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

Background and Purpose Cannabinoid CB2 receptors are up‐regulated in reactive microglia in the spinal cord of TDP‐43 (A315T) transgenic mice, an experimental model of amyotrophic lateral sclerosis. To determine whether this up‐regulation can be exploited pharmacologically, we investigated the effects of different treatments that affect CB2 receptor function. Experimental Approach We treated TDP‐43 (A315T) transgenic mice with the non‐selective agonist WIN55,212‐2, alone or combined with selective CB1 or CB2 antagonists, as well as with the selective CB2 agonist HU‐308, and evaluated their effects on the pathological phenotype. Key Results WIN55,212‐2 had modest beneficial effects in the rotarod test, Nissl staining of motor neurons, and GFAP and Iba‐1 immunostainings in the spinal cord, which were mediated in part by CB2 receptor activation. HU‐308 significantly improved the rotarod performance of the transgenic mice, with complete preservation of Nissl‐stained motor neurons in the ventral horn. Reactive astrogliosis labelled with GFAP was also attenuated by HU‐308 in the dorsal and ventral horns, in which CB2 receptors colocalize with this astroglial marker. Furthermore, HU‐308 reduced the elevated Iba‐1 immunostaining in the ventral horn of TDP‐43 transgenic mice, but did not affect this immunoreactivity in white matter, in which CB2 receptors also colocalize with this microglial marker. Conclusions and Implications Our study shows an important role for glial CB2 receptors in limiting the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice. Such benefits appear to derive from the activation of CB2 receptors concentrated in astrocytes and reactive microglia located in spinal dorsal and ventral horns. Linked Articles This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc