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The Cerebellum

, Volume 17, Issue 3, pp 326–335 | Cite as

Nicotinamide Inhibits Ethanol-Induced Caspase-3 and PARP-1 Over-activation and Subsequent Neurodegeneration in the Developing Mouse Cerebellum

  • Alessandro Ieraci
  • Daniel G. Herrera
Original Paper

Abstract

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.

Keywords

Fetal alcohol syndrome Apoptosis Caspase-3 Poly(ADP-ribose) polymerase Developing brain Nicotinamide 

Abbreviations

FASD

Fetal alcohol spectrum disorder

FAS

Fetal alcohol syndrome

EtOH

Ethanol

PARP-1

Poly (ADP-ribose) polymerase

FJB

Fluoro-Jade-B

PAR

Polymers of ADP-ribose

NAD+

Nicotinamide adenine dinucleotide

NADP+

Nicotinamide adenine dinucleotide phosphate

PD

Postnatal days

Notes

Funding Information

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.

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Authors and Affiliations

  1. 1.Department of PsychiatryWeill Medical College of Cornell UniversityNew YorkUSA
  2. 2.Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative DiseasesUniversità di MilanoMilanItaly
  3. 3.Department of Psychiatry Cambridge Health AllianceHarvard Medical School CambridgeCambridgeUSA

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