Neuroprotective effects and mechanism of saikosaponin A on acute spinal cord injury in rats_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHU Shuanglong ^1,2,3 , DUAN Huiquan ^1,2 , LIU Yingfu ⁴ , LI Guangzong ⁵ , LIU Yingjie ^1,2 , HUANG Mengqiang ^1,2 ,  CHEN Xuyi ³ ,  XU Yunqiang ^1,2

1. Graduate School, Tianjin Medical University, Tianjin, 300070, P.R.China;
2. Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, 300052, P.R.China;
3. Department of Brain, Affiliated Hospital, Logistics University of People’s Armed Police Force, Tianjin, 300162, P.R.China;
4. Department of Cell Biology, Logistics University of People’s Armed Police Force, Tianjin, 300309, P.R.China;
5. Rescue Institute, Affiliated Hospital, Logistics University of People’s Armed Police Force, Tianjin, 300162, P.R.China;

Corresponding?author：

CHEN Xuyi, Email: chenxuyi1979@126.com; XU Yunqiang, Email: docxu@sina.com

Keywords：

Saikosaponin a; spinal cord injury; inflammation response; aquaporin-4; neuroprotection; rat

DOI：

10.7507/1002-1892.201702106

Video：

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ObjectiveTo investigate the effect of saikosaponin a (SSa) on the levels of immune inflammation in rats with acute spinal cord injury and its possible mechanism.MethodsSeventy-two Sprague Dawley rats (weighing, 220-250 g) were randomly divided into sham operation group (group A), spinal cord injury group (group B), and SSa treatment group (group C) respectively, 24 rats in each group. The spinal cord injury model was induced by using the Allen’s method in groups B and C; the spinous process and vertebral plate at both sides were cut off by lamina excision to expose the spinal cord in group A. The rats were given intraperitoneal injection of 10 mg/kg SSa in group C and equal volume of normal saline in group B at immediate after injury. The spinal cord tissue was harvested from 18 rats of each group at 24 hours after operation to measure the levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) by ELISA, to detect the expressions of nuclear factor κB (NF-κB) P65, NF-κB P-P65, and aquaporin 4 (AQP4) by Western blot and to observe the morphology of spinal cord by HE staining. The motor function of the lower limbs was evaluated by BBB score and tiltboard experiment in 6 rats at 1, 3, 7, 14, 21, and 28 days after injury.ResultsThe BBB score and tiltboard experiment maximum angle were significantly higher in group A than groups B and C at each time point (P<0.05) and in group C than group B at 14, 21, and 28 days after operation (P<0.05). ELISA test showed that the concentrations of TNF-α and IL-6 were significantly lower in group A than groups B and C, and in group C than group B (P<0.05). Western blot results showed that the protein expression levels of NF-κB P65, NF-κB P-P65, and AQP4 were significantly lower in group A than groups B and C, and in group C than group B (P<0.05). HE staining demonstrated normal neurons of the spinal cord and no obvious lesion in group A; neuronal cells were observed in the injured area of group B, with hemorrhage, neutrophil infiltration, and nerve cell edema in the injured area; the neuronal cells were visible in the spinal cord of group C, with microglia mild hyperplasia, and the pathological changes were improved when compared with group B.ConclusionSSa has neuroprotective effects on acute spinal cord injury in rats by inhibiting NF-κB signaling pathway and AQP4 protein expression and reducing inflammation response and edema.

Citation： ZHU Shuanglong, DUAN Huiquan, LIU Yingfu, LI Guangzong, LIU Yingjie, HUANG Mengqiang, CHEN Xuyi, XU Yunqiang. Neuroprotective effects and mechanism of saikosaponin A on acute spinal cord injury in rats. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(7): 825-829. doi: 10.7507/1002-1892.201702106 Copy

