Motor Neuron Dysfunction in a Mouse Model of ALS: Gender-Dependent Effect of P2X7 Antagonism

Toxicology. 2013 Sep 6;311(1-2):69-77. doi: 10.1016/j.tox.2013.04.004. Epub 2013 Apr 11.


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative progressive currently untreatable disease, characterized by selective motor neuron degeneration; the incidence and prevalence of ALS are greater in men than in women. Although some important mechanisms that might contribute to the death of motor neurons have been identified, the mechanisms underlying disease pathophysiology are still uncertain. In particular, the mechanisms underlying the role of gender in ALS and whether treatments should take into account sexual dimorphism remain only partially understood. Recently, the P2X7 receptor for ATP was reported to display neurotoxic potential in motor neuron disorders, and antagonism of the receptor has been suggested to be helpful in these disorders. Studying transgenic mice with superoxide dismutase 1 gene mutations, widely used as model for ALS, may provide a better understanding of pathogenic mechanisms and of toxicity towards motor neurons, also possibly helping to understand whether treatments for ALS should take into account sexual dimorphism. The aim of the work was (1) investigating on gender-dependence of disease progression in the standard model for ALS - the transgenic mouse bearing superoxide dismutase 1 gene mutations - and (2) assessing if a P2X7 receptor antagonist treatment should take into account sexual dimorphism. We evaluated if gender affect the disease course, the motor performance, the weight loss and the lifespan in mice overexpressing mutant superoxide dismutase 1. We measured motor impairment, motor strength and coordination by rotarod and grip strength testing. Further, we assessed if a treatment with the P2X7 receptor antagonist Brilliant Blue G - a dye that can cross the blood-brain barrier, has low toxicity, and has exhibited therapeutic effects in animal models of neurodegenerative diseases - impact on the disease progression, in male and female ALS mice. We found that (1) the onset and the disease progression, and the survival were dependent on gender: male performed worst than female, lost body weight and died before; (2) treatment with the P2X7 receptor antagonist Brilliant Blue G ameliorated the disease progression. The treatment effect was gender-dependent: amelioration was greater in male than in female. In conclusions, we suggest that not only pathogenetic mechanism of motor neuron toxicity but also the drug treatment effectiveness may depend on gender; sexual dimorphism should be considered when investigating on ALS treatment efficacy in the ALS animal model. Our findings also point on the potential relevance of P2X7 receptor antagonism for ALS treatment, and highlight the importance of adopting a sex-specific approach to searching for treatment of ALS.

Keywords: ALS; Amyotrophic lateral sclerosis; BBG; Brilliant Blue G; Cu/Zn superoxide dismutase 1; Gender difference; Motor neuron; P2X7 receptor; SOD1; SOD1/G93A mice; amyotrophic lateral sclerosis; d; days of age; transgenic mice carrying a high copy number of a transgene encoding a variant of human superoxide dismutase 1 with a G93A mutation (Gly93Ala substitution).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Disease Models, Animal*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / physiology*
  • Purinergic P2X Receptor Antagonists / pharmacology
  • Purinergic P2X Receptor Antagonists / therapeutic use*
  • Receptors, Purinergic P2X7 / metabolism*
  • Sex Characteristics*


  • Purinergic P2X Receptor Antagonists
  • Receptors, Purinergic P2X7