ROLE OF CENTRAL NERVOUS SYSTEM INSULIN RESISTANCE IN FETAL ALCOHOL SPECTRUM DISORDERS
Main Article Content
Keywords
Insulin signaling, mitochondria, oxidative stress, energy metabolism, insulin sensitizer, insulin resistance, central nervous system
Abstract
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) level and caused by both impaired receptor binding and increased activation of phosphatases that reverse IR tyrosine kinase activity. As a result, insulin activation of PI3K-Akt, which mediates neuronal survival, motility, energy metabolism, and plasticity, is impaired. The neurotoxicant effects of ethanol promote DNA damage, which could contribute to mitochondrial dysfunction and oxidative stress. Therefore, chronic in utero ethanol exposure produces a dual state of CNS insulin resistance and oxidative stress, which we postulate plays a major role in ethanol neurobehavioral teratogenesis. We propose that many of the prominent adverse effects of chronic prenatal exposure to ethanol on CNS development and function may be prevented or reduced by treatment with peroxisome-proliferated activated receptor (PPAR) agonists which enhance insulin sensitivity by increasing expression and function of insulin-responsive genes, and reducing cellular oxidative stress.
References
1. Alcohol use among women of childbearing age-- United States, 1991-1999. MMWR Morb Mortal Wkly Rep 2002;51:273-6.
2. Riley EP, McGee CL. Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med (Maywood) 2005;230:357-65.
3. Astley SJ. Fetal alcohol syndrome prevention in Washington State: evidence of success. Paediatr Perinat Epidemiol 2004;18:344-51.
4. Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria. Pediatrics 2005;115:39-47.
5. Lupton C, Burd L, Harwood R. Cost of fetal alcohol spectrum disorders. Am J Med Genet C Semin Med Genet 2004;127:42-50.
6. Cudd TA. Animal model systems for the study of alcohol teratology. Exp Biol Med (Maywood) 2005;230:389-93.
7. Stromland K, Pinazo-Duran MD. Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies. Alcohol Alcohol 2002;37:2-8.
8. Monti PM, Miranda R, Jr., Nixon K, et al. Adolescence: booze, brains, and behavior. Alcohol Clin Exp Res 2005;29:207-20.
9. Brown SA, Tapert SF. Adolescence and the trajectory of alcohol use: basic to clinical studies. Ann N Y Acad Sci 2004;1021:234-44.
10. Medina KL, Schweinsburg AD, Cohen-Zion M, Nagel BJ, Tapert SF. Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry. Neurotoxicol Teratol 2007;29:141-52.
11. Tapert SF, Schweinsburg AD, Barlett VC, et al. Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders. Alcohol Clin Exp Res 2004;28: 1577-86.
12. Tapert SF, Pulido C, Paulus MP, Schuckit MA, Burke C. Level of response to alcohol and brain
13. response during visual working memory. J Stud Alcohol 2004;65:692-700.
14. Townshend JM, Duka T. Binge drinking, cognitive performance and mood in a population of young social drinkers. Alcohol Clin Exp Res 2005;29:317-25.
15. Tapert SF, Brown GG, Kindermann SS, Cheung EH, Frank LR, Brown SA. fMRI measurement of brain dysfunction in alcohol-dependent young women. Alcohol Clin Exp Res 2001;25:236-45.
16. Sher L. Functional magnetic resonance imaging in studies of neurocognitive effects of alcohol use on adolescents and young adults. Int J Adolesc Med Health 2006;18:3-7.
17. Burd L, Klug MG, Martsolf JT, Kerbeshian J. Fetal alcohol syndrome: neuropsychiatric phenomics. Neurotoxicol Teratol 2003;25:697-705.
18. O'Malley KD, Nanson J. Clinical implications of a link between fetal alcohol spectrum disorder and attention-deficit hyperactivity disorder. Can J Psychiatry 2002;47:349-54.
19. Coles CD. Fetal alcohol exposure and attention: moving beyond ADHD. Alcohol Res Health 2001;25:199-203.
20. Coffin JM, Baroody S, Schneider K, O'Neill J. Impaired cerebellar learning in children with prenatal alcohol exposure: a comparative study of eyeblink conditioning in children with ADHD and dyslexia. Cortex 2005;41:389-98.
21. Kaplan-Estrin M, Jacobson SW, Jacobson JL. Neurobehavioral effects of prenatal alcohol exposure at 26 months. Neurotoxicol Teratol 1999;21:503-11.
22. Ma X, Coles CD, Lynch ME, et al. Evaluation of corpus callosum anisotropy in young adults with fetal alcohol syndrome according to diffusion tensor imaging. Alcohol Clin Exp Res 2005;29: 1214-22.
23. Johnson JL, Leff M. Children of substance abusers: overview of research findings. Pediatrics 1999;103:1085-99.
24. Baumbach J. Some implications of prenatal alcohol exposure for the treatment of adolescents with sexual offending behaviors. Sex Abuse 2002;14:313-27.
25. Young NK. Effects of alcohol and other drugs on children. J Psychoactive Drugs 1997;29:23-42.
26. Barr HM, Bookstein FL, O'Malley KD, Connor PD, Huggins JE, Streissguth AP. Binge drinking during pregnancy as a predictor of psychiatric disorders on the Structured Clinical Interview for DSM-IV in young adult offspring. Am J Psychiatry 2006;163:1061-5.
27. Olson HC, Streissguth AP, Sampson PD, Barr HM, Bookstein FL, Thiede K. Association of prenatal alcohol exposure with behavioral and learning problems in early adolescence. J Am Acad Child Adolesc Psychiatry 1997;36:1187-94.
28. Pascual M, Boix J, Felipo V, Guerri C. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem 2009;108:920-31.
29. O'Hare ED, Kan E, Yoshii J, et al. Mapping cerebellar vermal morphology and cognitive correlates in prenatal alcohol exposure. Neuroreport 2005;16:1285-90.
30. Aronson M, Hagberg B. Neuropsychological disorders in children exposed to alcohol during pregnancy: a follow-up study of 24 children to alcoholic mothers in Goteborg, Sweden. Alcohol Clin Exp Res 1998;22:321-4.
31. Goodlett CR, Lundahl KR. Temporal determinants of neonatal alcohol-induced cerebellar damage and motor performance deficits. Pharmacol Biochem Behav 1996;55:531-40.
32. Thomas JD, Burchette TL, Dominguez HD, Riley EP. Neonatal alcohol exposure produces more severe motor coordination deficits in high alcohol sensitive rats compared to low alcohol sensitive rats. Alcohol 2000;20:93-9.
33. Mattson SN, Schoenfeld AM, Riley EP. Teratogenic effects of alcohol on brain and behavior. Alcohol Res Health 2001;25:185-91.
34. Abel EL. Prenatal effects of alcohol. Drug Alcohol Depend 1984;14:1-10.
35. O'Callaghan F V, O'Callaghan M, Najman JM, Williams GM, Bor W. Prenatal alcohol exposure and attention, learning and intellectual ability at 14 years: A prospective longitudinal study. Early Hum Dev 2007;83:115-23.
36. O'Callaghan FV, O'Callaghan M, Najman JM, Williams GM, Bor W. Maternal alcohol consumption during pregnancy and physical outcomes up to 5 years of age: a longitudinal study. Early Hum Dev 2003;71:137-48.
