Metabolic Brain Disease

, Volume 33, Issue 6, pp 1869–1875 | Cite as

Oxymatrine attenuates brain hypoxic-ischemic injury from apoptosis and oxidative stress: role of p-Akt/GSK3β/HO-1/Nrf-2 signaling pathway

  • Xu-Hua Ge
  • Li Shao
  • Guo-Ji ZhuEmail author
Original Article


To investigate the potential neuroprotection of oxymatrine in hypoxic-ischemic injury in rat’s brain and the associated underlying mechanisms, modified neurological severity scores (mNSS) for neurological functional deficits, 2,3,5-triphenyl-tetrazolium chloride (TTC) staining for infarct volume, TUNEL assay and flow cytometry analysis for apoptosis were assessed. The expressions of Akt, glycogen synthase kinase 3 beta (GSK3β), phosphorylated Akt (p-Akt), phosphorylated GSK3β (p-GSK3β), nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were measured by western blot. Our results showed that infarct volume and the apoptosis of NeuN-positive cells were significantly reduced in rats that administrated oxymatrine, with a corresponding improvement in neurological function after H/I. Upregulated p-Akt, p-GSK3β, Nrf-2 and HO-1 expressions were observed in response to oxymatrine treatment. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 counteracted the protective effect of oxymatrine, evidenced by western blot and histological outcomes. To conclude, our results suggested that oxymatrine could exert efficacious neuroprotective effect against H/I injury by inhibiting apoptosis and oxidative stress, which might be related to the activation of Akt and GSK3β and modulation of Nrf-2/HO-1 signaling pathway.


Oxymatrine Hypoxic-ischemic injury Apoptosis Akt/GSK3β pathway Nrf2/HO-1 pathway 



This work was sponsored by the National Natural Science Foundation of China (81370254).

Compliance with ethical standards

Declaration of conflicting interests

The authors declare that they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.


