Severity and treatment of alcohol withdrawal in the elderly versus younger patients. Alcohol Clin Exp Res. 1994;18:196–201.PubMedCrossRefGoogle Scholar
  100. 100.
    Kraemer KL, Mayo-Smith MF, Calkins DR. Impact of age on the severity, course, and complications of alcohol withdrawal. Arch Intern Med. 1997;157:2234–41.PubMedCrossRefGoogle Scholar
  101. 101.
    Maier DM, Pohorecky LA. The effect of repeated withdrawal episodes on subsequent withdrawal severity in ethanol-treated rats. Drug Alcohol Depend. 1989;23:103–110.PubMedCrossRefGoogle Scholar
  102. 102.
    Riihioja P, Jaatinen P, Haapalinna A, Kiianmaa K, Hervonen A. Effects of aging and intermittent ethanol exposure on rat locus coeruleus and ethanol withdrawal symptoms. Alcohol Alcohol. 1999;34:706–17.PubMedGoogle Scholar
  103. 103.
    Mhatre MC, Ticku MK. Aging related alterations in GABAA receptor subunit mRNA levels in Fischer rats. Brain Res Mol Brain Res. 1992;14:71–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Araki T, Kato H, Fujiwara T, Itoyama Y. Regional agerelated alterations in cholinergic and GABAergic receptors in the rat brain. Mech Ageing Dev. 1996;88:49–60.PubMedCrossRefGoogle Scholar
  105. 105.
    Bickford P. Motor learning deficits in aged rats are correlated with loss of cerebellar noradrenergic function. Brain Res. 1993;620:133–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Vallebuona F, Reiteri M. Age-related changes in the NMDA receptor/nitric oxide/cGMP pathway in the hippocampus and cerebellum of freely moving rats subjected to transcerebral microdialysis. Eur J Neurosci. 1995;7:694–701.PubMedCrossRefGoogle Scholar
  107. 107.
    Chalimoniuk M, Strosznajder JB. Aging modulated nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of amyloid beta peptide. Mol Chem Neuropathol. 1998;35:77–95.PubMedCrossRefGoogle Scholar
  108. 108.
    Bertoni-Freddari C, Fattoretti P, Giorgetti B, Solazzi M, Balietti M, Di Stefano G, Casoli T. Decay of mitochondrial metabolic competence in the aging cerebellum. Ann N Y Acad Sci. 2004;1019:29–32.PubMedCrossRefGoogle Scholar
  109. 109.
    Cooper JR, Pincus JH. The role of thiamine in nervous tissue. Neurochem Res. 1979;4:223–39.PubMedCrossRefGoogle Scholar
  110. 110.
    Thomson AD, Ryle PR, Shaw GK. Ethanol, thiamine, and brain damage. Alcohol Alcohol. 1983;18:27–43.Google Scholar
  111. 111.
    Gastaldi G, Casirola D, Ferrari G, Rindi G. Effect of chronic ethanol administration on thiamine transport in microvillous vesicles of rat small intestine. Alcohol Alcohol. 1989;24:83–9.PubMedGoogle Scholar
  112. 112.
    Laforenza U, Patrini C, Gastaldi G, Rindi G. Effects of acute and chronic ethanol administration on thiamine metabolizing enzymes in some brain areas and in other organs of the rat. Alcohol Alcohol. 1990;25:591–603.PubMedGoogle Scholar
  113. 113.
    Torvik A. Two types of brain lesions in Wernicke’s encephalopathy. Neuropath Appl Neurobiol. 1985;11:179–90.CrossRefGoogle Scholar
  114. 114.
    Mulholland PJ. Susceptibility of the cerebellum to thiamine deficiency. Cerebellum. 2006;5:55–63.PubMedCrossRefGoogle Scholar
  115. 115.
    Witt ED. Neuroanatomical consequences of thiamine deficiency: A comparative analysis. Alcohol Alcohol. 1985;20:201–21.PubMedGoogle Scholar
  116. 116.
