Saponins from Rhizoma Panacis Majoris protect against cerebral ischemia and reperfusion injury through modulation of PI3K/Akt signaling pathway in mice

doi:10.12092/j.issn.1009-2501.2019.07.005

Abstract

Abstract:

AIM: To study the protective effect and possible mechanism of saponins from Rhizoma Panacis Majoris (SRPM) on cerebral ischemia-reperfusion (I/R) injury in mice. METHODS: Male Kunming mice were randomly divided into sham operation group, model group, SRPM (100 mg/kg), SRPM (200 mg/kg) and nimodipine group (2 mg/kg). The drug groups were given corresponding drugs by gavage, while the sham operation group and the model group were given 0.5% sodium carboxymethyl cellulose solution by gavage once a day for 7 consecutive days. After 7 days of administration, the middle cerebral artery occlusion model was established in mice in the sham operation group. After 2 hours of ischemia and 24 hours of reperfusion, the neurological deficit score, brain edema, infarct area and brain histomorphology were analyzed. The levels of ROS, LDH, SOD, GSH-Px, CAT and MDA in blood were detected. The protein levels of p-PI3K, PI3K, p-Akt, Akt Bcl-2, Bax, cytochrome C, cleaved-caspase-9 and cleaved-caspase-3 in brain tissue were detected by Western blot. RESULTS:SRPM (100 and 200 mg/kg) and nimodipine (2 mg/kg) could significantly improve neurological deficit score, brain edema, infarct area and brain histomorphology in cerebral I/R injury mice, reduce the levels of ROS, LDH and MDA, increase SOD, GSH-Px, CAT activities in serum, up-regulate the protein expressions of p-PI3K, p-Akt, Bcl-2, and Bcl-2/Bax ratio, down-regulate the protein expressions of Bax, cytochrome C, cleaved-caspase-9 and cleaved-caspase-3. CONCLUSION: The protective effect of SRPM on I/R injury mice may be related to its activation of PI3K/Akt pathway and inhibition of mitochondrial-mediated apoptotic pathway.

Key words: Saponins from Rhizoma Panacis Majoris, cerebral ischemia and reperfusion injury, oxidative stress, PI3K/Akt signaling pathway and mitochondrial-mediated apoptotic pathway

CLC Number:

DUAN Jinning, XIANG Changqing, QIAN Aihong, LI Jin, CHEN Xiuquan, HAN Yongfeng, HUANG Na, FAN Lili. Saponins from Rhizoma Panacis Majoris protect against cerebral ischemia and reperfusion injury through modulation of PI3K/Akt signaling pathway in mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(7): 750-758.

