Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke



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Bravo Ferrer, Isbel and Cuartero Desviat, María Isabel and Zarruk, Juan G. and Pradillo, Jesús M. and Hurtado Moreno, Olivia and Romera, Victor G. and Díaz Alonso, Javier and García Segura, Juan Manuel and Guzmán, Manuel and Lizasoaín, Ignacio and Galve Roperh, Ismael and Moro, María A. (2017) Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke. Stroke, 48 (1). pp. 204-212. ISSN 0039-2499, ESSN: 1524-4628

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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-6Hdibenzo[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 vehicletreated 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.

Item Type:Article
Uncontrolled Keywords:Chronic phase; Neurogenesis; Neurons; Recovery; Sensorimotor function; Stem cells; Stroke
Subjects:Medical sciences > Biology > Biochemistry
Medical sciences > Biology > Neurosciences
ID Code:44683
Deposited On:18 Sep 2017 08:32
Last Modified:01 Mar 2018 09:29

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