2026-06-01T02:48:28Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1134782025-03-18T13:33:13Zcom_20.500.14352_14col_20.500.14352_15

Inactivation of the cb2 receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis. Rodríguez Cueto, Carmen Aurora Gómez Almería, Marta García Toscano, Laura Romero, Julián Hillard, Cecilia Lago Femia, Eva De Fernández Ruiz, José Javier 611.81 665 CB2 receptors TDP-43 (A315T) transgenic mice Amyotrophic lateral sclerosis Cannabinoids Astrocytes Reactive microglyal cells Neurociencias (Medicina) Ciencias Biomédicas 2490 Neurociencias 2403 Bioquímica The activation of the cannabinoid receptor type-2 (CB2 ) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP-43(A315T) transgenic mice were crossed with CB2 receptor knock-out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP-43 transgenic mice expressing the CB2 receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7 weeks, whereas rotarod performance was normal up to 11 weeks in transgenic mice with intact expression of the CB2 receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65 days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP-43 transgenic mice expressing the CB2 receptor. Evidence of glial reactivity, measured using GFAP and Iba-1 immunostaining, was seen in double mutants at 65 days, but not in TDP-43 transgenic mice expressing the CB2 receptor. However, at 90 days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB2 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-43 transgenic mice expressing the CB2 receptor. We also investigated the consequences of a pharmacological inactivation of the CB2 receptor using the selective antagonist AM630 in TDP-43 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB2 receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients. CIBERNED (CB06/05/0089 and PI2016/04-3) MICIU (RTI-2018-098885-B-100, SAF2016/75959-R and PID2019-108992-RB-100) ELA-Madrid-CM (B2017/BMD-3813) Spanish Ministry of Education (PR2009-0169) Sección Deptal. de Bioquímica y Biología Molecular (Medicina) Fac. de Medicina TRUE pub 2025-01-09T11:33:32Z 2025-01-09T11:33:32Z 2021-04-21 journal article VoR https://hdl.handle.net/20.500.14352/113478 XXXX-XXXX 10.1111/bpa.12972 1750-3639 eng Rodríguez‐Cueto, Carmen, et al. «Inactivation of the CB2 Receptor Accelerated the Neuropathological Deterioration in TDP‐43 Transgenic Mice, a Model of Amyotrophic Lateral Sclerosis». Brain Pathology, vol. 31, n.o 6, noviembre de 2021, p. e12972. DOI.org (Crossref), https://doi.org/10.1111/bpa.12972. Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf Wiley