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

Lynsey G. Bilsland^*, James R. T. Dick^*, Gareth Pryce, Stefania Petrosino, Vincenzo Di Marzo, David Baker and Linda Greensmith^*,1

^* Sobell Department of Motor Neuroscience and Movement Disorders and

Department of Neuroinflammation, Institute of Neurology, University College London, Queen Square, London, United Kingdom; and

Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy

¹Correspondence: Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Queen Square, London, WC1N 3BG, UK. E-mail: l.greensmith{at}ion.ucl.ac.uk

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 SOD1^G93A 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 SOD1^G93A 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.— Bilsland, L. G., Dick, J. R. T., Pryce, G., Petrosino, S., Di Marzo, V., Baker, D., Greensmith, L. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.

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