37. Tarelo-Acuna L, Olvera-Cortes E, Gonzalez- Burgos I. Prenatal and postnatal exposure to ethanol induces changes in the shape of the dendritic spines from hippocampal CA1 pyramidal neurons of the rat. Neurosci Lett 2000;286:13-6.
38. Ozer E, Sarioglu S, Gure A. Effects of prenatal ethanol exposure on neuronal migration, neuronogenesis and brain myelination in the mice brain. Clin Neuropathol 2000;19:21-5.
39. Volk B. Cerebellar histogenesis and synaptic maturation following pre- and postnatal alcohol administration. An electron-microscopic investigation of the rat cerebellar cortex. Acta Neuropathol 1984;63:57-65.
40. Edwards HG, Dow-Edwards DL. Craniofacial alterations in adult rats prenatally exposed to ethanol. Teratology 1991;44:373-8.
41. Soscia SJ, Tong M, Xu XJ, et al. Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain. Cell Mol Life Sci 2006;63:2039-56.
42. Clarren SK, Alvord EJ, Sumi SM, Streissguth AP, Smith DW. Brain malformations related to prenatal exposure to ethanol. J Pediatr 1978;92:64-7.
43. de la Monte SM, Tong M, Carlson RI, et al. Ethanol inhibition of aspartyl-asparaginyl-betahydroxylase in fetal alcohol spectrum disorder: potential link to the impairments in central nervous system neuronal migration. Alcohol 2009;43:225-40.
44. Kumada T, Jiang Y, Cameron DB, Komuro H. How does alcohol impair neuronal migration? J Neurosci Res 2007;85:465-70.
45. Bonthius DJ, Pantazis NJ, Karacay B, et al. Alcohol exposure during the brain growth spurt promotes hippocampal seizures, rapid kindling, and spreading depression. Alcohol Clin Exp Res 2001; 25:734-45.
46. Ge Y, Belcher SM, Light KE. Alterations of cerebellar mRNA specific for BDNF, p75NTR, and TrkB receptor isoforms occur within hours of ethanol administration to 4-day-old rat pups. Brain Res Dev Brain Res 2004;151:99-109.
47. 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. Brain Res Mol Brain Res 2004;129:124-34.
48. Kelly SJ, Pierce DR, West JR. Microencephaly and hyperactivity in adult rats can be induced by neonatal exposure to high blood alcohol concentrations. Exp Neurol 1987;96:580-93.
49. Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med 1978;298:1063-7.
50. de la Monte SM. Disproportionate atrophy of cerebral white matter in chronic alcoholics. Arch Neurol 1988;45:990-2.
51. de la Monte SM, Wands JR. Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. CMLS, CellMol Life Sci 2002;59:882-93.
52. Guerri C. Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal alcohol exposure. Alcohol Clin Exp Res 1998;22:304-12.
53. Kelm MK, Criswell HE, Breese GR. Calcium release from presynaptic internal stores is required for ethanol to increase spontaneous gamma-aminobutyric acid release onto cerebellum Purkinje neurons. J Pharmacol Exp Ther 2007;323:356-64.
54. Olney JW, Farber NB, Wozniak DF, Jevtovic- Todorovic V, Ikonomidou C. Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ Health Perspect 2000;108 Suppl 3:383-8.
55. Goodlett CR, Horn KH, Zhou FC. Alcohol teratogenesis: mechanisms of damage and strategies for intervention. Exp Biol Med (Maywood) 2005;230:394-406.
56. Miller MW, Mooney SM. Chronic exposure to ethanol alters neurotrophin content in the basal forebrain-cortex system in the mature rat: effects on autocrine-paracrine mechanisms. J Neurobiol 2004;60:490-8.
57. 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.
58. Breese CR, D'Costa A, Sonntag WE. Effect of in utero ethanol exposure on the postnatal ontogeny of insulin-like growth factor-1, and type-1 and type-2 insulin-like growth factor receptors in the rat brain. Neuroscience 1994;63:579-89.
59. Resnicoff M, Rubini M, Baserga R, Rubin R. Ethanol inhibits insulin-like growth factor-1- mediated signalling and proliferation of C6 rat glioblastoma cells. Lab Invest 1994;71:657-62.
60. Dees WL, Srivastava V, Hiney JK. Actions and interactions of alcohol and insulin-like growth factor-1 on female pubertal development. Alcohol Clin Exp Res 2009;33:1847-56.
61. McGough NN, Thomas JD, Dominguez HD, Riley EP. Insulin-like growth factor-I mitigates motor coordination deficits associated with neonatal alcohol exposure in rats. Neurotoxicol Teratol 2009; 31:40-8.
62. Luo J, Miller MW. Growth factor-mediated neural proliferation: target of ethanol toxicity. Brain Res Brain Res Rev 1998;27:157-67.
63. Tateno M, Ukai W, Ozawa H, et al. Ethanol inhibition of neural stem cell differentiation is reduced by neurotrophic factors. Alcohol Clin Exp Res 2004;28:134S-8S.
64. Biermann T, Reulbach U, Lenz B, et al. Nmethyl- D-aspartate 2b receptor subtype (NR2B) promoter methylation in patients during alcohol withdrawal. J Neural Transm 2009;116:615-22.
65. Ishii T, Hashimoto E, Ukai W, et al. [Epigenetic regulation in alcohol-related brain damage]. Nihon Arukoru Yakubutsu Igakkai Zasshi 2008;43:705-13.
66. Ouko LA, Shantikumar K, Knezovich J, Haycock P, Schnugh DJ, Ramsay M. Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IGDMR in male gametes: implications for fetal alcohol spectrum disorders. Alcohol Clin Exp Res 2009;33:1615-27.
67. Haycock PC. Fetal alcohol spectrum disorders: the epigenetic perspective. Biol Reprod 2009;81:607-17.
68. Liu Y, Balaraman Y, Wang G, Nephew KP, Zhou FC. Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation. Epigenetics 2009;4:500-11.
69. Haycock PC, Ramsay M. Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol Reprod 2009;81:618-27.
70. Gammeltoft S, Fehlmann M, Van OE. Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Biochimie 1985;67:1147-53.
71. Goodyer CG, De SL, Lai WH, Guyda HJ, Posner BI. Characterization of insulin-like growth factor receptors in rat anterior pituitary, hypothalamus, and brain. Endocrinology 1984;114:1187-95.
72. Hill JM, Lesniak MA, Pert CB, Roth J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 1986;17:1127-38.
73. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis 2005;7:45-61.
74. Myers MG, White MF. The new elements of insulin signaling. Insulin receptor substrate-1 and proteins with SH2 domains. Diabetes 1993;42:643-50.
75. Kido Y, Nakae J, Accili D. Clinical review 125: The insulin receptor and its cellular targets. J Clin Endocrinol Metab 2001;86:972-9.
76. Del Valle L, Wang JY, Lassak A, et al. Insulinlike growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas. J Neurovirol 2002;8 Suppl 2:138-47.
77. Folli F, Saad MJ, Kahn CR. Insulin receptor/IRS-1/PI 3-kinase signaling system in corticosteroid-induced insulin resistance. Acta Diabetol 1996;33:185-92.