    Rindi G, Patrini C, Comincioli V, Reggiani C. Thiamine content and turnover rates of some rat nervous regions, using labeled thiamine as a tracer. Brain Res. 1980;181:369–80.PubMedCrossRefGoogle Scholar
  117. 117.
    Aschner M, Allen JW. Astrocytes in methylmercury, ammonia, methionine sulfoximine and alcohol-induced neurotoxicity. Neurotoxicology. 2000;21:573–9.PubMedGoogle Scholar
  118. 118.
    Guerri C, Renau-Piqueras J. Alcohol, astroglia and brain development. Mol Neurobiol. 1997;15:65–81.PubMedCrossRefGoogle Scholar
  119. 119.
    Snyder AK. Responses of glia to alcohol. In: Aschner M, Kimelberg HK, editors. The role of glia in neurotoxicity. Boca Raton, Fl: CRC Press, 1996. pp 111–35.Google Scholar
  120. 120.
    Kimelberg HK, Aschner M. Astrocytes and their functions. In: Lancaster FE, editor. Alcohol and glial cells, vol. 27, NIAAA Research Monograph. Washington DC: US Government Printing Office, 1994. pp 1–40.Google Scholar
  121. 121.
    Hannsson E, Rönnbäck L. Astrocytes in glutamate neurotransmission. FASEB J. 1995;9:343–50.Google Scholar
  122. 122.
    Martin DL. Synthesis and release of neuroactive substances by glial cells. Glia. 1992;5:81–94.PubMedCrossRefGoogle Scholar
  123. 123.
    Tsacopoulos M, Magistretti PJ. Metabolic coupling between glia and neurons. J Neurosci. 1996;16:877–85.PubMedGoogle Scholar
  124. 124.
    Watts LT, Rathinam ML, Schenker S, Henderson GI. Astrocytes protect neurons from ethanol-induced oxidative stress and apoptotic death. J Neurosci Res. 2005;80:655–66.PubMedCrossRefGoogle Scholar
  125. 125.
    Hatten ME, Liem RK, Shelanski ML, Mason CA. Astroglia in CNS injury. Glia. 1991;4:232–43.Google Scholar
  126. 126.
    Dlugos CA, Pentney RJ. Quantitative immunocytochemistry of glia in the cerebellar cortex of old ethanol-fed rats. Alcohol. 2001;23:63–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Smith DE, Davies DL. Effect of perinatal administration of ethanol on the CA1 pyramidal cell of the hippocampus and Purkinje cell of the cerebellum: an ultrastructural survey. J Neurocytol. 1990;19:708–17.PubMedCrossRefGoogle Scholar
  128. 128.
    Kimelberg HK, Cheema M, O’Connor ER, Tong H, Goderie SK, Rossman PA. Ethanol-induced aspartate and taurine release from primary astrocyte cultures. J Neurochem. 1993;60:1682–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Rakic P. Mechanisms of neuronal migration in developing cerebellar cortex. In: Edelman GM, Gall WE, Cowan WM, editors. Molecular bases of neural development. New York: John Wiley & Sons, 1985. pp 139–60.Google Scholar
  130. 130.
    Shetty AK, Phillips DE. Effects of prenatal ethanol exposure on the development of Bergman glia and astrocytes in the rat cerebellum: an immunohistochemical study. J Comp Neurol. 1992;321:19–32.PubMedCrossRefGoogle Scholar
  131. 131.
    Shetty AK, Burrows RC, Wall KA, Phillips DE. Combined pre- and postnatal ethanol exposure alters the development of Bergmann glia in rat cerebellum. Int J Dev Neurosci. 1994;12:641–9.PubMedCrossRefGoogle Scholar
  132. 132.
    Zoeller RT, Butnariu OV, Fletcher DL, Riley EP. Limited postnatal ethanol exposure permanently alters the expression of mRNAs encoding myelin basic protein and myelin associated glycoprotein in cerebellum. Alcohol Clin Exp Res. 1994;18:909–16.PubMedCrossRefGoogle Scholar
  133. 133.