References

［1］赵仁, 赵毅, 李东明. 珠子参研究进展［J］. 中国现代中药, 2008, 10 (7): 3-6.
［2］国家药典委员会. 中国药典(一部)［M］. 北京: 中国医药科技出版社, 2015: 271-272.
［3］Chan HH, Sun HD, Reddy MVB, et al. Potent α-glucosidase inhibitors from the roots of Panax japonicus C. A. Meyer var. major［J］. Phytochemistry, 2010, 71(1112): 1360-1364.
［4］金家红, 贺海波, 石孟琼, 等. 珠子参总皂苷对小鼠局灶性脑缺血的保护作用［J］. 第三军医大学学报, 2011, 33 (24): 2631-2633.
［5］Ou JJ, Kou L, Liang LY, et al. MiR-375 attenuates injury of cerebral ischemia/reperfusion via targetting Ctgf ［J］. Biosci Rep, 2017, 37(6): BSR20171242.
［6］El-Marasy SA, Abdel-Rahman RF, Abd-Elsalam RM. Neuroprotective effect of vildagliptin against cerebral ischemia in rats［J］. Naunyn Schmiedebergs Arch Pharmacol, 2018, 391 (10): 1133-1145.
［7］Wang Y, Tu L, Li YB, et al. Notoginsenoside R1 protects against neonatal cerebral hypoxic-ischemic injury through estrogen receptor-dependent activation of endoplasmic reticulum stress pathways［J］. J Pharmacol Exp Ther, 2016, 357 (3): 591-605.
［8］He HB, Li XM, Li DJ, et al. Saponins from Rhizoma Panacis Majoris attenuate myocardial ischemia/reperfusion injury via the activation of the Sirt1/FoxO1/Pgc-1α and Nrf2/ antioxidant defense pathways in rats［J］. Pharmacognosy Magazine, 2018, 14 (56): 297- 307.
［9］Huang SL, He HB, Zou K, et al. Protective effect of tomatine against hydrogen peroxide-induced neurotoxicity in neuroblastoma (SH-SY5Y) cells［J］. J Pharm Pharm, 2014, 66 (6): 844-854.
［10］Kanavaki A, Spengos K, Moraki M, et al. Serum levels of S100b and NSE proteins in patients with non-transfusion-dependent thalassemia as biomarkers of brain ischemia and cerebral vasculopathy［J］. Int J Mol Sci, 2017, 18 (12): pii: E2724.
［11］Leonard SS, Harris GK, Shi X. Metal-induced oxidative stress and signal transduction［J］. Free Radic Biol Med, 2004, 37 (12): 1921-1942.
［12］徐慧, 张民远, 戴勤学. miR-145通过调节SOD活性介导人参皂苷Rb1对脑缺血再灌注损伤大鼠的脑保护作用［J］. 中国临床药理学与治疗学, 2018, 23(1): 1215-1220.
［13］Khwanraj K, Madlah S, Grataitong K, et al. Comparative mRNA expression of eEF1A isoforms and a PI3K/Akt/mTOR pathway in a cellular model of Parkinson's disease［J］. Parkinsons Dis, 2016: 8716016.
［14］Chen A, Xiong LJ, Tong Y, et al. Neuroprotective effect of brain-derived neurotrophic factor mediated by autophagy through the PI3K/Akt/mTOR pathway［J］. Mol Med Rep, 2013, 8 (4): 1011-1016.
［15］Tu L, Wang Y, Chen D, et al. Protective effects of Notoginsenoside R1 via regulation of the PI3K-Akt-mTOR/JNK pathway in neonatal cerebral hypoxic-ischemic brain injury［J］. Neurochem Res, 2018,43 (6): 1210- 1226.
［16］Huang LF, Chen CW, Zhang X, et al. Neuroprotective effect of curcumin against cerebral ischemia-reperfusion via mediating autophagy and inflammation［J］. J Mol Neurosci, 2018, 64 (1): 129-139.
［17］Guo XD, Sun GL, Zhou TT, et al. Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance［J］. Acta Pharmacol Sin, 2016, 37 (10): 1281-1297.
［18］Pan YD, Wang N, Xia PP, et al. Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl-2/Rac1 complex formation in mitochondria through PI3K/ Akt/mTOR pathway［J］. Exp Neurol, 2018, 300: 149-166.
［19］Chong SJ, Low IC, Pervaiz S. Mitochondrial ROS and involvement of Bcl-2 as a mitochondrial ROS regulator［J］. Mitochondrion, 2014, 19 (Part A): 39-48.
［20］Han B, Jiang P, Li ZX, et al. Coptisine-induced apoptosis in human colon cancer cells (HCT-116) is mediated by PI3K/Akt and mitochondrial-associated apoptotic pathway［J］. Phytomedicine, 2018, 48: 152-160.
［21］Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death［J］. Nat Rev Mol Cell Biol, 2008, 9 (1): 47-59.
［22］Ryu DS, Kim SH, Kwon JH, et al. Orostachys japonicus induces apoptosis and cell cycle arrest through the mitochondria-dependent apoptotic pathway in AGS human gastric cancer cells［J］. Int J Oncol, 2014, 45(1): 459-469.