78. Nakae J, Kido Y, Accili D. Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 2001;22:818-35.
79. 78. Giovannone B, Scaldaferri ML, Federici M, et al. Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential. Diabetes Metab Res Rev 2000;16:434-41.
80. Xu YY, Bhavani K, Wands JR, de la Monte SM. Ethanol inhibits insulin receptor substrate-1 tyrosine phosphorylation and insulin-stimulated neuronal thread protein gene expression. Biochem J 1995;310:125-32.
81. Mauceri HJ, Lee WH, Conway S. Effect of ethanol on insulin-like growth factor-II release from fetal organs. Alcohol Clin Exp Res 1994;18:35-41.
82. Luo J, Miller MW. Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. Alcohol Clin Exp Res 1997;21:1186-94.
83. Luo J, Miller MW. Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action. J Neurosci 1999;19:10014-25.
84. Luo J, West JR, Cook RT, Pantazis NJ. Ethanol induces cell death and cell cycle delay in cultures of pheochromocytoma PC12 cells. Alcohol Clin Exp Res 1999;23:644-56.
85. Chu J, Tong M, de la Monte SM. Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. Acta Neuropathol (Berl) 2007;113: 659-73.
86. de la Monte SM, Wands JR. Mitochondrial DNA damage and impaired mitochondrial function contribute to apoptosis of insulinstimulated ethanol-exposed neuronal cells. Alcohol Clin Exp Res 2001;25:898-906.
87. Miller MW. A longitudinal study of the effects of prenatal ethanol exposure on neuronal acquisition and death in the principal sensory nucleus of the trigeminal nerve: interaction with changes induced by transection of the infraorbital nerve. J Neurocytol 1999;28:999-1015.
88. West JR, Goodlett CR, Bonthius DJ, Hamre KM, Marcussen BL. Cell population depletion associated with fetal alcohol brain damage: mechanisms of BAC-dependent cell loss. Alcohol Clin Exp Res 1990;14:813-8.
89. 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.
90. Acquaah-Mensah GK, Kehrer JP, Leslie SW. In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model. J Pharmacol Exp Ther 2002;301:277-83.
91. Carter JJ, Tong M, Silbermann E, et al. Ethanol impaired neuronal migration is associated with reduced aspartyl-asparaginyl-beta-hydroxylase expression. Acta Neuropathol 2008.
92. Chakraborty G, Saito M, Mao RF, Wang R, Vadasz C, Saito M. Lithium blocks ethanolinduced modulation of protein kinases in the developing brain. Biochem Biophys Res Commun 2008;367: 597-602.
93. Luo J. GSK3beta in ethanol neurotoxicity. Mol Neurobiol 2009;40:108-21.
94. Takadera T, Ohyashiki T. Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons. Eur J Pharmacol 2004;499:239-45.
95. Sasaki Y, Wands JR. Ethanol impairs insulin receptor substrate-1 mediated signal transduction during rat liver regeneration. Biochem Biophys Res Commun 1994;199:403- 9.
96. de la Monte SM, Ganju N, Tanaka S, et al. Differential effects of ethanol on insulinsignaling through the insulin receptor substrate- 1. Alcohol Clin Exp Res 1999;23:770-7.
97. Banerjee K, Mohr L, Wands JR, de la Monte SM. Ethanol inhibition of insulin signaling in hepatocellular carcinoma cells. Alcohol Clin Exp Res 1998;22:2093-101.
98. Mohr L, Tanaka S, Wands JR. Ethanol inhibits hepatocyte proliferation in insulin receptor substrate 1 transgenic mice. Gastroenterology 1998;115:1558-65.
99. Xu J, Yeon JE, Chang H, et al. Ethanol impairs insulin-stimulated neuronal survival in the developing brain: role of PTEN phosphatase. J Biol Chem 2003;278:26929-37.
100. Diehl AM, Yang SQ, Cote P, Wand GS. Chronic ethanol consumption disturbs G-protein expression and inhibits cyclic AMP-dependent signaling in regenerating rat liver. Hepatology 1992;16: 1212-9.
101. Gordon AS, Collier K, Diamond I. Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol. Proc Natl Acad Sci U S A 1986;83:2105-8.
102. de la Monte SM, Ganju N, Banerjee K, Brown NV, Luong T, Wands JR. Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol-3-kinase. Alcohol Clin Exp Res 2000;24:716-26.
103. Yeon JE, Califano S, Xu J, Wands JR, De La Monte SM. Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. Hepatology 2003;38:703-14.
104. Domenicotti C, Paola D, Lamedica A, et al. Effects of ethanol metabolism on PKC activity in isolated rat hepatocytes. Chem Biol Interact 1996;100:155-63.
105. Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt [see comments]. Science 1997;275:661-5.
106. Bhave SV, Hoffman PL. Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA. J Neurochem 1997;68:578-86.
107. Ikonomidou C, Bittigau P, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000;287:1056-60.
108. Olney JW, Ishimaru MJ, Bittigau P, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing brain. Apoptosis 2000;5:515- 21.
109. de la Monte SM, Neely TR, Cannon J, Wands JR. Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons. Cell Mol Life Sci 2001;58:1950-60.
110. Hallak H, Seiler AE, Green JS, Henderson A, Ross BN, Rubin R. Inhibition of insulin-like growth factor-I signaling by ethanol in neuronal cells. Alcohol Clin Exp Res 2001;25:1058-64.
111. Camp MC, Mayfield RD, McCracken M, McCracken L, Alcantara AA. Neuroadaptations of Cdk5 in cholinergic interneurons of the nucleus accumbens and prefrontal cortex of inbred alcohol-preferring rats following voluntary alcohol drinking. Alcohol Clin Exp Res 2006;30:1322-35.
112. Rajgopal Y, Vemuri MC. Ethanol induced changes in cyclin-dependent kinase-5 activity and its activators, P35, P67 (Munc-18) in rat brain. Neurosci Lett 2001;308:173-6.
113. 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.
114. Bannigan J, Cottell D. Ethanol teratogenicity in mice: an electron microscopic study. Teratology 1984;30:281-90.
115. Farrar RP, Seibert C, Gnau K, Leslie SW. Development of tolerance in brain mitochondria for calcium uptake following chronic ethanol ingestion. Brain Res 1989;500:374-8.
116. Goodlett CR, Horn KH. Mechanisms of alcoholinduced damage to the developing nervous system. Alcohol Res Health 2001;25:175-84.
117. Henderson GI, Chen JJ, Schenker S. Ethanol, oxidative stress, reactive aldehydes, and the fetus. Front Biosci 1999;4:D541-50.
118. Mansouri A, Demeilliers C, Amsellem S, Pessayre D, Fromenty B. Acute ethanol administration oxidatively damages and depletes mitochondrial dna in mouse liver, brain, heart, and skeletal muscles: protective effects of antioxidants. J Pharmacol Exp Ther 2001;298:737-43.
119. Xu YJ, Liu P, Li Y. [Effect of alcohol on brain mitochondria development of mouse embryos]. Wei Sheng Yan Jiu 2005;34:61-3.
