3-Acetylpyridine neurotoxicity in mice

Neurotoxicology. 2017 Jan;58:143-152. doi: 10.1016/j.neuro.2016.11.010. Epub 2016 Dec 13.

Abstract

3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p<0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior.

Keywords: 3-acetylpyridine; Ataxia; Balance; Gait; Inferior olive; Mouse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gait / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neurotoxicity Syndromes / complications*
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxins / toxicity*
  • Niacinamide / pharmacology
  • Phosphopyruvate Hydratase / metabolism
  • Postural Balance / drug effects
  • Psychomotor Disorders / etiology*
  • Pyridines / toxicity*
  • Species Specificity
  • Time Factors
  • Vitamin B Complex / pharmacology

Substances

  • Neurotoxins
  • Pyridines
  • 3-acetylpyridine
  • Vitamin B Complex
  • Niacinamide
  • Phosphopyruvate Hydratase