Long-term oral administration of the NMDA receptor antagonist memantine extends life span in spinocerebellar ataxia type 1 knock-in mice

Neurosci Lett. 2015 Apr 10;592:37-41. doi: 10.1016/j.neulet.2015.02.055. Epub 2015 Feb 25.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by extension of a CAG repeat in the Sca1gene. Although the mechanisms underlying the symptoms of SCA1 have not been determined, aberrant neuronal activation potentially contributes to the neuronal cell death characteristic of the disease. Here we examined the potential involvement of extrasynaptic N-methyl-d-aspartate receptor (NMDAR) activation in the pathogenesis of SCA1 by administering memantine, a low-affinity noncompetitive NMDAR antagonist, in SCA1 knock-in (KI) mice. In KI mice, the exon in the ataxin 1 gene is replaced with abnormally expanded 154CAG repeats. Memantine was administered orally to the SCA1 KI mice from 4 weeks of age until death. The treatment significantly attenuated body-weight loss and prolonged the life span of SCA1 KI mice. Furthermore, memantine significantly suppressed the loss of Purkinje cells in the cerebellum and motor neurons in the dorsal motor nucleus of the vagus, which are critical for motor function and parasympathetic function, respectively. These findings support the contribution of aberrant activation of extrasynaptic NMDARs to neuronal cell death in SCA1 KI mice and suggest that memantine may also have therapeutic benefits in human SCA1 patients.

Keywords: Dorsal motor nucleus of vagus; Memantine; NMDA receptor; Neurodegenerative disease; Purkinje cells; Spinocerebellar ataxia type 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Death / drug effects
  • Chromosomal Proteins, Non-Histone / genetics
  • Gene Knock-In Techniques
  • Longevity / drug effects*
  • Memantine / administration & dosage
  • Memantine / pharmacology*
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / pathology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / pathology
  • Spinocerebellar Ataxias / physiopathology*

Substances

  • Chromosomal Proteins, Non-Histone
  • Receptors, N-Methyl-D-Aspartate
  • Ska1 protein, mouse
  • Memantine