120. Cahill A, Wang X, Hoek JB. Increased oxidative damage to mitochondrial DNA following chronic ethanol consumption. Biochem Biophys Res Commun 1997;235:286-90.
121. Lee RD, An SM, Kim SS, et al. Neurotoxic effects of alcohol and acetaldehyde during embryonic development. J Toxicol Environ Health A 2005;68:2147-62.
122. Pastorino JG. Potentiation by chronic, ethanol treatment of the mitochondrial permeability transition. Biochem Biophys Res Commun 1999;265:405-9.
123. Wieland P, Lauterburg BH. Oxidation of mitochondrial proteins and DNA following administration of ethanol. Biochem Biophys Res Commun 1995;213:815-9.
124. Almansa I, Fernandez A, Garcia-Ruiz C, et al. Brain mitochondrial alterations after chronic alcohol consumption. J Physiol Biochem 2009;65:305-12.
125. Cherian PP, Schenker S, Henderson GI. Ethanolmediated DNA damage and PARP-1 apoptotic responses in cultured fetal cortical neurons. Alcohol Clin Exp Res 2008;32:1884-92.
126. Green CR, Watts LT, Kobus SM, Henderson GI, Reynolds JN, Brien JF. Effects of chronic prenatal ethanol exposure on mitochondrial glutathione and 8-iso-prostaglandin F2alpha concentrations in the hippocampus of the perinatal guinea pig. Reprod Fertil Dev 2006;18:517-24.
127. 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 defense systems. Brain Res 2005;1052:202-11.
128. Albano E, French SW, Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity. Front Biosci 1999;4:D533-40.
129. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci 2002;65:166-76.
130. Fadda F, Rossetti ZL. Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Prog Neurobiol 1998;56:385-431.
131. Heaton MB, Mitchell JJ, Paiva M. Amelioration of ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy. Alcohol Clin Exp Res 2000;24:512-8.
132. Kim JH, Kim JE, Kim HJ, et al. Ethanol decreases the expression of mitochondrial cytochrome c oxidase mRNA in the rat. Neurosci Lett 2001;305:107-10.
133. Wallin C, Puka-Sundvall M, Hagberg H, Weber SG, Sandberg M. Alterations in glutathione and amino acid concentrations after hypoxiaischemia in the immature rat brain. Brain Res Dev Brain Res 2000;125:51-60.
134. 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.
135. Mill JF, Chao MV, Ishii DN. Insulin, insulinlike growth factor II, and nerve growth factor effects on tubulin mRNA levels and neurite formation. Proc Natl Acad Sci U S A 1985;82:7126-30.
136. Puro DG, Agardh E. Insulin-mediated regulation of neuronal maturation. Science 1984;225:1170-2.
137. de la Monte SM, Chen GJ, Rivera E, Wands JR. Neuronal thread protein regulation and interaction with microtubule-associated proteins in SH-Sy5y neuronal cells. Cell Mol Life Sci 2003;60: 2679-91.
138. Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997;272:19547-53.
139. Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta 2005;1739:298-310.
140. Tsujio I, Tanaka T, Kudo T, et al. Inactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation. FEBS Lett 2000;469:111-7.
141. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. J Alzheimers Dis 2006;9:13-33.
142. de la Monte SM, Tong M, Lester-Coll N, Plater M, Jr., Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: Relevance to Alzheimer's disease. J Alzheimers Dis 2006;10:89-109.
143. Arendt T. Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol. J Neural Transm Suppl 1994;44:173-87.
144. Cohen AC, Tong M, Wands JR, de la Monte SM. Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model. Alcohol Clin Exp Res 2007; 31:1558-73.
145. Dymecki J, Medynska E, Walski M. The influence of ethanol intoxication on cholinergic axon terminals in the rat brain. (Morphometric evaluation). Exp Pathol 1982;22:73-83.
146. West JR, Dewey SL, Cassell MD. Prenatal ethanol exposure alters the post-lesion reorganization (sprouting) of acetylcholinesterase staining in the dentate gyrus of adult rats. Brain Res 1984; 314:83-95.
147. Diamond I, Gordon AS. Cellular and molecular neuroscience of alcoholism. Physiol Rev 1997;77:1-20.
148. Eravci M, Schulz O, Grospietsch T, et al. Gene expression of receptors and enzymes involved in GABAergic and glutamatergic neurotransmission in the CNS of rats behaviourally dependent on ethanol. Br J Pharmacol 2000;131:423-32.
149. Hamid A, Wani NA, Kaur J. New perspectives on folate transport in relation to alcoholisminduced folate malabsorption--association with epigenome stability and cancer development. FEBS J 2009;276:2175-91.
150. Lancaster FE. Alcohol, nitric oxide, and neurotoxicity: is there a connection?--a review. Alcohol Clin Exp Res 1992;16:539-41.
151. Savage DD, Montano CY, Otero MA, Paxton LL. Prenatal ethanol exposure decreases hippocampal NMDA-sensitive [3H]-glutamate binding site density in 45-day-old rats. Alcohol 1991;8: 193-201.
152. Breese CR, D'Costa A, Booze RM, Sonntag WE. Distribution of insulin-like growth factor 1 (IGF-1) and 2 (IGF-2) receptors in the hippocampal formation of rats and mice. Adv Exp Med Biol 1991; 293:449-58.
153. Kliewer SA, Lehmann JM, Milburn MV, Willson TM. The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog Horm Res 1999;54:345-67; discussion 67-8.
154. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302:93-109.
155. Gilde AJ, Van Bilsen M. Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand 2003;178:425-34.
156. Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003;144:2201-7.
157. Savkur RS, Miller AR. Investigational PPARgamma agonists for the treatment of Type 2 diabetes. Expert Opin Investig Drugs 2006;15:763-78.
158. Tao L, Liu HR, Gao E, et al. Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptorgamma agonist in hypercholesterolemia. Circulation 2003;108: 2805-11.
159. Zhao X, Quigley JE, Yuan J, Wang MH, Zhou Y, Imig JD. PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats. Am J Physiol Heart Circ Physiol 2006;290:H2187-95.
160. Barroso I, Gurnell M, Crowley VE, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999;402: 880-3.
161. Bishop-Bailey D, Warner TD. PPARgamma ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator-activated receptorgamma antagonist. Faseb J 2003;17:1925-7.
162. Markesbery WR, Carney JM. Oxidative alterations in Alzheimer's disease. Brain Pathol 1999;9:133-46.
163. Montine KS, Kim PJ, Olson SJ, Markesbery WR, Montine TJ. 4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease. J Neuropathol Exp Neurol 1997;56:866-71.
164. Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenalderived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 1997; 68:2092-7.
165. de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis 2006;9: 167-81.
166. Ghafourifar P, Klein SD, Schucht O, et al. Ceramide induces cytochrome c release from isolated mitochondria. Importance of mitochondrial redox state. J Biol Chem 1999;274:6080-4.
167. de Licona HK, Karacay B, Mahoney J, McDonald E, Luang T, Bonthius DJ. A single exposure to alcohol during brain development induces microencephaly and neuronal losses in genetically susceptible mice, but not in wild type mice. Neurotoxicology 2009;30:459-70.