    Guerri C, Montoliu C, Renau-Piqueras J. Involvement of free radical mechanism in the toxic effects of alcohol: implications for fetal alcohol syndrome. Adv Exp Med Biol. 1994;366:291–305.PubMedGoogle Scholar
  134. 134.
    Montoliu C, Sancho-Tello M, Azorin I, Burgal M, Vallés S, Renau-Pigueras J, Guerri C. Ethanol increases cytochrome P4502E1 and induces oxidative stress in astrocytes. J Neurochem. 1995;65:2561–70.PubMedGoogle Scholar
  135. 135.
    Eysseric H, Gonthier B, Soybeyran A, Richard MJ, Daveloose D, Barrett L. Effects of chronic ethanol exposure on acetaldehyde and free radical production by astrocytes in culture. Alcohol. 2000;21:117–25.PubMedCrossRefGoogle Scholar
  136. 136.
    Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C. Regional distribution of ethanol-inducible cytochrome P450 IIE1 in rat central nervous system. Neuroscience. 1990;34:451–63.PubMedCrossRefGoogle Scholar
  137. 137.
    Persson JO, Terelius Y, Ingelman-Sundberg M. Cytochrome P450-dependent formation of oxygen radicals. Isoenzyme-specific inhibition of P450-mediated reduction of oxygen and carbon tetrachloride. Xenobiotica. 1990;20:887–900.PubMedGoogle Scholar
  138. 138.
    McCaffery P, Koul O, Smith D, Napoli JL, Chen N, Ullman MD. Ethanol increases retinoic acid production in cerebellar astrocytes and in cerebellum. Brain Res. 2004;153:233–41.CrossRefGoogle Scholar
  139. 139.
    Holson RR, Adams J, Ferguson SA. Gestational stagespecific effects of retinoic acid exposure in the rat. Neurotoxicol Teratol. 1999;21:393–402.PubMedCrossRefGoogle Scholar
  140. 140.
    Yamamoto M, Ullman MD, Drager UC, McCaffery P. Postnatal effects of retinoic acid on cerebellar development. Neurotoxicol Teratol. 1999;21:141–6.PubMedCrossRefGoogle Scholar
  141. 141.
    Riikonen J, Jaatinen P, Rintala J, Pörsti I, Karjala K, Hervonen A. Intermittent ethanol exposure increases the number of cerebellar microglia. Alcohol Alcohol. 2002;37:421–6.PubMedGoogle Scholar
  142. 142.
    Colton CA, Snell-Callanan J, Chernyshev ON. Ethanolinduced changes in superoxide anion and nitric oxide in cultured microglia. Alcohol Clin Exp Res. 1998;22:710–16.PubMedGoogle Scholar
  143. 143.
    Henderson CE. Role of neurotrophic factors in neuronal development. Curr Opin Neurobiol. 1996;6:64–70.PubMedCrossRefGoogle Scholar
  144. 144.
    Dohrman DP, West JR, Pantazis NJ. Ethanol reduces expression of the nerve growth factor receptor, but not nerve growth factor protein levels in the neonatal rat cerebellum. Alcohol Clin Exp Res. 1997;21:882–93.PubMedGoogle Scholar
  145. 145.
    Heaton MB, Mitchell JJ, Paiva M. Ethanol-induced alterations in neurotrophin expression in developing cerebellum: Relationship to periods of temporal susceptibility. Alcohol Clin Exp Res. 1999;23:1637–42.PubMedGoogle Scholar
  146. 146.
    Heaton MB, Moore DB, Paiva M, Madorsky I, Mayer J, Shaw G. The role of neurotrophic factors, apoptosis-related proteins, and endogenous antioxidants in the differential temporal vulnerability of neonatal cerebellum to ethanol. Alcohol Clin Exp Res. 2003;27:657–69.PubMedGoogle Scholar
  147. 147.
