Endocannabinoids and amyotrophic lateral sclerosis

Targeting glial cannabinoid CB2 receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis

“…Given the predominant presence of these receptors in glial elements in the spinal cord of TDP‐43 (A315T) transgenic mice, the CB 2 receptor‐dependent benefits are likely to be mediated through control of the toxic effects of these cells on neurons, a fact largely investigated in ALS and other neurodegenerative disorders (reviewed in Fernández‐Ruiz et al ., , ; de Lago et al ., ). In our previous study (Espejo‐Porras et al ., ), we demonstrated the presence of CB 2 receptors in reactive microglial cells located in the spinal ventral horn, which is the area in which the cell bodies of the damaged spinal motor neurons are located.…”

“…Such a hypothesis is related to the non‐cell autonomous toxicity exerted by both deteriorated astrocytes and microglial cells on neurons, which is well‐known to contribute to ALS progression (Yamanaka et al ., ; Ilieva et al ., ; Haidet‐Phillips et al ., ; Lee et al ., ), and to the way by which the activation of glial CB 2 receptors may mitigate such toxicity. Based on work conducted in other neurodegenerative disorders, the activation of CB 2 receptors in astrocytes may enhance the metabolic support exerted by these cells for neurons, as well as facilitating their key role in glutamate clearance in the vicinity of glutamatergic synapses limiting excitotoxic damage (reviewed in Fernández‐Ruiz et al ., ; de Lago et al ., ). In the case of microglial CB 2 receptors, their activation may reduce the generation of pro‐inflammatory factors and promote the shift of macrophages from M1 to M2 phenotypes with evident benefits for neuronal survival (reviewed in Fernández‐Ruiz et al ., ; de Lago et al ., ).…”

“…Despite the efforts addressed to develop effective treatments able to alleviate specific symptoms or to delay disease progression in ALS, this disorder still lacks an effective therapy, the anti‐excitotoxic agent riluzole (Rilutek®) and the antioxidant compound edaravone (Radicava®), being the only approved medicines, but having only modest effects (Habib and Mitsumoto, ; Bova and Kinney, ; Rothstein, ). Recent preclinical studies have demonstrated neuroprotective effects with cannabinoids (reviewed by de Lago et al ., ), including the phytocannabinoids Δ 9 ‐tetrahydrocannabinol (Raman et al ., ) and cannabinol (Weydt et al ., ), and, to a lesser extent, the phytocannabinoid‐based formulation Sativex® (Moreno‐Martet et al ., ). Beneficial effects were also obtained with synthetic cannabinoids such as WIN55,212‐2 (Bilsland et al ., ), the selective cannabinoid receptor type‐2 (CB 2 receptor) agonist AM1241 (Kim et al ., ; Shoemaker et al ., ) and fatty acid amide hydrolase (FAAH) inhibitors (Bilsland et al ., ).…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…This solid pharmacological evidence is also supported by data collected from double mutants generated by crossing SOD-1 mutant mice with some of the different mice deficient in endocannabinoid genes (e.g., FAAH -/-, CB 1 -/-), which not only reinforced the interest of CB 1 R agonists, but also the elevation of endocannabinoid levels with FAAH inhibitors [156]. Collectively, it appears that the neuroprotective effects of cannabinoids in ALS were apparently caused by 11) a CB 2 R-mediated (and possibly involving PPAR-γ, too) reduction in microglial activation and neuroinflammation; 2) a CB 1 R-mediated reduction in excitotoxic damage; and 3) antioxidant effects that appear to be receptor-independent and/or related to PPAR-γ/Nrf-2 signaling [159].…”

“…Two additional studies again indicated good tolerability of Δ 9 -THC in patients with ALS and a nonsignificant attenuation on cramps and fasciculations [167,168]. There are no clinical studies so far that have tried to investigate the potential of cannabinoids as disease-modifying therapies, for example with the recently licensed cannabinoid-based medicine Sativex (GWPharma), which, given its broad-spectrum profile, may be adequate for clinical studies in patients with ALS following the results obtained in the preclinical studies (reviewed in [159]). In support of this possibility, we recently conducted a pharmacologi c a l s t u d y w i t h a S a t i v e x -l i k e c o m b i n a t i o n o f phytocannabinoids in postsymptomatic SOD-1 mutant mice [161].…”