168. Li Z, Zharikova A, Vaughan CH, et al. Intermittent high-dose ethanol exposures increase motivation for operant ethanol selfadministration: possible neurochemical mechanism. Brain Res;1310: 142-53.
169. Pang M, de la Monte SM, Longato L, et al. PPARdelta agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair. J Hepatol 2009;50:1192-201.
170. Monville C, Torres EM, Dunnett SB. Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods 2006; 158:219-23.
2. Riley EP, McGee CL. Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior. Exp Biol Med (Maywood) 2005;230:357-65.
3. Astley SJ. Fetal alcohol syndrome prevention in Washington State: evidence of success. Paediatr Perinat Epidemiol 2004;18:344-51.
4. Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria. Pediatrics 2005;115:39-47.
5. Lupton C, Burd L, Harwood R. Cost of fetal alcohol spectrum disorders. Am J Med Genet C Semin Med Genet 2004;127:42-50.
6. Cudd TA. Animal model systems for the study of alcohol teratology. Exp Biol Med (Maywood) 2005;230:389-93.
7. Stromland K, Pinazo-Duran MD. Ophthalmic involvement in the fetal alcohol syndrome: clinical and animal model studies. Alcohol Alcohol 2002;37:2-8.
8. Monti PM, Miranda R, Jr., Nixon K, et al. Adolescence: booze, brains, and behavior. Alcohol Clin Exp Res 2005;29:207-20.
9. Brown SA, Tapert SF. Adolescence and the trajectory of alcohol use: basic to clinical studies. Ann N Y Acad Sci 2004;1021:234-44.
10. Medina KL, Schweinsburg AD, Cohen-Zion M, Nagel BJ, Tapert SF. Effects of alcohol and combined marijuana and alcohol use during adolescence on hippocampal volume and asymmetry. Neurotoxicol Teratol 2007;29:141-52.
11. Tapert SF, Schweinsburg AD, Barlett VC, et al. Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders. Alcohol Clin Exp Res 2004;28: 1577-86.
12. Tapert SF, Pulido C, Paulus MP, Schuckit MA, Burke C. Level of response to alcohol and brain
13. response during visual working memory. J Stud Alcohol 2004;65:692-700.
14. Townshend JM, Duka T. Binge drinking, cognitive performance and mood in a population of young social drinkers. Alcohol Clin Exp Res 2005;29:317-25.
15. Tapert SF, Brown GG, Kindermann SS, Cheung EH, Frank LR, Brown SA. fMRI measurement of brain dysfunction in alcohol-dependent young women. Alcohol Clin Exp Res 2001;25:236-45.
16. Sher L. Functional magnetic resonance imaging in studies of neurocognitive effects of alcohol use on adolescents and young adults. Int J Adolesc Med Health 2006;18:3-7.
17. Burd L, Klug MG, Martsolf JT, Kerbeshian J. Fetal alcohol syndrome: neuropsychiatric phenomics. Neurotoxicol Teratol 2003;25:697-705.
18. O'Malley KD, Nanson J. Clinical implications of a link between fetal alcohol spectrum disorder and attention-deficit hyperactivity disorder. Can J Psychiatry 2002;47:349-54.
19. Coles CD. Fetal alcohol exposure and attention: moving beyond ADHD. Alcohol Res Health 2001;25:199-203.
20. Coffin JM, Baroody S, Schneider K, O'Neill J. Impaired cerebellar learning in children with prenatal alcohol exposure: a comparative study of eyeblink conditioning in children with ADHD and dyslexia. Cortex 2005;41:389-98.
21. Kaplan-Estrin M, Jacobson SW, Jacobson JL. Neurobehavioral effects of prenatal alcohol exposure at 26 months. Neurotoxicol Teratol 1999;21:503-11.
22. Ma X, Coles CD, Lynch ME, et al. Evaluation of corpus callosum anisotropy in young adults with fetal alcohol syndrome according to diffusion tensor imaging. Alcohol Clin Exp Res 2005;29: 1214-22.
23. Johnson JL, Leff M. Children of substance abusers: overview of research findings. Pediatrics 1999;103:1085-99.
24. Baumbach J. Some implications of prenatal alcohol exposure for the treatment of adolescents with sexual offending behaviors. Sex Abuse 2002;14:313-27.
25. Young NK. Effects of alcohol and other drugs on children. J Psychoactive Drugs 1997;29:23-42.
26. Barr HM, Bookstein FL, O'Malley KD, Connor PD, Huggins JE, Streissguth AP. Binge drinking during pregnancy as a predictor of psychiatric disorders on the Structured Clinical Interview for DSM-IV in young adult offspring. Am J Psychiatry 2006;163:1061-5.
27. Olson HC, Streissguth AP, Sampson PD, Barr HM, Bookstein FL, Thiede K. Association of prenatal alcohol exposure with behavioral and learning problems in early adolescence. J Am Acad Child Adolesc Psychiatry 1997;36:1187-94.
28. Pascual M, Boix J, Felipo V, Guerri C. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem 2009;108:920-31.
29. O'Hare ED, Kan E, Yoshii J, et al. Mapping cerebellar vermal morphology and cognitive correlates in prenatal alcohol exposure. Neuroreport 2005;16:1285-90.
30. Aronson M, Hagberg B. Neuropsychological disorders in children exposed to alcohol during pregnancy: a follow-up study of 24 children to alcoholic mothers in Goteborg, Sweden. Alcohol Clin Exp Res 1998;22:321-4.
31. Goodlett CR, Lundahl KR. Temporal determinants of neonatal alcohol-induced cerebellar damage and motor performance deficits. Pharmacol Biochem Behav 1996;55:531-40.
32. Thomas JD, Burchette TL, Dominguez HD, Riley EP. Neonatal alcohol exposure produces more severe motor coordination deficits in high alcohol sensitive rats compared to low alcohol sensitive rats. Alcohol 2000;20:93-9.
33. Mattson SN, Schoenfeld AM, Riley EP. Teratogenic effects of alcohol on brain and behavior. Alcohol Res Health 2001;25:185-91.
34. Abel EL. Prenatal effects of alcohol. Drug Alcohol Depend 1984;14:1-10.
35. O'Callaghan F V, O'Callaghan M, Najman JM, Williams GM, Bor W. Prenatal alcohol exposure and attention, learning and intellectual ability at 14 years: A prospective longitudinal study. Early Hum Dev 2007;83:115-23.
36. O'Callaghan FV, O'Callaghan M, Najman JM, Williams GM, Bor W. Maternal alcohol consumption during pregnancy and physical outcomes up to 5 years of age: a longitudinal study. Early Hum Dev 2003;71:137-48.
37. Tarelo-Acuna L, Olvera-Cortes E, Gonzalez- Burgos I. Prenatal and postnatal exposure to ethanol induces changes in the shape of the dendritic spines from hippocampal CA1 pyramidal neurons of the rat. Neurosci Lett 2000;286:13-6.
38. Ozer E, Sarioglu S, Gure A. Effects of prenatal ethanol exposure on neuronal migration, neuronogenesis and brain myelination in the mice brain. Clin Neuropathol 2000;19:21-5.
39. Volk B. Cerebellar histogenesis and synaptic maturation following pre- and postnatal alcohol administration. An electron-microscopic investigation of the rat cerebellar cortex. Acta Neuropathol 1984;63:57-65.