[1]	LIU Lijing, QIAN Hong, MENG Qingxin, ZHANG Xiang, HE Bin, HE Jianbin, WEI Yingmin. Sinomenine inhibits oxidative stress and pulmonary fibrosis by activating the Keap1/Nrf2 signaling pathway [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(9): 979-987.
[2]	LI Yating, YUE Hongmei, LIU Miaomiao, XU Jinhui, WU Xingdong, ZHU Haobin. The possibility of phosphodiesterase 4 inhibitors as drug therapy for idiopathic pulmonary fibrosis [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(7): 818-823.
[3]	WANG Donghui, JIANG Suwen, HU Airong, ZHU Bo, HE Zheyun, ZHANG Lukan, WANG Jialan, FAN Ying, LIN Ken . Mulberry exerts antioxidant stress effect in rats with nonalcoholic fatty liver disease [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(6): 609-616.
[4]	BAI Jia, YANG Hong, LI Lingling, ZHANG Yangyang, YANG Ying, LV Haihong. Study on the effect of vitamin D on diabetic neuropathy through mitochondrial/autophagy pathway [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(2): 214-219.
[5]	ZHU Haobin, YUE Hongmei, WU Xingdong, LIU Miaomiao, LI Yating, XU Jinhui. Research progress on the role of the Nrf2 signaling pathway in the complications associated with obstructive sleep apnea [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(11): 1283-1291.
[6]	YANG Zhian, ZHAO Yan, HE Yao, LIU Weiying, YU Qin. Pyroptosis mediated renal injury caused by chronic intermittent hypoxia and the intervention effect of edaravone in rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2023, 28(1): 10-18.
[7]	HUA Haiyan, YAN Jie, QIN Yufen. Experimental study of schisandrin B attenuates acute myocardial ischemia injury in rats by inhibiting cardiomyocyte apoptosis [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(8): 848-856.
[8]	WANG Jinhuo, GAO Xinyue, GUO Jianrong. Effect of COX-2 inhibitors on postoperative delirium in elderly patients undergoing orthopedic surgery and its possible mechanism [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(8): 863-869.
[9]	LI Xueheng, LI Long. Research progress on the relationship between melatonin and idiopathic pulmonary fibrosis [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(6): 715-720.
[10]	WANG Xinli, XU Xiaqing, FANG Hanbing, GUO Yuzhong. Study of TPA on enhancing the anti-tumor effects of cisplatin and reducing its renal toxicity [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(5): 535-543.
[11]	REN Yixing, LENG Yufang, GUO Mingjun, ZHANG Jianmin, SHI Yajing, CHEN Feng, LIU Xin. Role and mechanism of SIRT3 in attenuation of intestinal ischemia-reperfusion injury by dexmedetomidine in mice [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(3): 253-259.
[12]	HE Liyang, WEI Wenjie, YIN Qin, LIU Lijing, ZHONG Boying, LIU Cungen, ZHOU Meiling, HE Jianbin. Preventive and therapeutic effects of the Kiwi fruit essence (unsaturated fatty acid of actinidia chinesis planch seed oil) on radiation-induced lung injury rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(2): 154-162.
[13]	LIN Naping, WU Yutang, HUANG Defen, XU Chaoxiang. Effects of miR-195-5p on ox-LDL-induced vascular endothelial cell injury through regulating FBXW7 [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(2): 163-170.
[14]	LI Ying, YAO Wei, WANG Meng, YU Zhihong, GONG Yuanqi, LAN Haibing, QI Xiefei. Experimental study of irisin alleviates house dust mite-induced airway epithelial cells inflammation and apoptosis via the NF-κB and JNK signaling pathways [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(10): 1106-1112.
[15]	GUO Yuting, LI Shanshan, LI Qinglin. Tianma Gouteng Yin protects rotenone-induced PC12 cell damage by inhibiting ferroptosis-lipid metabolism [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(1): 8-14.