Targeting glial 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:

CB₂ receptors up-regulate in reactive microglia in the spinal cord of TDP-43(A315T) transgenic mice, an experimental model of ALS. To determine whether such up-regulation may be pharmacologically exploited, we investigated different treatments modulating the 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:

We found modest benefits after the treatment with WIN55,212-2 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 activation. The treatment with HU-308 resulted in a significant improvement in the rotarod performance with a 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 colocalized with this astroglial marker. HU-308 also reduced the elevated Iba-1 immunostaining in the ventral horn of TDP-43(A315T) transgenic mice, but it did not affect such immunoreactivity in the white matter areas, in which CB₂ receptors also colocalized 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 derived apparently from the activation of CB₂receptors concentrated in astrocytes and reactive microglia located in spinal dorsal and ventral horns.

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