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

Cerebellum. 2018 Jun;17(3):326-335. doi: 10.1007/s12311-017-0916-z.

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzamides / pharmacology
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Central Nervous System Depressants / adverse effects
  • Cerebellum / drug effects*
  • Cerebellum / growth & development
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Disease Models, Animal
  • Ethanol / adverse effects
  • Female
  • Fetal Alcohol Spectrum Disorders / drug therapy*
  • Fetal Alcohol Spectrum Disorders / metabolism
  • Fetal Alcohol Spectrum Disorders / pathology
  • Male
  • Mice
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Niacinamide / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / metabolism

Substances

  • Benzamides
  • Central Nervous System Depressants
  • Neuroprotective Agents
  • Niacinamide
  • Ethanol
  • 3-aminobenzamide
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Casp3 protein, mouse
  • Caspase 3