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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice
Lynsey G Bilsland1, James R T Dick, Gareth Pryce
1Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, United Kingdom.
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.
Insights
Cannabinoids show neuroprotective effects in amyotrophic lateral sclerosis (ALS) mouse models, delaying disease progression. However, these treatments did not impact lifespan, suggesting non-CB1 receptor pathways are involved.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment.
- Motoneuron loss in the spinal cord, brain stem, and motor cortex characterizes ALS.
Purpose of the Study:
- To investigate the neuroprotective effects of cannabinoids in a mouse model of ALS.
- To explore the role of cannabinoid receptors (CB1) and FAAH enzyme in ALS progression.
Main Methods:
- Treatment of SOD1G93A mice with a synthetic cannabinoid (WIN55,212-2).
- Genetic ablation of the FAAH enzyme to increase anandamide levels.
- Assessment of disease onset, progression, and lifespan in treated mice.
- Investigation of CB1 receptor knockout mice.
Main Results:
- WIN55,212-2 treatment significantly delayed disease progression in postsymptomatic SOD1G93A mice.
- FAAH gene ablation, increasing endocannabinoid levels, prevented disease signs in SOD1G93A mice.
- Neither WIN55,212-2 nor FAAH ablation affected lifespan.
- CB1 receptor ablation did not alter disease onset but significantly extended lifespan.
Conclusions:
- Cannabinoids exert significant neuroprotective effects in this ALS mouse model.
- The beneficial effects of cannabinoids in ALS may involve non-CB1 receptor mechanisms.
- Targeting cannabinoid pathways offers potential therapeutic strategies for ALS.