40. Edwards HG, Dow-Edwards DL. Craniofacial alterations in adult rats prenatally exposed to ethanol. Teratology 1991;44:373-8.
41. Soscia SJ, Tong M, Xu XJ, et al. Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain. Cell Mol Life Sci 2006;63:2039-56.
42. Clarren SK, Alvord EJ, Sumi SM, Streissguth AP, Smith DW. Brain malformations related to prenatal exposure to ethanol. J Pediatr 1978;92:64-7.
43. de la Monte SM, Tong M, Carlson RI, et al. Ethanol inhibition of aspartyl-asparaginyl-betahydroxylase in fetal alcohol spectrum disorder: potential link to the impairments in central nervous system neuronal migration. Alcohol 2009;43:225-40.
44. Kumada T, Jiang Y, Cameron DB, Komuro H. How does alcohol impair neuronal migration? J Neurosci Res 2007;85:465-70.
45. Bonthius DJ, Pantazis NJ, Karacay B, et al. Alcohol exposure during the brain growth spurt promotes hippocampal seizures, rapid kindling, and spreading depression. Alcohol Clin Exp Res 2001; 25:734-45.
46. Ge Y, Belcher SM, Light KE. Alterations of cerebellar mRNA specific for BDNF, p75NTR, and TrkB receptor isoforms occur within hours of ethanol administration to 4-day-old rat pups. Brain Res Dev Brain Res 2004;151:99-109.
47. 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. Brain Res Mol Brain Res 2004;129:124-34.
48. Kelly SJ, Pierce DR, West JR. Microencephaly and hyperactivity in adult rats can be induced by neonatal exposure to high blood alcohol concentrations. Exp Neurol 1987;96:580-93.
49. Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med 1978;298:1063-7.
50. de la Monte SM. Disproportionate atrophy of cerebral white matter in chronic alcoholics. Arch Neurol 1988;45:990-2.
51. de la Monte SM, Wands JR. Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons. CMLS, CellMol Life Sci 2002;59:882-93.
52. Guerri C. Neuroanatomical and neurophysiological mechanisms involved in central nervous system dysfunctions induced by prenatal alcohol exposure. Alcohol Clin Exp Res 1998;22:304-12.
53. Kelm MK, Criswell HE, Breese GR. Calcium release from presynaptic internal stores is required for ethanol to increase spontaneous gamma-aminobutyric acid release onto cerebellum Purkinje neurons. J Pharmacol Exp Ther 2007;323:356-64.
54. Olney JW, Farber NB, Wozniak DF, Jevtovic- Todorovic V, Ikonomidou C. Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ Health Perspect 2000;108 Suppl 3:383-8.
55. Goodlett CR, Horn KH, Zhou FC. Alcohol teratogenesis: mechanisms of damage and strategies for intervention. Exp Biol Med (Maywood) 2005;230:394-406.
56. Miller MW, Mooney SM. Chronic exposure to ethanol alters neurotrophin content in the basal forebrain-cortex system in the mature rat: effects on autocrine-paracrine mechanisms. J Neurobiol 2004;60:490-8.
57. 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.
58. Breese CR, D'Costa A, Sonntag WE. Effect of in utero ethanol exposure on the postnatal ontogeny of insulin-like growth factor-1, and type-1 and type-2 insulin-like growth factor receptors in the rat brain. Neuroscience 1994;63:579-89.
59. Resnicoff M, Rubini M, Baserga R, Rubin R. Ethanol inhibits insulin-like growth factor-1- mediated signalling and proliferation of C6 rat glioblastoma cells. Lab Invest 1994;71:657-62.
60. Dees WL, Srivastava V, Hiney JK. Actions and interactions of alcohol and insulin-like growth factor-1 on female pubertal development. Alcohol Clin Exp Res 2009;33:1847-56.
61. McGough NN, Thomas JD, Dominguez HD, Riley EP. Insulin-like growth factor-I mitigates motor coordination deficits associated with neonatal alcohol exposure in rats. Neurotoxicol Teratol 2009; 31:40-8.
62. Luo J, Miller MW. Growth factor-mediated neural proliferation: target of ethanol toxicity. Brain Res Brain Res Rev 1998;27:157-67.
63. Tateno M, Ukai W, Ozawa H, et al. Ethanol inhibition of neural stem cell differentiation is reduced by neurotrophic factors. Alcohol Clin Exp Res 2004;28:134S-8S.
64. Biermann T, Reulbach U, Lenz B, et al. Nmethyl- D-aspartate 2b receptor subtype (NR2B) promoter methylation in patients during alcohol withdrawal. J Neural Transm 2009;116:615-22.
65. Ishii T, Hashimoto E, Ukai W, et al. [Epigenetic regulation in alcohol-related brain damage]. Nihon Arukoru Yakubutsu Igakkai Zasshi 2008;43:705-13.
66. Ouko LA, Shantikumar K, Knezovich J, Haycock P, Schnugh DJ, Ramsay M. Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IGDMR in male gametes: implications for fetal alcohol spectrum disorders. Alcohol Clin Exp Res 2009;33:1615-27.
67. Haycock PC. Fetal alcohol spectrum disorders: the epigenetic perspective. Biol Reprod 2009;81:607-17.
68. Liu Y, Balaraman Y, Wang G, Nephew KP, Zhou FC. Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation. Epigenetics 2009;4:500-11.
69. Haycock PC, Ramsay M. Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol Reprod 2009;81:618-27.
70. Gammeltoft S, Fehlmann M, Van OE. Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Biochimie 1985;67:1147-53.
71. Goodyer CG, De SL, Lai WH, Guyda HJ, Posner BI. Characterization of insulin-like growth factor receptors in rat anterior pituitary, hypothalamus, and brain. Endocrinology 1984;114:1187-95.
72. Hill JM, Lesniak MA, Pert CB, Roth J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 1986;17:1127-38.
73. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis 2005;7:45-61.
74. Myers MG, White MF. The new elements of insulin signaling. Insulin receptor substrate-1 and proteins with SH2 domains. Diabetes 1993;42:643-50.
75. Kido Y, Nakae J, Accili D. Clinical review 125: The insulin receptor and its cellular targets. J Clin Endocrinol Metab 2001;86:972-9.
76. Del Valle L, Wang JY, Lassak A, et al. Insulinlike growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas. J Neurovirol 2002;8 Suppl 2:138-47.
77. Folli F, Saad MJ, Kahn CR. Insulin receptor/IRS-1/PI 3-kinase signaling system in corticosteroid-induced insulin resistance. Acta Diabetol 1996;33:185-92.
78. Nakae J, Kido Y, Accili D. Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 2001;22:818-35.
79. 78. Giovannone B, Scaldaferri ML, Federici M, et al. Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential. Diabetes Metab Res Rev 2000;16:434-41.
80. Xu YY, Bhavani K, Wands JR, de la Monte SM. Ethanol inhibits insulin receptor substrate-1 tyrosine phosphorylation and insulin-stimulated neuronal thread protein gene expression. Biochem J 1995;310:125-32.
81. Mauceri HJ, Lee WH, Conway S. Effect of ethanol on insulin-like growth factor-II release from fetal organs. Alcohol Clin Exp Res 1994;18:35-41.