1.	Kong X, Gao J. Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J Cell Mol Med, 2017, 21(5): 941-954.
2.	徐立, 梁軍, 金濤, 等. 芒果苷對大鼠急性脊髓損傷的保護作用及相關機制研究. 中國修復重建外科雜志, 2016, 30(8): 1019-1925.
3.	Guo L, Quan ZX, Zhao ZH, et al. Effects of musk ketone on nerve recovery after spinal cord injury. Genet Mol Res, 2015, 14(2): 2958-2963.
4.	萬峪岑, 孫師, 趙利娜, 等. 小劑量超短波治療對大鼠脊髓損傷后炎癥反應及水腫的影響. 中國康復理論與實踐, 2016, 22(2): 150-155.
5.	Zhang C, Ma J, Fan LH, et al. Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating. Tissue Cell, 2015, 47(3): 291-300.
6.	Liu CJ, Shi ZB, Fan LH, et al. Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Res, 2011, 1374: 100-109.
7.	Khanna S, Park H, Sen C et al. Neuroprotective and antiinflammatory properties of a novel demethylated curcuminoid. Antioxid Redox Signal, 2009, 11(3): 449-468.
8.	Xie W, Yu YH, Du YP, et al. Saikosaponin a Enhances Transient Inactivating Potassium Current in Rat Hippocampal CA1 Neurons. Evid Based Complement Alternat Med, 2013, 2013: 413092.
9.	Mao X, Miao GZ, Tao XG, et al. Saikosaponin a protects TBI rats after controlled cortical impact and the underlying mechanism. Am J Transl Res, 2016, 8(1): 133-141.
10.	Hohlfeld R, Kerschensteiner M, Meinl E. Dual role of inflammation in CNS disease. Neurology, 2007, 68(Suppl 3): S58-S63.
11.	王濤麗, 顧兵, 李華南, 等. 急性脊髓損傷后的炎癥反應及其抗炎治療. 中國藥理學通報, 2015, 31(4): 452-457.
12.	趙夢瀅, 朱鈺文, 黃立丹, 等. 腫瘤壞死因子-α 與脊髓損傷的研究進展. 神經損傷與功能重建, 2016, 11(2): 155-157.
13.	Zhang X, Shi LL, Gao X, et al. Lentivirus-mediated inhibition of tumour necrosis factor-alpha improves motor function associated with PRDX6 in spinal cord contusion rats. Sci Rep, 2015, 5: 8486.
14.	徐玉生, 張松, 金偉林, 等. 褪黑素對大鼠脊髓損傷后腫瘤壞死因子-a 表達的影響. 鄭州大學學報(醫學版), 2014, 49(1): 41-44.
15.	Pishva1 AA, Akbari M, Farahabadi A, et al. Effect of estrogen therapy on TNF-α and iNOS gene expression in spinal cord injury model. Acta Med Iran, 2016, 54(5): 296-301.
16.	Liu XH, Bauman WA, Cardozo C, ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-kappaB signaling activity. Biochem Biophys Res Commun, 2015, 464(1): 208-213.
17.	Yarar-Fisher C, Bickl CS, Kelly NA, et al. Heightened TWEAK-NF-kappaB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury. Am J Physiol Endocrinol Metab, 2016, 310(9): E754-761.
18.	Bethea JR, Castro M, Keane RW, et al. Traumatic spinal cord injury induces nuclear factor-B activation. J Neurosci, 1998, 18(9): 3251-3260.
19.	Brambilla R, Bracchi-Ricard V, Hu WH, et al. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med, 2005, 202(1): 145-156.
20.	Oklinski MK, Skowronski M, Skowronska AT, et al. Aquaporins in the Spinal Cord. Int J Mol Sci, 2016, 17(12). pii: E2050.
21.	Liu X, Wang Y, Yang J, et al. Anti-edema effect of melatonin on spinal cord injury in rats. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2015, 159(2): 220-226.
22.	Ito H, Yamamoto N, Arima H, et al. Interleukin-1beta induces the expression of aquaporin-4 through a nuclear factor-kappaB pathway in rat astrocytes. J Neurochem, 2006, 99(1): 107-118.
23.	李野. AQP4 和 Kir4. 1 在急性脊髓損傷后脊髓水腫中的作用機制研究. 吉林: 吉林大學, 2015.