  1. Ali T, Kim T, Rehman SU, Khan MS, Amin FU, Khan M, Ikram M, Kim MO (2017) Natural dietary supplementation of anthocyanins via PI3K/Akt/Nrf2/HO-1 pathways mitigate oxidative stress, neurodegeneration, and memory impairment in a mouse model of Alzheimer's disease. Mol Neurobiol 55(7):6076–6093CrossRefGoogle Scholar
  2. Buendia I, Michalska P, Navarro E, Gameiro I, Egea J, Leon R (2016) Nrf2-ARE pathway: an emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol Ther 157:84–104CrossRefGoogle Scholar
  3. Cao S, Du J, Hei Q (2017) Lycium barbarum polysaccharide protects against neurotoxicity via the Nrf2-HO-1 pathway. Exp Ther Med 14:4919–4927PubMedPubMedCentralGoogle Scholar
  4. Cheng L, Jin Z, Zhao R, Ren K, Deng C, Yu S (2015) Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. Int J Clin Exp Med 8:10420–10428PubMedPubMedCentralGoogle Scholar
  5. Cui L, Zhang X, Yang R, Wang L, Liu L, Li M, Du W (2011) Neuroprotection and underlying mechanisms of oxymatrine in cerebral ischemia of rats. Neurol Res 33:319–324CrossRefGoogle Scholar
  6. Fan H, Li L, Zhang X, Liu Y, Yang C, Yang Y, Yin J (2009) Oxymatrine downregulates TLR4, TLR2, MyD88, and NF-kappaB and protects rat brains against focal ischemia. Mediat Inflamm 2009:704706CrossRefGoogle Scholar
  7. He M, Siow RC, Sugden D, Gao L, Cheng X, Mann GE (2011) Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: a role for Nrf2 in vascular protection in diabetes. Nutr Metab Cardiovasc Dis 21:277–285PubMedGoogle Scholar
  8. Hu Y, Zhan Q, Zhang H, Liu X, Huang L, Li H, Yuan Q (2017) Increased susceptibility to ischemic brain injury in Neuroplastin 65-deficient mice likely via glutamate excitotoxicity. Front Cell Neurosci 11:110PubMedPubMedCentralGoogle Scholar
  9. Jiang G, Liu X, Wang M, Chen H, Chen Z, Qiu T (2015) Oxymatrine ameliorates renal ischemia-reperfusion injury from oxidative stress through Nrf2/HO-1 pathway. Acta Cir Bras 30:422–429CrossRefGoogle Scholar
  10. Jiang LJ, Zhang SM, Li CW, Tang JY, Che FY, Lu YC (2017) Roles of the Nrf2/HO-1 pathway in the anti-oxidative stress response to ischemia-reperfusion brain injury in rats. Eur Rev Med Pharmacol Sci 21:1532–1540PubMedGoogle Scholar
  11. Kilic U, Caglayan AB, Beker MC, Gunal MY, Caglayan B, Yalcin E, Kelestemur T, Gundogdu RZ, Yulug B, Yilmaz B, Kerman BE, Kilic E (2017) Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin's neuroprotective activity after focal cerebral ischemia in mice. Redox Biol 12:657–665CrossRefGoogle Scholar
  12. Li M, Zhang X, Cui L, Yang R, Wang L, Liu L, Du W (2011) The neuroprotection of oxymatrine in cerebral ischemia/reperfusion is related to nuclear factor erythroid 2-related factor 2 (nrf2)-mediated antioxidant response: role of nrf2 and hemeoxygenase-1 expression. Biol Pharm Bull 34:595–601CrossRefGoogle Scholar
  13. Liu Y, Zhang XJ, Yang CH, Fan HG (2009) Oxymatrine protects rat brains against permanent focal ischemia and downregulates NF-kappaB expression. Brain Res 1268:174–180CrossRefGoogle Scholar
  14. Lu ML, Xiang XH, Xia SH (2016) Potential signaling pathways involved in the clinical application of Oxymatrine. Phytother Res 30:1104–1112CrossRefGoogle Scholar
  15. Vannucci RC, Vannucci SJ (2005) Perinatal hypoxic-ischemic brain damage: evolution of an animal model. Dev Neurosci 27:81–86CrossRefGoogle Scholar
  16. Zhai X, Lin H, Chen Y, Chen X, Shi J, Chen O, Li J, Sun X (2016) Hyperbaric oxygen preconditioning ameliorates hypoxia-ischemia brain damage by activating Nrf2 expression in vivo and in vitro. Free Radic Res 50:454–466CrossRefGoogle Scholar
  17. Zhang Y, Sun S, Chen J, Ren P, Hu Y, Cao Z, Sun H, Ding Y (2014) Oxymatrine induces mitochondria dependent apoptosis in human osteosarcoma MNNG/HOS cells through inhibition of PI3K/Akt pathway. Tumour Biol 35:1619–1625CrossRefGoogle Scholar
  18. Zhao P, Zhou R, Li HN, Yao WX, Qiao HQ, Wang SJ, Niu Y, Sun T, Li YX, Yu JQ (2015) Oxymatrine attenuated hypoxic-ischemic brain damage in neonatal rats via improving antioxidant enzyme activities and inhibiting cell death. Neurochem Int 89:17–27CrossRefGoogle Scholar
  19. Zhao SM, Gao HL, Wang YL, Xu Q, Guo CY (2017) Attenuation of high glucose-induced rat cardiomyocyte apoptosis by Exendin-4 via intervention of HO-1/Nrf-2 and the PI3K/AKT signaling pathway. Chin J Phys 60:89–96CrossRefGoogle Scholar
  20. Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, Ruan Y, Xu A (2016) The neuroprotection of Liraglutide against Ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci Rep 6:26859CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of General medicine, Yangpu HospitalTongji University School of MedicineShanghaiPeople’s Republic of China
  2. 2.Department of Neruology, Xuzhou First People’s HospitalThe Municipal Hospital Affiliated to Xuzhou Medical UniversityXuzhouPeople’s Republic of China
  3. 3.Department of Internal MedicineSoochow University Affiliated Children’s HospitalSuzhouPeople’s Republic of China

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