    Muller Y, Tangre K, Clos J. Autocrine regulation of apoptosis and bcl-2 exspression by nerve growth factor in early differentiating cerebellar granule neurons involves low affinity neurotrophin receptor. Neurochem Int. 1997;31:177–91.PubMedCrossRefGoogle Scholar
  148. 148.
    Nistico G, Ciriolo MR, Fiskin K, Iannone M, De Martino A, Rotilio G. NGF restores decrease in catalase activity and increases superoxide dismutase and glutathione peroxidase activity in the brain of aged rats. Free Radic Biol Med. 1992;12:177–81.PubMedCrossRefGoogle Scholar
  149. 149.
    Light KE, Brown DP, Newton BW, Belcher SM, Kane CJ. Ethanol-induced alterations of neurotrophin receptor expression on Purkinje cells in the neonatal rat cerebellum. Brain Res. 2002;4:71–81.CrossRefGoogle Scholar
  150. 150.
    Moore DB, Madorsky I, Paiva M, Heaton MB. Ethanol exposure alters neurotrophin receptor expression in the rat central nervous system: Effects of prenatal exposure. J Neurobiol. 2004;60:101–13.PubMedCrossRefGoogle Scholar
  151. 151.
    Moore DB, Madorsky I, Paiva M, Heaton MB. Ethanol exposure alters neurotrophin receptor expression in the rat central nervous system: Effects of neonatal exposure. J Neurobiol. 2004;60:114–26.PubMedCrossRefGoogle Scholar
  152. 152.
    Li Z, Ding M, Thiele CJ, Luo J. Ethanol inhibits brainderived neurotrophic factor-mediated intracellular signaling and activator protein-1 activation in cerebellar granule neurons. Neuroscience. 2004;126:149–62.PubMedCrossRefGoogle Scholar
  153. 153.
    Ohrtman JD, Stancik EK, Lovinger DM, Davis MI. Ethanol inhibits brain-derived neurotrophic factor stimulation of extracellular signal-regulated/mitogen-activated protein kinase in cerebellar granule cells. Alcohol. 2006;39:29–37.PubMedCrossRefGoogle Scholar
  154. 154.
    Luo J, West J, Pantazis N. Nerve growth factor and basic fibroblast growth factor protect rat cerebellar granule cells in culture against ethanol-induced cell death. Alcohol Clin Exp Res. 1997;21:1108–20.PubMedGoogle Scholar
  155. 155.
    McAlhany RE, West JR, Miranda RC. Glial-derived neurotrophic factor rescues calbindin-D 28k-immunoreactive neurons in alcohol-treated cerebellar explant cultures. J Neurobiol. 1997;33:835–47.PubMedCrossRefGoogle Scholar
  156. 156.
    Bhave SV, Ghoda L, Hoffmann PL. Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: Signal transduction cascades and site of ethanol action. J Neurosci. 1999;19:3277–86.PubMedGoogle Scholar
  157. 157.
    Heaton MB, Mitchell JJ, Paiva M. Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum. J Neurobiol. 2000;45:95–104.PubMedCrossRefGoogle Scholar
  158. 158.
    Heaton MB, Madorsky I, Paiva M, Mayer J. Influence of ethanol on neonatal cerebellum of BDNF-deleted animals: analysis of effects on Purkinje cells, apoptosis-related proteins, and endogenous antioxidants. J Neurobiol. 2002;51:160–76.PubMedCrossRefGoogle Scholar
  159. 159.
    Heidenreich KA, Toledo SP. Insulin receptors mediate growth effects in cultured fetal neurons. Endocrinology. 1989;125:1451–7.PubMedGoogle Scholar
  160. 160.
    Pahlman S, Meyerson G, Lindgren E, Schalling M, Johansson I. Insulin-like growth factor I shifts from promoting cell division to potentiating maturation during neonatal differentiation. Proc Natl Acad Sci USA. 1991;88:9994–8.PubMedCrossRefGoogle Scholar
  161. 161.
    De la Monte SM, Wands JR. Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. Cell Mol Life Sci. 2002;59:882–93.PubMedCrossRefGoogle Scholar
  162. 162.
