Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex(®) -like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis.
OBJECTIVE
Cannabinoids afford neuroprotection in SOD1(G93A) mutant mice, an experimental model of amyotrophic lateral sclerosis (ALS). However, these mice have been poorly studied to identify alterations in those elements of the endocannabinoid system targeted by these treatments. Moreover, we studied the neuroprotective effect of the phytocannabinoid-based medicine Sativex(®) in these mice.


METHODS
First, we analyzed the endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice at a late stage of the disease. Second, 10-week-old transgenic mice were daily treated with an equimolecular combination of Δ(9) -tetrahydrocannabinol- and cannabidiol-enriched botanical extracts (20 mg/kg for each phytocannabinoid).


RESULTS
We found a significant increase of CB2 receptors and NAPE-PLD enzyme in SOD1(G93A) transgenic males and only CB2 receptors in females. Pharmacological experiments demonstrated that the treatment of these mice with the Sativex(®) -like combination of phytocannabinoids only produced weak improvements in the progression of neurological deficits and in the animal survival, particularly in females.


CONCLUSIONS
Our results demonstrated changes in endocannabinoid signaling, in particular a marked up-regulation of CB2 receptors, in SOD1(G93A) transgenic mice, and provide support that Sativex(®) may serve as a novel disease-modifying therapy in ALS.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Miguel
M
Moreno-Martet
Francisco
F
Espejo-Porras
Javier
J
Fernández-Ruiz
Eva
E
de Lago
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D002185:Cannabidiol; D013759:Dronabinol; D004338:Drug Combinations; D063388:Endocannabinoids / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D010739:Phospholipase D / Q000378:metabolism*; D010936:Plant Extracts / Q000627:therapeutic use*; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics
D002185:Cannabidiol; D013759:Dronabinol; D004338:Drug Combinations; D063388:Endocannabinoids; D010739:Phospholipase D; D010936:Plant Extracts; D043882:Receptors, Cannabinoid; D013482:Superoxide Dismutase; C109415:SOD1 G93A protein; C506062:Napepld protein, mouse; C587251:nabiximols
Amyotrophic lateral sclerosis; CB1 and CB2 receptors; Cannabinoids; Endocannabinoid enzymes; SOD1 mutant mice; Sativex-like combination of phytocannabinoids