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The objective of this study was to further investigate the relevance of the CB<jats:sub>2<\/jats:sub> receptor through investigating the consequences of its inactivation. TDP\u201043(A315T) transgenic mice were crossed with CB<jats:sub>2<\/jats:sub> receptor knock\u2010out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP\u201043 transgenic mice expressing the CB<jats:sub>2<\/jats:sub> receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7\u00a0weeks, whereas rotarod performance was normal up to 11\u00a0weeks in transgenic mice with intact expression of the CB<jats:sub>2<\/jats:sub> receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65\u00a0days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP\u201043 transgenic mice expressing the CB<jats:sub>2<\/jats:sub> receptor. Evidence of glial reactivity, measured using GFAP and Iba\u20101 immunostaining, was seen in double mutants at 65\u00a0days, but not in TDP\u201043 transgenic mice expressing the CB<jats:sub>2<\/jats:sub> receptor. However, at 90\u00a0days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB<jats:sub>2<\/jats:sub> receptor that were not as evident in the presence of this receptor. This faster deterioration seen in double mutants led to premature mortality compared with TDP\u201043 transgenic mice expressing the CB<jats:sub>2<\/jats:sub> receptor. We also investigated the consequences of a pharmacological inactivation of the CB<jats:sub>2<\/jats:sub> receptor using the selective antagonist AM630 in TDP\u201043 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB<jats:sub>2<\/jats:sub> receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients.<\/jats:p>","DOI":"10.1111\/bpa.12972","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T14:56:29Z","timestamp":1620917789000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Inactivation of the CB<sub>2<\/sub> receptor accelerated the neuropathological deterioration in TDP\u201043 transgenic mice, a model of amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"31","author":[{"given":"Carmen","family":"Rodr\u00edguez\u2010Cueto","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular Facultad de Medicina Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica Universidad Complutense Madrid 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