Abstract
Aim:
To explore whether the synthetic cannabinoid receptor agonist WIN55,212-2 could protect oligodendrocyte precursor cells (OPCs) in stroke penumbra, thereby providing neuroprotection following permanent focal cerebral ischemia in rats.
Methods:
Adult male SD rats were subjected to permanent middle cerebral artery occlusion (p-MCAO). The animals were administered WIN55,212-2 at 2 h, and sacrificed at 24 h after the ischemic insult. The infarct volumes and brain swelling were assessed. The expression of cannabinoid receptor type 1 (CB1) in the stroke penumbra was examined using Western blot assay. The pathological changes and proliferation of neural glial antigen 2-positive OPCs (NG2+ cells) in the stroke penumbra were studied using immunohistochemistry staining.
Results:
p-MCAO significantly increased the expression of CB1 within the stroke penumbra with the highest level appearing at 2 h following the ischemic insult. Administration of WIN55,212-2 (9 mg/kg, iv) significantly attenuated the brain swelling, and reduced the infarct volume as well as the number of tau-immunoreactive NG2+ cells (tau-1+/NG2+ cells) in the stroke penumbra. Moreover, WIN55,212-2 significantly promoted the proliferation of NG2+ cells in the stroke penumbra and in the ipsilateral subventricular zone at 24 h following the ischemic insult. Administration of the selective CB1 antagonist rimonabant (1 mg/kg, iv) partially blocked the effects caused by WIN55,212-2.
Conclusion:
Tau-1 is expressed in NG2+ cells following permanent focal cerebral ischemic injury. Treatment with WIN55,212-2 reduces the number of tau-1+/NG2+ cells and promotes NG2+ cell proliferation in the stroke penumbra, which are mediated partially via CB1 and may contribute to its neuroprotective effects.
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Acknowledgements
This research was supported in part by the National Natural Science Foundation of China (No 81070967) and the Natural Science Foundation of Jiangsu Province (No BK2009296). We wish to thank Su-juan YUAN in Yancheng City No 1 People's Hospital for technological assistance.
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Supplementary figure is available at the Acta Pharmacologica Sinica website.
Supplementary information
Supplementary Fig. 1
Define the penumbral areas (DOC 654 kb)
Supplementary Fig. 2
Dose-response preliminary finding experiments (DOC 250 kb)
Supplementary Fig. 3
WIN55, 212-2 increases the proliferation of ipsilateral SVZ NG2-positive progenitor cells partially through CB1 (DOC 4605 kb)
Supplementary Fig. 4
Identification of BrdU-positive cells in ipsilateral SVZ following administration of WIN55, 212-2 (DOC 889 kb)
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Sun, J., Fang, Yq., Ren, H. et al. WIN55,212-2 protects oligodendrocyte precursor cells in stroke penumbra following permanent focal cerebral ischemia in rats. Acta Pharmacol Sin 34, 119–128 (2013). https://doi.org/10.1038/aps.2012.141
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DOI: https://doi.org/10.1038/aps.2012.141
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