    De la Monte SM, Xu XJ, Wands JR. Ethanol inhibits insulin expression and actions in the developing brain. Cell Mol Life Sci. 2005;62:1131–45.PubMedCrossRefGoogle Scholar
  163. 163.
    Marinelli PW, Gianoulakis C, Kar S. Effects of voluntary ethanol drinking on [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin receptor binding in the mouse hippocampus and cerebellum. Neuroscience. 2000;98:687–95.PubMedCrossRefGoogle Scholar
  164. 164.
    Zhang FX, Rubin R, Rooney TA. Ethanol induces apoptosis in cerebellar granule neurons by inhibiting insulin-like growth factor 1 signaling. J Neurochem. 1998;71:196–204.PubMedCrossRefGoogle Scholar
  165. 165.
    Gericke CA, Schulte-Herbrüggen O, Arendt T, Hellweg R. Chronic alcohol intoxication in rats leads to a strong but transient increase in NGF levels in distinct brain regions. J Neural Transm. 2006;113:813–20.PubMedCrossRefGoogle Scholar
  166. 166.
    Katoh-Semba R, Semba R, Takeuchi IK, Kato K. Agerelated changes in levels of brain-derived neurotrophic factor in selected brain regions of rats, normal mice and senescence-accelerated mice: a comparison to those of nerve growth factor and neurotrophin-3. Neurosci Res. 1998;31:227–34.PubMedCrossRefGoogle Scholar
  167. 167.
    Lee C, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice. Nature Genetics. 2000;25:294–7.PubMedCrossRefGoogle Scholar
  168. 168.
    Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453–501.PubMedCrossRefGoogle Scholar
  169. 169.
    Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: Lessons from the nervous system. Science. 1993;262:695–700.PubMedCrossRefGoogle Scholar
  170. 170.
    Freund G. Apoptosis and gene expression: Perspectives on alcohol-induced brain damage. Alcohol. 1994;11:385–7.PubMedCrossRefGoogle Scholar
  171. 171.
    Liesi P. Ethanol-exposed central neurons fail to migrate and undergo apoptosis. J Neurosci Res. 1997;48:439–48.PubMedCrossRefGoogle Scholar
  172. 172.
    Light KE, Belcher SM, Pierce DR. Time course and manner of Purkinje neuron death following a single ethanol exposure on postnatal day 4 in the developing rat. Neuroscience. 2002;114:327–37.PubMedCrossRefGoogle Scholar
  173. 173.
    Nowoslavski L, Klocke BJ, Roth KA. Molecular regulation of acute ethanol-induced neuron apoptosis. J Neuropathol Exp Neurol. 2005;64:490–7.Google Scholar
  174. 174.
    Moore DB, Walker DW, Heaton MB. Neonatal ethanol exposure alters bcl-2 family mRNA levels in the rat cerebellar vermis. Alcohol Clin Exp Res. 1999;21:1251–61.CrossRefGoogle Scholar
  175. 175.
    Ge Y, Belcher SM, Pierce DR, Light KE. Altered expression of Bcl2, Bad and Bax mRNA occurs in the rat cerebellum within hours after ethanol exposure on postnatal day 4 but not on postnatal day 9. Mol Brain Res. 2004;129:124–34.PubMedCrossRefGoogle Scholar
  176. 176.
    Siler-Marsiglio KI, Madorsky I, Pan Q, Paiva M, Neeley AW, Shaw G, Heaton MB. Effects of acute ethanol exposure on regulatory mechanisms of Bcl-2-associated apoptosis promoter, bad, in neonatal rat cerebellum: Differential effects during vulnerable and resistant developmental periods. Alcohol Clin Exp Res. 2006;30:1031–8.PubMedCrossRefGoogle Scholar
  177. 177.
    Heaton MB, Moore DB, Paiva M, Gibbs T, Bernard O. Bcl-2 overexpression protects the neonatal cerebellum from ethanol neurotoxicity. Brain Res. 1999;817:13–18.PubMedCrossRefGoogle Scholar
  178. 178.