82. Luo J, Miller MW. Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. Alcohol Clin Exp Res 1997;21:1186-94.
83. Luo J, Miller MW. Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action. J Neurosci 1999;19:10014-25.
84. Luo J, West JR, Cook RT, Pantazis NJ. Ethanol induces cell death and cell cycle delay in cultures of pheochromocytoma PC12 cells. Alcohol Clin Exp Res 1999;23:644-56.
85. Chu J, Tong M, de la Monte SM. Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. Acta Neuropathol (Berl) 2007;113: 659-73.
86. de la Monte SM, Wands JR. Mitochondrial DNA damage and impaired mitochondrial function contribute to apoptosis of insulinstimulated ethanol-exposed neuronal cells. Alcohol Clin Exp Res 2001;25:898-906.
87. Miller MW. A longitudinal study of the effects of prenatal ethanol exposure on neuronal acquisition and death in the principal sensory nucleus of the trigeminal nerve: interaction with changes induced by transection of the infraorbital nerve. J Neurocytol 1999;28:999-1015.
88. West JR, Goodlett CR, Bonthius DJ, Hamre KM, Marcussen BL. Cell population depletion associated with fetal alcohol brain damage: mechanisms of BAC-dependent cell loss. Alcohol Clin Exp Res 1990;14:813-8.
89. 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.
90. Acquaah-Mensah GK, Kehrer JP, Leslie SW. In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model. J Pharmacol Exp Ther 2002;301:277-83.
91. Carter JJ, Tong M, Silbermann E, et al. Ethanol impaired neuronal migration is associated with reduced aspartyl-asparaginyl-beta-hydroxylase expression. Acta Neuropathol 2008.
92. Chakraborty G, Saito M, Mao RF, Wang R, Vadasz C, Saito M. Lithium blocks ethanolinduced modulation of protein kinases in the developing brain. Biochem Biophys Res Commun 2008;367: 597-602.
93. Luo J. GSK3beta in ethanol neurotoxicity. Mol Neurobiol 2009;40:108-21.
94. Takadera T, Ohyashiki T. Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons. Eur J Pharmacol 2004;499:239-45.
95. Sasaki Y, Wands JR. Ethanol impairs insulin receptor substrate-1 mediated signal transduction during rat liver regeneration. Biochem Biophys Res Commun 1994;199:403- 9.
96. de la Monte SM, Ganju N, Tanaka S, et al. Differential effects of ethanol on insulinsignaling through the insulin receptor substrate- 1. Alcohol Clin Exp Res 1999;23:770-7.
97. Banerjee K, Mohr L, Wands JR, de la Monte SM. Ethanol inhibition of insulin signaling in hepatocellular carcinoma cells. Alcohol Clin Exp Res 1998;22:2093-101.
98. Mohr L, Tanaka S, Wands JR. Ethanol inhibits hepatocyte proliferation in insulin receptor substrate 1 transgenic mice. Gastroenterology 1998;115:1558-65.
99. Xu J, Yeon JE, Chang H, et al. Ethanol impairs insulin-stimulated neuronal survival in the developing brain: role of PTEN phosphatase. J Biol Chem 2003;278:26929-37.
100. Diehl AM, Yang SQ, Cote P, Wand GS. Chronic ethanol consumption disturbs G-protein expression and inhibits cyclic AMP-dependent signaling in regenerating rat liver. Hepatology 1992;16: 1212-9.
101. Gordon AS, Collier K, Diamond I. Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol. Proc Natl Acad Sci U S A 1986;83:2105-8.
102. de la Monte SM, Ganju N, Banerjee K, Brown NV, Luong T, Wands JR. Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol-3-kinase. Alcohol Clin Exp Res 2000;24:716-26.
103. Yeon JE, Califano S, Xu J, Wands JR, De La Monte SM. Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. Hepatology 2003;38:703-14.
104. Domenicotti C, Paola D, Lamedica A, et al. Effects of ethanol metabolism on PKC activity in isolated rat hepatocytes. Chem Biol Interact 1996;100:155-63.
105. Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt [see comments]. Science 1997;275:661-5.
106. Bhave SV, Hoffman PL. Ethanol promotes apoptosis in cerebellar granule cells by inhibiting the trophic effect of NMDA. J Neurochem 1997;68:578-86.
107. Ikonomidou C, Bittigau P, Ishimaru MJ, et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000;287:1056-60.
108. Olney JW, Ishimaru MJ, Bittigau P, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing brain. Apoptosis 2000;5:515- 21.
109. de la Monte SM, Neely TR, Cannon J, Wands JR. Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons. Cell Mol Life Sci 2001;58:1950-60.
110. Hallak H, Seiler AE, Green JS, Henderson A, Ross BN, Rubin R. Inhibition of insulin-like growth factor-I signaling by ethanol in neuronal cells. Alcohol Clin Exp Res 2001;25:1058-64.
111. Camp MC, Mayfield RD, McCracken M, McCracken L, Alcantara AA. Neuroadaptations of Cdk5 in cholinergic interneurons of the nucleus accumbens and prefrontal cortex of inbred alcohol-preferring rats following voluntary alcohol drinking. Alcohol Clin Exp Res 2006;30:1322-35.
112. Rajgopal Y, Vemuri MC. Ethanol induced changes in cyclin-dependent kinase-5 activity and its activators, P35, P67 (Munc-18) in rat brain. Neurosci Lett 2001;308:173-6.
113. 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.
114. Bannigan J, Cottell D. Ethanol teratogenicity in mice: an electron microscopic study. Teratology 1984;30:281-90.
115. Farrar RP, Seibert C, Gnau K, Leslie SW. Development of tolerance in brain mitochondria for calcium uptake following chronic ethanol ingestion. Brain Res 1989;500:374-8.
116. Goodlett CR, Horn KH. Mechanisms of alcoholinduced damage to the developing nervous system. Alcohol Res Health 2001;25:175-84.
117. Henderson GI, Chen JJ, Schenker S. Ethanol, oxidative stress, reactive aldehydes, and the fetus. Front Biosci 1999;4:D541-50.
118. Mansouri A, Demeilliers C, Amsellem S, Pessayre D, Fromenty B. Acute ethanol administration oxidatively damages and depletes mitochondrial dna in mouse liver, brain, heart, and skeletal muscles: protective effects of antioxidants. J Pharmacol Exp Ther 2001;298:737-43.
119. Xu YJ, Liu P, Li Y. [Effect of alcohol on brain mitochondria development of mouse embryos]. Wei Sheng Yan Jiu 2005;34:61-3.
120. Cahill A, Wang X, Hoek JB. Increased oxidative damage to mitochondrial DNA following chronic ethanol consumption. Biochem Biophys Res Commun 1997;235:286-90.
121. Lee RD, An SM, Kim SS, et al. Neurotoxic effects of alcohol and acetaldehyde during embryonic development. J Toxicol Environ Health A 2005;68:2147-62.
122. Pastorino JG. Potentiation by chronic, ethanol treatment of the mitochondrial permeability transition. Biochem Biophys Res Commun 1999;265:405-9.
123. Wieland P, Lauterburg BH. Oxidation of mitochondrial proteins and DNA following administration of ethanol. Biochem Biophys Res Commun 1995;213:815-9.
