Nicotinamide Inhibits Ethanol-Induced Caspase-3 and PARP-1 Over-activation and Subsequent Neurodegeneration in the Developing Mouse Cerebellum
Fetal alcohol spectrum disorder (FASD) is the principal preventable cause of mental retardation in the western countries resulting from alcohol exposure during pregnancy. Ethanol-induced massive neuronal cell death occurs mainly in immature neurons during the brain growth spurt period. The cerebellum is one of the brain areas that are most sensitive to ethanol neurotoxicity. Currently, there is no effective treatment that targets the causes of these disorders and efficient treatments to counteract or reverse FASD are desirable. In this study, we investigated the effects of nicotinamide on ethanol-induced neuronal cell death in the developing cerebellum. Subcutaneous administration of ethanol in postnatal 4-day-old mice induced an over-activation of caspase-3 and PARP-1 followed by a massive neurodegeneration in the developing cerebellum. Interestingly, treatment with nicotinamide, immediately or 2 h after ethanol exposure, diminished caspase-3 and PARP-1 over-activation and reduced ethanol-induced neurodegeneration. Conversely, treatment with 3-aminobenzadine, a specific PARP-1 inhibitor, was able to completely block PARP-1 activation, but not caspase-3 activation or ethanol-induced neurodegeneration in the developing cerebellum. Our results showed that nicotinamide reduces ethanol-induced neuronal cell death and inhibits both caspase-3 and PARP-1 alcohol-induced activation in the developing cerebellum, suggesting that nicotinamide might be a promising and safe neuroprotective agent for treating FASD and other neurodegenerative disorders in the developing brain that shares similar cell death pathways.
KeywordsFetal alcohol syndrome Apoptosis Caspase-3 Poly(ADP-ribose) polymerase Developing brain Nicotinamide
Fetal alcohol spectrum disorder
Fetal alcohol syndrome
Poly (ADP-ribose) polymerase
Polymers of ADP-ribose
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide phosphate
A.I. was supported by the De Witt-Reader’s Digest Fellowship, and D.G.H. was supported by grants from the National Alliance for Research on Schizophrenia and Depression and the Reader’s Digest Foundation.
Compliance with Ethical Standards
All animal procedures were approved by the Institutional Animal Care and Use Committees of Weill Cornell Medical College and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 1.May PA, Gossage JP, Kalberg WO, Robinson LK, Buckley D, Manning M, et al. Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies. Dev Disabil Res Rev. 2009;15(3):176–92. https://doi.org/10.1002/ddrr.68.CrossRefPubMedGoogle Scholar
- 3.Bonthius DJ, West JR. Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure. Alcohol Clin Exp Res. 1990;14(1):107–18. https://doi.org/10.1111/j.1530-0277.1990.tb00455.x.CrossRefPubMedGoogle Scholar
- 8.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-V. Alcohol Clin Exp Res. 1996;20(1):31–4. https://doi.org/10.1111/j.1530-0277.1996.tb01039.x.CrossRefPubMedGoogle Scholar
- 12.Siler-Marsiglio KI, Madorsky I, Pan Q, Paiva M, Neeley AW, Shaw G, et al. 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(6):1031–8. https://doi.org/10.1111/j.1530-0277.2006.000126.x.CrossRefPubMedGoogle Scholar
- 13.Siler-Marsiglio KI, Paiva M, Madorsky I, Pan Q, Shaw G, Heaton MB. Functional mechanisms of apoptosis-related proteins in neonatal rat cerebellum are differentially influenced by ethanol at postnatal days 4 and 7. J Neurosci Res. 2005;81(5):632–43. https://doi.org/10.1002/jnr.20591.CrossRefPubMedGoogle Scholar
- 15.Cebolla AM, Cheron G, Hourez R, Bearzatto B, Dan B, Servais L. Effects of maternal alcohol consumption during breastfeeding on motor and cerebellar Purkinje cells behavior in mice. Neurosci Lett. 2009;455(1):4–7. https://doi.org/10.1016/j.neulet.2009.03.034.
- 18.Idrus NM, McGough NNH, Spinetta MJ, Thomas JD, Riley EP. The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats. Neurotoxicol Teratol. 2011;33(4):444–50. https://doi.org/10.1016/j.ntt.2011.04.004.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, et al. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008;28(45):11500–10. https://doi.org/10.1523/JNEUROSCI.3203-08.2008.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Kauppinen TM, Swanson RA. The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience. 2007;145(4):1267–72. https://doi.org/10.1016/j.neuroscience.2006.09.034.CrossRefPubMedGoogle Scholar
- 30.Martire S, Mosca L, D’Erme M. PARP-1 involvement in neurodegeneration: a focus on Alzheimer’s and Parkinson’s diseases. Mech Ageing Dev. 2015;146–148:53–64. https://doi.org/10.1016/j.mad.2015.04.001.
- 35.Outeiro TF, Grammatopoulos TN, Altmann S, Amore A, Standaert DG, Hyman BT, et al. Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+-induced cytotoxicity in Parkinson’s disease in vitro models. Biochem Biophys Res Commun. 2007;357(3):596–602. https://doi.org/10.1016/j.bbrc.2007.03.163.CrossRefPubMedGoogle Scholar
- 36.Yokoyama H, Kuroiwa H, Tsukada T, Uchida H, Kato H, Araki T. Poly(ADP-ribose)polymerase inhibitor can attenuate the neuronal death after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice. J Neurosci Res. 2010;88(7):1522–36. https://doi.org/10.1002/jnr.22310.PubMedGoogle Scholar
- 37.Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr. 2008;28(1):115–30. https://doi.org/10.1146/annurev.nutr.28.061807.155443.CrossRefPubMedGoogle Scholar
- 44.Hanners NW, Eitson JL, Usui N, Richardson RB, Wexler EM, Konopka G, et al. Western Zika virus in human fetal neural progenitors persists long term with partial cytopathic and limited immunogenic effects. Cell Rep. 2016;15(11):2315–22. https://doi.org/10.1016/j.celrep.2016.05.075.CrossRefPubMedPubMedCentralGoogle Scholar
- 46.Feng Y, Paul IA, LeBlanc MH. Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat. Brain Res Bull. 2006;69(2):117–22. https://doi.org/10.1016/j.brainresbull.2005.11.011.CrossRefPubMedGoogle Scholar
- 54.Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law PP, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet. 2014;384(9942):504–13. https://doi.org/10.1016/S0140-6736(14)60382-2.CrossRefPubMedGoogle Scholar
- 55.Olmos PR, Hodgson MI, Maiz A, Manrique M, De Valdes MD, Foncea R, et al. Nicotinamide protected first-phase insulin response (FPIR) and prevented clinical disease in first-degree relatives of type-1 diabetics. Diabetes Res Clin Pract. 2006;71(3):320–33. https://doi.org/10.1016/j.diabres.2005.07.009.CrossRefPubMedGoogle Scholar
- 57.Crino A, Schiaffini R, Manfrini S, Mesturino C, Visalli N, Beretta Anguissola G, et al. A randomized trial of nicotinamide and vitamin E in children with recent onset type 1 diabetes (IMDIAB IX). Eur J Endocrinol. 2004;150(5):719–24. https://doi.org/10.1530/eje.0.1500719.CrossRefPubMedGoogle Scholar