    Rajgopal Y, Chetty CS, Vemuri MC. Differential modulation of apoptosis-associated proteins by ethanol in rat cerebral cortex and cerebellum. Eur J Pharmacol. 2003;470:117–24.PubMedCrossRefGoogle Scholar
  179. 179.
    Nicholson DW. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 1999;6:1028–42.PubMedCrossRefGoogle Scholar
  180. 180.
    Chrysis D, Calikoglu AS, Ye P, D’Ercole AJ. Insulin-like growth factor-1 overexpression attenuates cerebellar apoptosis by altering the expression of bcl family proteins in a developmentally specific manner. J Neurosci. 2001;21:1481–9.PubMedGoogle Scholar
  181. 181.
    Rouach H, Park MK, Orfanelli MT, Janvier B, Nordmann R. Ethanol-induced oxidative stress in the rat cerebellum. AlcoholAlcohol. 1987;Suppl. 1:207–11.Google Scholar
  182. 182.
    Sun AY, Sun GY. Ethanol and oxidative mechanisms in the brain. J Biomed Sci. 2001;8:37–43.PubMedCrossRefGoogle Scholar
  183. 183.
    Celec P, Jani P, Smrekova L, Mrlian A, Kudela M, Hodosy J, et al. Effects of anabolic steroids and antioxidant vitamins on ethanol-induced tissue injury. Life Sci. 2003;72:419–34.CrossRefGoogle Scholar
  184. 184.
    Rouach H, Houze P, Gentil M, Orfanelli MT, Nordmann R. Changes in some pro- and antioxidants in rat cerebellum after chronic alcohol intake. Biochem Pharmacol. 1997;53:539–45.PubMedCrossRefGoogle Scholar
  185. 185.
    Vallett M, Tabatabaie T, Briscoe RJ, Baird TJ, Beatty WW, Floyd RA, et al. Free radical production during ethanol intoxication, dependence, and withdrawal. Alcohol Clin Exp Res. 1997;21:275–85.PubMedGoogle Scholar
  186. 186.
    Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT. Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psych. 1998;155:726–32.Google Scholar
  187. 187.
    Jung ME, Rewal M, Perez E, Wen Y, Simpkins JW. Estrogen protects against brain lipid peroxidation in ethanol-withdrawn rats. Pharmacol Biochem Behav. 2004;79:573–86.PubMedCrossRefGoogle Scholar
  188. 188.
    Carrillo MC, Kanai S, Sato Y, Kitani K. Age-related changes in antioxidant enzyme activities are region and organ, as well as sex, selective in the rat. Mech Ageing Dev. 1992;65:187–98.PubMedCrossRefGoogle Scholar
  189. 189.
    Tsay H, Wang P, Wang S, Ku H. Age-associated changes of superoxide dismutase and catalase activities in the rat brain. J Biomed Sci. 2000;7:466–74.PubMedCrossRefGoogle Scholar
  190. 190.
    Siqueira IR, Fochesatto C, de Andrade A, Santos M, Hagen M, Bello-Klein A, Netto CA. Total antioxidant capacity is impaired in different structures from aged rat brain. Int J Dev Neurosci. 2005;23:663–71.PubMedCrossRefGoogle Scholar
  191. 191.
    Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci. 1996;93:4765–9.PubMedCrossRefGoogle Scholar
  192. 192.
    Zhu Y, Carvey PM, Ling Z. Age-related changes in glutathione and glutathione-related enzymes in rat brain. Brain Res. 2006;1090:35–44.PubMedCrossRefGoogle Scholar
  193. 193.
    Gonthier B, Singnorini-Allibe N, Soubeyran A, Eysseric H, Lamarche F, Barret L. Ethanol can modify the effects of certain free radical-generating systems of astrocytes. Alcohol Clin Exp Res. 2004;28:526–34.PubMedCrossRefGoogle Scholar
  194. 194.
