Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1(G93A) transgenic mice, an experimental model of amyotrophic lateral sclerosis

Antioxidant phytocannabinoids, synthetic compounds targeting the CB2 receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1(G93A) mutant mice, a model of ALS. These effects may involve the activation of PPAR-gamma too. Here, we have investigated the neuroprotective effects in SOD1(G93A) mutant mice of the cannabigerol derivative VCE-003.2, which works as neuroprotectant by activating PPAR-gamma. Mice were treated with VCE-003.2 from 60 days up to an advanced stage in disease progression (18 weeks), when they were euthanized and used for analysis of neuropathological signs. As expected, SOD1(G93A) transgenic mice experienced a progressive weight loss and neurological deterioration, which was associated with a marked loss of spinal cholinergic motor neurons, glial reactivity, and elevations in several biochemical markers (cytokines, glutamate transporters) that indirectly reflect the glial proliferation and activation in the spinal cord. The treatment with VCE-003.2 improved most of these neuropathological signs. It attenuated the weight loss and the anomalies in neurological parameters, preserved spinal cholinergic motor neurons, and reduced astroglial reactivity. VCE-003.2 also reduced the elevations in IL-1 beta and glial glutamate transporters. Lastly, VCE-003.2 attenuated the LPS-induced generation of TNF-alpha and IL-1 beta in cultured astrocytes obtained from SOD1(G93A) transgenic newborns, an effect also produced by rosiglitazone, then indicating a probable PPAR-gamma activation as responsible of its neuroprotective effects. In summary, our results showed benefits with VCE-003.2 in SOD1(G93A) transgenic mice supporting PPAR-gamma as an additional neuroprotective target available for cannabinoids in ALS. Such benefits would need to be validated in other ALS models prior to be translated to the clinical level.