124. Almansa I, Fernandez A, Garcia-Ruiz C, et al. Brain mitochondrial alterations after chronic alcohol consumption. J Physiol Biochem 2009;65:305-12.
125. Cherian PP, Schenker S, Henderson GI. Ethanolmediated DNA damage and PARP-1 apoptotic responses in cultured fetal cortical neurons. Alcohol Clin Exp Res 2008;32:1884-92.
126. Green CR, Watts LT, Kobus SM, Henderson GI, Reynolds JN, Brien JF. Effects of chronic prenatal ethanol exposure on mitochondrial glutathione and 8-iso-prostaglandin F2alpha concentrations in the hippocampus of the perinatal guinea pig. Reprod Fertil Dev 2006;18:517-24.
127. 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 defense systems. Brain Res 2005;1052:202-11.
128. Albano E, French SW, Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatotoxicity. Front Biosci 1999;4:D533-40.
129. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci 2002;65:166-76.
130. Fadda F, Rossetti ZL. Chronic ethanol consumption: from neuroadaptation to neurodegeneration. Prog Neurobiol 1998;56:385-431.
131. Heaton MB, Mitchell JJ, Paiva M. Amelioration of ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy. Alcohol Clin Exp Res 2000;24:512-8.
132. Kim JH, Kim JE, Kim HJ, et al. Ethanol decreases the expression of mitochondrial cytochrome c oxidase mRNA in the rat. Neurosci Lett 2001;305:107-10.
133. Wallin C, Puka-Sundvall M, Hagberg H, Weber SG, Sandberg M. Alterations in glutathione and amino acid concentrations after hypoxiaischemia in the immature rat brain. Brain Res Dev Brain Res 2000;125:51-60.
134. 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.
135. Mill JF, Chao MV, Ishii DN. Insulin, insulinlike growth factor II, and nerve growth factor effects on tubulin mRNA levels and neurite formation. Proc Natl Acad Sci U S A 1985;82:7126-30.
136. Puro DG, Agardh E. Insulin-mediated regulation of neuronal maturation. Science 1984;225:1170-2.
137. de la Monte SM, Chen GJ, Rivera E, Wands JR. Neuronal thread protein regulation and interaction with microtubule-associated proteins in SH-Sy5y neuronal cells. Cell Mol Life Sci 2003;60: 2679-91.
138. Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997;272:19547-53.
139. Kosik KS, Shimura H. Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta 2005;1739:298-310.
140. Tsujio I, Tanaka T, Kudo T, et al. Inactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation. FEBS Lett 2000;469:111-7.
141. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. J Alzheimers Dis 2006;9:13-33.
142. de la Monte SM, Tong M, Lester-Coll N, Plater M, Jr., Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: Relevance to Alzheimer's disease. J Alzheimers Dis 2006;10:89-109.
143. Arendt T. Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol. J Neural Transm Suppl 1994;44:173-87.
144. Cohen AC, Tong M, Wands JR, de la Monte SM. Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model. Alcohol Clin Exp Res 2007; 31:1558-73.
145. Dymecki J, Medynska E, Walski M. The influence of ethanol intoxication on cholinergic axon terminals in the rat brain. (Morphometric evaluation). Exp Pathol 1982;22:73-83.
146. West JR, Dewey SL, Cassell MD. Prenatal ethanol exposure alters the post-lesion reorganization (sprouting) of acetylcholinesterase staining in the dentate gyrus of adult rats. Brain Res 1984; 314:83-95.
147. Diamond I, Gordon AS. Cellular and molecular neuroscience of alcoholism. Physiol Rev 1997;77:1-20.
148. Eravci M, Schulz O, Grospietsch T, et al. Gene expression of receptors and enzymes involved in GABAergic and glutamatergic neurotransmission in the CNS of rats behaviourally dependent on ethanol. Br J Pharmacol 2000;131:423-32.
149. Hamid A, Wani NA, Kaur J. New perspectives on folate transport in relation to alcoholisminduced folate malabsorption--association with epigenome stability and cancer development. FEBS J 2009;276:2175-91.
150. Lancaster FE. Alcohol, nitric oxide, and neurotoxicity: is there a connection?--a review. Alcohol Clin Exp Res 1992;16:539-41.
151. Savage DD, Montano CY, Otero MA, Paxton LL. Prenatal ethanol exposure decreases hippocampal NMDA-sensitive [3H]-glutamate binding site density in 45-day-old rats. Alcohol 1991;8: 193-201.
152. Breese CR, D'Costa A, Booze RM, Sonntag WE. Distribution of insulin-like growth factor 1 (IGF-1) and 2 (IGF-2) receptors in the hippocampal formation of rats and mice. Adv Exp Med Biol 1991; 293:449-58.
153. Kliewer SA, Lehmann JM, Milburn MV, Willson TM. The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog Horm Res 1999;54:345-67; discussion 67-8.
154. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302:93-109.
155. Gilde AJ, Van Bilsen M. Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand 2003;178:425-34.
156. Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003;144:2201-7.
157. Savkur RS, Miller AR. Investigational PPARgamma agonists for the treatment of Type 2 diabetes. Expert Opin Investig Drugs 2006;15:763-78.
158. Tao L, Liu HR, Gao E, et al. Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptorgamma agonist in hypercholesterolemia. Circulation 2003;108: 2805-11.
159. Zhao X, Quigley JE, Yuan J, Wang MH, Zhou Y, Imig JD. PPAR-alpha activator fenofibrate increases renal CYP-derived eicosanoid synthesis and improves endothelial dilator function in obese Zucker rats. Am J Physiol Heart Circ Physiol 2006;290:H2187-95.
160. Barroso I, Gurnell M, Crowley VE, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999;402: 880-3.
161. Bishop-Bailey D, Warner TD. PPARgamma ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator-activated receptorgamma antagonist. Faseb J 2003;17:1925-7.
162. Markesbery WR, Carney JM. Oxidative alterations in Alzheimer's disease. Brain Pathol 1999;9:133-46.
163. Montine KS, Kim PJ, Olson SJ, Markesbery WR, Montine TJ. 4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease. J Neuropathol Exp Neurol 1997;56:866-71.
164. Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenalderived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 1997; 68:2092-7.
165. de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis 2006;9: 167-81.
166. Ghafourifar P, Klein SD, Schucht O, et al. Ceramide induces cytochrome c release from isolated mitochondria. Importance of mitochondrial redox state. J Biol Chem 1999;274:6080-4.
167. de Licona HK, Karacay B, Mahoney J, McDonald E, Luang T, Bonthius DJ. A single exposure to alcohol during brain development induces microencephaly and neuronal losses in genetically susceptible mice, but not in wild type mice. Neurotoxicology 2009;30:459-70.
168. Li Z, Zharikova A, Vaughan CH, et al. Intermittent high-dose ethanol exposures increase motivation for operant ethanol selfadministration: possible neurochemical mechanism. Brain Res;1310: 142-53.
169. Pang M, de la Monte SM, Longato L, et al. PPARdelta agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair. J Hepatol 2009;50:1192-201.
170. Monville C, Torres EM, Dunnett SB. Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods 2006; 158:219-23.