    Howard LA, Miksys S, Hoffmann E, Mash D, Tyndale RF. Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics. Br J Pharmacol. 2003;138:1376–86.PubMedCrossRefGoogle Scholar
  195. 195.
    Yadav S, Dhawan A, Singh RL, Seth PK, Parmar D. Expression of constitutive and inducible cytochrome P450 2E1 in rat brain. Mol Cell Biochem. 2006;286:171–80.PubMedCrossRefGoogle Scholar
  196. 196.
    Rintala J, Jaatinen P, Parkkila S, Sarviharju M, Kiianmaa K, Hervonen A, Niemelä O. Evidence of acetaldehyde-protein adduct formation in rat brain after lifelong consumption of ethanol. Alcohol Alcohol. 2000;35:458–63.PubMedGoogle Scholar
  197. 197.
    Heaton MB, Paiva M, Mayer J, Miller R. Ethanol-mediated generation of reactive oxygen species in developing rat cerebellum. Neurosci Lett. 2002;334:83–6.PubMedCrossRefGoogle Scholar
  198. 198.
    Shivakumar BR, Anandatheerthavarada HK, Ravindranath V. Free radical scavenging systems in developing rat brain. Int J Dev Neurosci. 1991;9:181–5.PubMedCrossRefGoogle Scholar
  199. 199.
    Heaton MB, Mitchell JJ, Paiva M. Amelioration of ethanolinduced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy. Alcohol Clin Exp Res. 2000;24:512–18.PubMedCrossRefGoogle Scholar
  200. 200.
    Heaton MB, Madorsky I, Paiva M, Siler-Marsiglio KI. Ethanol-induced reduction of neurotrophin secretion in neonatal rat cerebellar granule cells is mitigated by vitamin E. Neurosci Lett. 2004;370:51–4.PubMedCrossRefGoogle Scholar
  201. 201.
    Heaton MB, Madorsky I, Paiva M, Siler-Marsiglio KI. Vitamin E amelioration of ethanol neurotoxicity involves modulation of apoptosis-related protein levels in neonatal rat cerebellar granule cells. Dev Brain Res. 2004;150:117–24.CrossRefGoogle Scholar
  202. 202.
    Siler-Marsiglio KI, Shaw G, Heaton MB. Pycnogenol and vitamin E inhibit ethanol-induced apoptosis in rat cerebellar granule cells. J Neurobiol. 2004;59:261–71.PubMedCrossRefGoogle Scholar
  203. 203.
    Siler-Marsiglio KI, Pan Q, Paiva M, Madorsky I, Khurana NC, Heaton MB. Mitochondrially targeted vitamin E and vitamin E mitigate ethanol-mediated effects on cerebellar granule cell antioxidant defence systems. Brain Res. 2005;1052:202–11.PubMedCrossRefGoogle Scholar
  204. 204.
    Edwards RB, Manzana EJ, Chen WJ. Melatonin (an antioxidant) does not ameliorate alcohol-induced Purkinje cell loss in the developing cerebellum. Alcohol Clin Exp Res. 2002;26:1003–09.PubMedCrossRefGoogle Scholar
  205. 205.
    Grisel JJ, Chen WJ. Antioxidant pretreatment does not ameliorate alcohol-induced Purkinje cell loss in the developing rat cerebellum. Alcohol Clin Exp Res. 2005;29:1223–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Pierce DR, Cook CC, Hinson JA, Light KE. Are oxidative mechanisms primary in ethanol-induced Purkinje neuron death of the neonatal rat? Neurosci Lett. 2006;400:130–4.PubMedCrossRefGoogle Scholar
  207. 207.
    Manfredi G, Beal MF. The role of mitochondria in the pathogenesis of neurodegenerative diseases. Brain Pathol. 2000;10:462–72.PubMedGoogle Scholar
  208. 208.
    Ramachandran V, Perez A, Chen J, Senthil D, Schenker S, Henderson GI. In utero ethanol exposure causes mitochondrial dysfunction, which can result in apoptotic cell death in fetal brain: A potential role for 4-hydroxynonenal. Alcohol Clin Exp Res. 2001;25:862–71.PubMedCrossRefGoogle Scholar
  209. 209.
    Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ. Heart mitochondria response to alcohol is different than brain and liver. Alcohol Clin Exp Res. 1995;19:1463–6.PubMedCrossRefGoogle Scholar
  210. 210.
    Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ. Mitochondrial dysfunction after fetal alcohol exposure. Alcohol Clin Exp Res. 1996;20:1029–32.PubMedCrossRefGoogle Scholar
  211. 211.
    Jaatinen P, Riikonen J, Riihioja P, Kajander O, Hervonen A. Interaction of aging and intermittent ethanol exposure on brain cytochrome c oxidase activity levels. Alcohol. 2003;29:91–100.PubMedCrossRefGoogle Scholar
  212. 212.
    Jung ME, Agarwal R, Simpkins JW. Ethanol withdrawal posttranslationally decreases the activity of cytochrome c oxidase in an estrogen reversible manner. Neuroscience Lett. 2007;416:160–4.CrossRefGoogle Scholar
  213. 213.
    Ravagnan L, Roumier T, Kroemer G. Mitochondria, the killer organelles and their weapons. J Cell Physiol. 2002;192:131–7.PubMedCrossRefGoogle Scholar
  214. 214.
    Fattoretti P, Bertoni-Freddari C, Casoli T, Di Stefano G, Giorgetti G, Solazzi M. Ethanol-induced decrease of the expression of glucose transport protein (Glut3) in the central nervous system as a predisposing condition to apoptosis: The effect of age. Ann NY Acad Sci. 2003;1010:500–03.PubMedCrossRefGoogle Scholar
  215. 215.
    Kroemer G, Reed JC. Mitochondrial control of cell death. Nature Med. 2000;6:513–19.PubMedCrossRefGoogle Scholar
  216. 216.
    Young C, Klocke BJ, Tenkova T, Choi J, Labruyere J, Qin Y-Q, et al. Ethanol-induced neuronal apoptosis in vivo requires BAX in the developing mouse brain. Cell Death Differ. 2003;10:1148–55.PubMedCrossRefGoogle Scholar
  217. 217.
    Ito Y, Arakawa M, Ishige K, Fukuda H. Comparative study of survival signal withdrawal and 4-hydroxynonenal-iinduced cell death in cerebellar granule cells. Neurosci Res. 1999;35:321–7.PubMedCrossRefGoogle Scholar
  218. 218.
    Diamond I, Gordon AS. Cellular and molecular neuroscience of alcoholism. Physiol Rev. 1997;77:1–20.PubMedGoogle Scholar
  219. 219.
    Costa LG, Guizzetti M, Lu H, Bordi F, Vitalone A, Tita B, et al. Intracellular signal transduction pathways as targets for neurotoxicants. Toxicology. 2001;160:19–26.PubMedCrossRefGoogle Scholar
  220. 220.
    Kumada T, Lakshmana MK, Komuro H. Reversal of neuronal migration in a mouse model of fetal alcohol syndrome by controlling second-messenger signalings. J Neurosci. 2006;26:742–56.PubMedCrossRefGoogle Scholar
  221. 221.
    Bearer CF. L1 cell adhesion molecule signal cascades: Targets for ethanol developmental neurotoxicity. Neurotoxicology. 2001;22:625–33.PubMedCrossRefGoogle Scholar
  222. 222.
    Tang N, He M, O’Riordan MA, Farkas C, Buck K, Lemmon V, Bearer CF. Ethanol inhibits L1 cell adhesion molecule activation of mitogen-activated protein kinases. J Neurochem. 2006;96:1480–90.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Medical School and Tampere University Hospital, Department of Internal MedicineUniversity of TampereTampereFinland
  2. 2.Suomen Terveystalo OyjTampereFinland
  3. 3.Department of Internal MedicineTampere University HospitalTampereFinland

Personalised recommendations