Targeting glial cannabinoid CB 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 CB 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 CB receptor function.

Experimental Approach: We treated TDP-43 (A315T) transgenic mice with the non-selective agonist WIN55,212-2, alone or combined with selective CB or CB antagonists, as well as with the selective CB 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 CB 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 CB 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 CB receptors also colocalize with this microglial marker.

Conclusions And Implications: Our study shows an important role for glial CB receptors in limiting the progression of the pathological phenotype in TDP-43 (A315T) transgenic mice. Such benefits appear to derive from the activation of CB 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 8 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.