Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.
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.
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, United Kingdom.
Lynsey G
LG
Bilsland
James R T
JR
Dick
Gareth
G
Pryce
Stefania
S
Petrosino
Vincenzo
V
Di Marzo
David
D
Baker
Linda
L
Greensmith
D000581:Amidohydrolases / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use*; D009046:Motor Neurons / Q000378:metabolism; D018763:Muscle Fatigue / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use*; D009479:Neuropeptides / Q000235:genetics; D000091363:Protocadherins; D011956:Receptors, Cell Surface / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D048588:Benzoxazines; D002186:Cannabinoids; D015816:Cell Adhesion Molecules, Neuronal; D009025:Morpholines; D009281:Naphthalenes; D009479:Neuropeptides; D000091363:Protocadherins; D011956:Receptors, Cell Surface; D013482:Superoxide Dismutase; D000099252:Fatty Acid Amide Hydrolases; C113143:Pcdha4 protein, mouse; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C109415:SOD1 G93A protein