1. Kong X, Gao J. Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J Cell Mol Med, 2017, 21(5): 941-954.
2. 徐立, 梁軍, 金濤, 等. 芒果苷對大鼠急性脊髓損傷的保護作用及相關機制研究. 中國修復重建外科雜志, 2016, 30(8): 1019-1925.
3. Guo L, Quan ZX, Zhao ZH, et al. Effects of musk ketone on nerve recovery after spinal cord injury. Genet Mol Res, 2015, 14(2): 2958-2963.
4. 萬峪岑, 孫師, 趙利娜, 等. 小劑量超短波治療對大鼠脊髓損傷后炎癥反應及水腫的影響. 中國康復理論與實踐, 2016, 22(2): 150-155.
5. Zhang C, Ma J, Fan LH, et al. Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating. Tissue Cell, 2015, 47(3): 291-300.
6. Liu CJ, Shi ZB, Fan LH, et al. Resveratrol improves neuron protection and functional recovery in rat model of spinal cord injury. Brain Res, 2011, 1374: 100-109.
7. Khanna S, Park H, Sen C et al. Neuroprotective and antiinflammatory properties of a novel demethylated curcuminoid. Antioxid Redox Signal, 2009, 11(3): 449-468.
8. Xie W, Yu YH, Du YP, et al. Saikosaponin a Enhances Transient Inactivating Potassium Current in Rat Hippocampal CA1 Neurons. Evid Based Complement Alternat Med, 2013, 2013: 413092.
9. Mao X, Miao GZ, Tao XG, et al. Saikosaponin a protects TBI rats after controlled cortical impact and the underlying mechanism. Am J Transl Res, 2016, 8(1): 133-141.
10. Hohlfeld R, Kerschensteiner M, Meinl E. Dual role of inflammation in CNS disease. Neurology, 2007, 68(Suppl 3): S58-S63.
11. 王濤麗, 顧兵, 李華南, 等. 急性脊髓損傷后的炎癥反應及其抗炎治療. 中國藥理學通報, 2015, 31(4): 452-457.
12. 趙夢瀅, 朱鈺文, 黃立丹, 等. 腫瘤壞死因子-α 與脊髓損傷的研究進展. 神經損傷與功能重建, 2016, 11(2): 155-157.
13. Zhang X, Shi LL, Gao X, et al. Lentivirus-mediated inhibition of tumour necrosis factor-alpha improves motor function associated with PRDX6 in spinal cord contusion rats. Sci Rep, 2015, 5: 8486.
14. 徐玉生, 張松, 金偉林, 等. 褪黑素對大鼠脊髓損傷后腫瘤壞死因子-a 表達的影響. 鄭州大學學報(醫學版), 2014, 49(1): 41-44.
15. Pishva1 AA, Akbari M, Farahabadi A, et al. Effect of estrogen therapy on TNF-α and iNOS gene expression in spinal cord injury model. Acta Med Iran, 2016, 54(5): 296-301.
16. Liu XH, Bauman WA, Cardozo C, ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-kappaB signaling activity. Biochem Biophys Res Commun, 2015, 464(1): 208-213.
17. Yarar-Fisher C, Bickl CS, Kelly NA, et al. Heightened TWEAK-NF-kappaB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury. Am J Physiol Endocrinol Metab, 2016, 310(9): E754-761.
18. Bethea JR, Castro M, Keane RW, et al. Traumatic spinal cord injury induces nuclear factor-B activation. J Neurosci, 1998, 18(9): 3251-3260.
19. Brambilla R, Bracchi-Ricard V, Hu WH, et al. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med, 2005, 202(1): 145-156.
20. Oklinski MK, Skowronski M, Skowronska AT, et al. Aquaporins in the Spinal Cord. Int J Mol Sci, 2016, 17(12). pii: E2050.
21. Liu X, Wang Y, Yang J, et al. Anti-edema effect of melatonin on spinal cord injury in rats. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2015, 159(2): 220-226.
22. Ito H, Yamamoto N, Arima H, et al. Interleukin-1beta induces the expression of aquaporin-4 through a nuclear factor-kappaB pathway in rat astrocytes. J Neurochem, 2006, 99(1): 107-118.
23. 李野. AQP4 和 Kir4. 1 在急性脊髓損傷后脊髓水腫中的作用機制研究. 吉林: 吉林大學, 2015.

Chinese Journal of Reparative and Reconstructive Surgery

Neuroprotective effects and mechanism of saikosaponin A on acute spinal cord injury in rats

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