Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice

FASEB J. 2006 May;20(7):1003-5. doi: 10.1096/fj.05-4743fje. Epub 2006 Mar 29.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motoneurons in the spinal cord, brain stem, and motor cortex. However, despite intensive research, an effective treatment for this disease remains elusive. In this study we show that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delays disease progression. Furthermore, genetic ablation of the Faah enzyme, which results in raised levels of the endocannabinoid anandamide, prevented the appearance of disease signs in 90-day-old SOD1G93A mice. Surprisingly, elevation of cannabinoid levels with either WIN55,212-2 or Faah ablation had no effect on life span. Ablation of the CB1 receptor, in contrast, had no effect on disease onset in SOD1(G93A) mice but significantly extended life span. Together these results show that cannabinoids have significant neuroprotective effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / genetics
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Benzoxazines
  • Cannabinoids / metabolism*
  • Cell Adhesion Molecules, Neuronal / genetics
  • Disease Progression
  • Female
  • Humans
  • Longevity / drug effects
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Morpholines / pharmacology*
  • Morpholines / therapeutic use*
  • Motor Neurons / metabolism
  • Muscle Fatigue / drug effects
  • Muscle Fatigue / genetics
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Naphthalenes / pharmacology*
  • Naphthalenes / therapeutic use*
  • Neuropeptides / genetics
  • Receptors, Cell Surface / genetics
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism

Substances

  • Benzoxazines
  • Cannabinoids
  • Cell Adhesion Molecules, Neuronal
  • Morpholines
  • Naphthalenes
  • Neuropeptides
  • Pcdha4 protein, mouse
  • Receptors, Cell Surface
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Amidohydrolases
  • fatty-acid amide hydrolase