WIN55,212-2 protects oligodendrocyte precursor cells in stroke penumbra following permanent focal cerebral ischemia in rats
Abstract
Jing SUN1, Yin-quan FANG1, Hong REN1, Tao CHEN1, Jing-jing GUO1, Jun YAN1, Shu SONG2, Lu-yong ZHANG1, 3, Hong LIAO1, 3, *
1Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; 2Department of Pathology, Yancheng City No 1 People’s Hospital, Yancheng 224001, China; 3State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
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.
Keywords: stroke; permanent focal cerebral ischemia; penumbra; oligodendrocyte precursor cells; neural glial antigen 2 (NG2); tau-1; cannabinoid receptor type 1 (CB1); WIN55,212-2; rimonabant
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.
* To whom correspondence should be addressed.
E-mail hliao@cpu.edu.cn
Received 2012-05-19 Accepted 2012-09-18
Keywords:
1Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, China; 2Department of Pathology, Yancheng City No 1 People’s Hospital, Yancheng 224001, China; 3State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
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.
Keywords: stroke; permanent focal cerebral ischemia; penumbra; oligodendrocyte precursor cells; neural glial antigen 2 (NG2); tau-1; cannabinoid receptor type 1 (CB1); WIN55,212-2; rimonabant
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.
* To whom correspondence should be addressed.
E-mail hliao@cpu.edu.cn
Received 2012-05-19 Accepted 2012-09-18