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Objective: We have investigated the endocannabinoid system in the motor cortex of motor neuron disease (MND) patients., Methods: Post-mortem samples from MND patients and controls were used for immunostaining and/or Western blotting analysis of endocannabinoid elements., Results: We did not find any evidence of neuronal losses in the motor cortex of MND patients, but elevations in glial markers Iba-1 and GFAP were evident. We found no changes in FAAH and MAGL enzymes and in the CB 1 receptor, which correlated with the lack of cortical neuron death. By contrast, the Western blotting analysis of CB 2 receptors proved an increase in the motor cortex corroborated by immunostaining, correlating with the elevated gliosis in these patients. Double-labeling analyses revealed that this elevated CB 2 receptor immunostaining was located in GFAP-labelled astroglial cells. However, we also found CB 2 receptor labeling in cortical neurons confirmed with double immunofluorescence with the neuronal marker MAP-2. This was also found in the spinal cord, using double-labeling with the spinal motor neuron marker choline-acetyl transferase. This happened in both patients and controls, despite these neurons experienced an important degeneration in patients reflected in reduced Nissl staining, TDP-43 immunostaining and CB 1 receptor levels measured by Western blotting., Conclusion: We have confirmed that CB 2 receptors are elevated in the motor cortex of MND patients associated with the reactive gliosis. This phenomenon is previous to neuronal losses. We also found CB 2 receptors in cortical and spinal motor neurons. These observations support that targeting this receptor may serve for developing neuroprotective therapies in MNDs.

Aims: 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., (© 2014 John Wiley & Sons Ltd.)

Aims Cannabinoids afford neuroprotection in SOD1G93A 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 SOD1G93A transgenic mice at a late stage of the disease. Second, 10-week-old transgenic mice were daily treated with an equimolecular combination of Δ9-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 SOD1G93A 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 SOD1G93A transgenic mice, and provide support that Sativex® may serve as a novel disease-modifying therapy in ALS. [ABSTRACT FROM AUTHOR]