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Xuesaitong May Protect Against Ischemic Stroke by Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis via the STAT3 Signaling Pathway.
CNS Neurol Disord Drug Targets. 2019; 18(2):115-123.CN

Abstract

BACKGROUND

Xuesaitong mainly comprises Panax notoginseng saponins and has shown a promising feature in an acute ischemic stroke model; however, its effect on long-term recovery following stroke, and the related mechanisms, are unknown.

METHODS

The objective of this study was to investigate the long-term protective effects of xuesaitong against ischemic stroke and its effect on microglial polarization. Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 45 min, and C57BL/6 mice were immediately injected with xuesaitong or vehicle through the caudal vein at the onset of cerebral reperfusion consecutively for 14 days. The animals were randomly divided into three groups: a sham-operated group, vehicle-treated group and xuesaitong-treated group at a dose of 15μg/g. Subsequently, 2,3,5-triphenyltetrazolium chloride staining was used to assess infarct volume, and adhesive removal tests and balance beam tests were used to evaluate neurological deficits at days 1, 3, 7 and 14 following ischemia. Reverse-transcriptase polymerase chain reaction and immunofluorescence staining for M1 markers (CD16, iNOS) and M2 markers (CD206, arginase-1) were performed to characterize phenotypic changes in microglia. Elisa was used to determine the release of pro-inflammatory and anti-inflammatory cytokines. TUNEL staining was conducted to detect neuronal cell apoptosis, and western blots were used to determine the activation of signal transducer and activator of transcription 3 (STAT3).

RESULTS

Our results revealed that xuesaitong treatment, compared with vehicle treatment, significantly reduced cerebral infarct volume 1 and 3 days after MCAO and resulted in significant improvements in long-term neurological outcomes. Furthermore, xuesaitong treatment, compared with vehicle treatment, significantly reduced M1 markers and elevated M2 markers 7 and 14 days after MCAO at both the mRNA and protein level in ipsilateral brain tissue. This finding was also accompanied by a reduction in neuronal cell apoptosis and p-STAT3 transcription factor levels in the xuesaitong-treated group compared with the vehicle-treated group.

CONCLUSION

We demonstrated that xuesaitong has long-term neuroprotective effects against ischemic stroke, possibly by promoting the polarization of microglia to an M2 phenotype and by inhibiting neuronal cell death via down-regulation of the STAT3 signaling pathway, providing new evidence that xuesaitong might be a promising therapeutic strategy for ischemic stroke.

Authors+Show Affiliations

Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China. Beijing Institute for Brain Disorders, Beijing, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30426907

Citation

Li, Fangfang, et al. "Xuesaitong May Protect Against Ischemic Stroke By Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis Via the STAT3 Signaling Pathway." CNS & Neurological Disorders Drug Targets, vol. 18, no. 2, 2019, pp. 115-123.
Li F, Zhao H, Han Z, et al. Xuesaitong May Protect Against Ischemic Stroke by Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis via the STAT3 Signaling Pathway. CNS Neurol Disord Drug Targets. 2019;18(2):115-123.
Li, F., Zhao, H., Han, Z., Wang, R., Tao, Z., Fan, Z., Zhang, S., Li, G., Chen, Z., & Luo, Y. (2019). Xuesaitong May Protect Against Ischemic Stroke by Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis via the STAT3 Signaling Pathway. CNS & Neurological Disorders Drug Targets, 18(2), 115-123. https://doi.org/10.2174/1871527317666181114140340
Li F, et al. Xuesaitong May Protect Against Ischemic Stroke By Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis Via the STAT3 Signaling Pathway. CNS Neurol Disord Drug Targets. 2019;18(2):115-123. PubMed PMID: 30426907.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Xuesaitong May Protect Against Ischemic Stroke by Modulating Microglial Phenotypes and Inhibiting Neuronal Cell Apoptosis via the STAT3 Signaling Pathway. AU - Li,Fangfang, AU - Zhao,Haiping, AU - Han,Ziping, AU - Wang,Rongliang, AU - Tao,Zhen, AU - Fan,Zhibin, AU - Zhang,Sijia, AU - Li,Guangwen, AU - Chen,Zhigang, AU - Luo,Yumin, PY - 2018/07/23/received PY - 2018/09/20/revised PY - 2018/11/11/accepted PY - 2018/11/15/pubmed PY - 2020/5/14/medline PY - 2018/11/15/entrez KW - STAT3 KW - Xuesaitong KW - cerebral ischemia KW - microglia KW - phenotype KW - polarization. SP - 115 EP - 123 JF - CNS & neurological disorders drug targets JO - CNS Neurol Disord Drug Targets VL - 18 IS - 2 N2 - BACKGROUND: Xuesaitong mainly comprises Panax notoginseng saponins and has shown a promising feature in an acute ischemic stroke model; however, its effect on long-term recovery following stroke, and the related mechanisms, are unknown. METHODS: The objective of this study was to investigate the long-term protective effects of xuesaitong against ischemic stroke and its effect on microglial polarization. Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 45 min, and C57BL/6 mice were immediately injected with xuesaitong or vehicle through the caudal vein at the onset of cerebral reperfusion consecutively for 14 days. The animals were randomly divided into three groups: a sham-operated group, vehicle-treated group and xuesaitong-treated group at a dose of 15μg/g. Subsequently, 2,3,5-triphenyltetrazolium chloride staining was used to assess infarct volume, and adhesive removal tests and balance beam tests were used to evaluate neurological deficits at days 1, 3, 7 and 14 following ischemia. Reverse-transcriptase polymerase chain reaction and immunofluorescence staining for M1 markers (CD16, iNOS) and M2 markers (CD206, arginase-1) were performed to characterize phenotypic changes in microglia. Elisa was used to determine the release of pro-inflammatory and anti-inflammatory cytokines. TUNEL staining was conducted to detect neuronal cell apoptosis, and western blots were used to determine the activation of signal transducer and activator of transcription 3 (STAT3). RESULTS: Our results revealed that xuesaitong treatment, compared with vehicle treatment, significantly reduced cerebral infarct volume 1 and 3 days after MCAO and resulted in significant improvements in long-term neurological outcomes. Furthermore, xuesaitong treatment, compared with vehicle treatment, significantly reduced M1 markers and elevated M2 markers 7 and 14 days after MCAO at both the mRNA and protein level in ipsilateral brain tissue. This finding was also accompanied by a reduction in neuronal cell apoptosis and p-STAT3 transcription factor levels in the xuesaitong-treated group compared with the vehicle-treated group. CONCLUSION: We demonstrated that xuesaitong has long-term neuroprotective effects against ischemic stroke, possibly by promoting the polarization of microglia to an M2 phenotype and by inhibiting neuronal cell death via down-regulation of the STAT3 signaling pathway, providing new evidence that xuesaitong might be a promising therapeutic strategy for ischemic stroke. SN - 1996-3181 UR - https://www.unboundmedicine.com/medline/citation/30426907/Xuesaitong_May_Protect_Against_Ischemic_Stroke_by_Modulating_Microglial_Phenotypes_and_Inhibiting_Neuronal_Cell_Apoptosis_via_the_STAT3_Signaling_Pathway_ DB - PRIME DP - Unbound Medicine ER -