Isabel Bravo-Ferrer1, María I Cuartero2, Juan G Zarruk1, Jesús M Pradillo1, Olivia Hurtado1, Víctor G Romera1, Javier Díaz-Alonso1, Juan M García-Segura1, Manuel Guzmán1, Ignacio Lizasoain1, Ismael Galve-Roperh1, María A Moro2. 1. From the Departamento de Farmacología, Facultad de Medicina, Instituto de Investigación Hospital 12 de Octubre (i+12) (I.B.-F., M.I.C., J.G.Z., J.M.P., O.H., V.G.R., I.L., M.A.M.), Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED) (J.D.-A., J.M.G.-S., M.G., I.G.-R.), and Instituto Universitario de Investigación en Neuroquímica (I.B.-F., M.I.C., J.M.P., O.H., J.D.-A., M.G., I.L., I.G.-R., M.A.M.), Universidad Complutense (UCM), Madrid, Spain. 2. From the Departamento de Farmacología, Facultad de Medicina, Instituto de Investigación Hospital 12 de Octubre (i+12) (I.B.-F., M.I.C., J.G.Z., J.M.P., O.H., V.G.R., I.L., M.A.M.), Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED) (J.D.-A., J.M.G.-S., M.G., I.G.-R.), and Instituto Universitario de Investigación en Neuroquímica (I.B.-F., M.I.C., J.M.P., O.H., J.D.-A., M.G., I.L., I.G.-R., M.A.M.), Universidad Complutense (UCM), Madrid, Spain. neurona@med.ucm.es maribel_cd@hotmail.com.
Abstract
BACKGROUND AND PURPOSE: Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms. However, its role in chronic stroke is still unknown. METHODS: Stroke was induced by permanent middle cerebral artery occlusion in mice; CB2R modulation was assessed by administering the CB2R agonist JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran) or the CB2R antagonist SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo-[2.2.1]-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) once daily from day 3 to the end of the experiment or by CB2R genetic deletion. Analysis of immunofluorescence-labeled brain sections, 5-bromo-2´-deoxyuridine (BrdU) staining, fluorescence-activated cell sorter analysis of brain cell suspensions, and behavioral tests were performed. RESULTS: SR144528 decreased neuroblast migration toward the boundary of the infarct area when compared with vehicle-treated mice 14 days after middle cerebral artery occlusion. Consistently, mice on this pharmacological treatment, like mice with CB2R genetic deletion, displayed a lower number of new neurons (NeuN+/BrdU+ cells) in peri-infarct cortex 28 days after stroke when compared with vehicle-treated group, an effect accompanied by a worse sensorimotor performance in behavioral tests. The CB2R agonist did not affect neurogenesis or outcome in vivo, but increased the migration of neural progenitor cells in vitro; the CB2R antagonist alone did not affect in vitro migration. CONCLUSIONS: Our data support that CB2R is fundamental for driving neuroblast migration and suggest that an endocannabinoid tone is required for poststroke neurogenesis by promoting neuroblast migration toward the injured brain tissue, increasing the number of new cortical neurons and, conceivably, enhancing motor functional recovery after stroke.
BACKGROUND AND PURPOSE:Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms. However, its role in chronic stroke is still unknown. METHODS:Stroke was induced by permanent middle cerebral artery occlusion in mice; CB2R modulation was assessed by administering the CB2R agonist JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran) or the CB2R antagonist SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo-[2.2.1]-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) once daily from day 3 to the end of the experiment or by CB2R genetic deletion. Analysis of immunofluorescence-labeled brain sections, 5-bromo-2´-deoxyuridine (BrdU) staining, fluorescence-activated cell sorter analysis of brain cell suspensions, and behavioral tests were performed. RESULTS:SR144528 decreased neuroblast migration toward the boundary of the infarct area when compared with vehicle-treated mice 14 days after middle cerebral artery occlusion. Consistently, mice on this pharmacological treatment, like mice with CB2R genetic deletion, displayed a lower number of new neurons (NeuN+/BrdU+ cells) in peri-infarct cortex 28 days after stroke when compared with vehicle-treated group, an effect accompanied by a worse sensorimotor performance in behavioral tests. The CB2R agonist did not affect neurogenesis or outcome in vivo, but increased the migration of neural progenitor cells in vitro; the CB2R antagonist alone did not affect in vitro migration. CONCLUSIONS: Our data support that CB2R is fundamental for driving neuroblast migration and suggest that an endocannabinoid tone is required for poststroke neurogenesis by promoting neuroblast migration toward the injured brain tissue, increasing the number of new cortical neurons and, conceivably, enhancing motor functional recovery after stroke.
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