Abstract
Focal cerebral ischemia is associated with ischemia/reperfusion (I/R) injury. Hispidulin is a flavonoid compound with a variety of pharmacological properties. The neuroprotective effects of hispidulin have not been fully elucidated. Herein, we demonstrated that pretreatment of animals with hispidulin improved the neurological outcomes and decreased the infarct size and brain edema in the cerebral focal I/R model. Mechanistically, we showed in vivo and in vitro that hispidulin exerted a protective effect against I/R injury by inducing the Nrf2 antioxidant pathway through modulation of AMPK/GSK3β signaling. Taken together, our results suggest that hispidulin may be a useful neuroprotective agent against ischemia/reperfusion (I/R) injury.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alexandrova ML, Bochev PG, Markova VI, Bechev BG, Popova MA, Danovska MP, Simeonova VK (2003) Oxidative stress in the chronic phase after stroke. Redox Rep 8(3):169–176. https://doi.org/10.1179/135100003225001548
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346(8):557–563. https://doi.org/10.1056/NEJMoa003289
Bourdillat B, Delautier D, Labat C, Benveniste J, Potier P, Brink C (1988) Hispidulin, a natural flavone, inhibits human platelet aggregation by increasing cAMP levels. Eur J Pharmacol 147(1):1–6
Bugarski Ignjatovic V, Semnic M, Gebauer Bukurov K, Kozic D (2015) Cognitive impairment and functional ability in the acute phase of ischemic stroke. Eur Rev Med Pharmacol Sci 19(17):3251–3256
Byun SJ, Son Y, Pae HO (2014) Cytoprotective effect of beta-lapachone by inducing heme oxygenase-1 expression and AMP-activated protein kinase activation in human endothelial cells. Eur Rev Med Pharmacol Sci 18(7):949–958
Chen Y, Li CH, Wang YX, Zhang CH, Dong Z, Zhang FF, Wang JH, Zhang PL (2015) Safety and effectiveness of intravenous thrombolysis with recombinant tissue plasminogen activator in eighty years and older acute ischemic stroke patients. Eur Rev Med Pharmacol Sci 19(10):1852–1858
Culmsee C, Monnig J, Kemp BE, Mattson MP (2001) AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 17(1):45–58. https://doi.org/10.1385/JMN:17:1:45
Duan J, Yin Y, Cui J, Yan J, Zhu Y, Guan Y, Wei G, Weng Y, Wu X, Guo C, Wang Y, Xi M, Wen A (2016) Chikusetsu saponin IVa ameliorates cerebral ischemia reperfusion injury in diabetic mice via adiponectin-mediated AMPK/GSK-3beta pathway in vivo and in vitro. Mol Neurobiol 53(1):728–743. https://doi.org/10.1007/s12035-014-9033-x
Gao H, Wang H, Peng J (2014) Hispidulin induces apoptosis through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway in HepG2 cancer cells. Cell Biochem Biophys 69(1):27–34. https://doi.org/10.1007/s12013-013-9762-x
Gao H, Xie J, Peng J, Han Y, Jiang Q, Han M, Wang C (2015) Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1alpha. Exp Cell Res 332(2):236–246. https://doi.org/10.1016/j.yexcr.2014.11.021
Gao MQ, Gao H, Han M, Liu KL, Peng JJ, Han YT (2017) Hispidulin suppresses tumor growth and metastasis in renal cell carcinoma by modulating ceramide-sphingosine 1-phosphate rheostat. Am J Cancer Res 7(7):1501–1514
Garcia-Gil M, Pesi R, Perna S, Allegrini S, Giannecchini M, Camici M, Tozzi MG (2003) 5’-Aminoimidazole-4-carboxamide riboside induces apoptosis in human neuroblastoma cells. Neuroscience 117(4):811–820
Gursoy-Ozdemir Y, Can A, Dalkara T (2004) Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35(6):1449–1453. https://doi.org/10.1161/01.STR.0000126044.83777.f4
Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785. https://doi.org/10.1038/nrm2249
Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17(7):796–808. https://doi.org/10.1038/nm.2399
Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1:45–49. https://doi.org/10.1016/j.redox.2012.10.001
Kavvadias D, Monschein V, Sand P, Riederer P, Schreier P (2003) Constituents of sage (Salvia officinalis) with in vitro affinity to human brain benzodiazepine receptor. Planta Med 69(2):113–117. https://doi.org/10.1055/s-2003-37712
Kavvadias D, Sand P, Youdim KA, Qaiser MZ, Rice-Evans C, Baur R, Sigel E, Rausch WD, Riederer P, Schreier P (2004) The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood-brain barrier and exhibits anticonvulsive effects. Br J Pharmacol 142(5):811–820. https://doi.org/10.1038/sj.bjp.0705828
Lee SJ, Shin TJ, Kang IS, Ha JH, Lee SC, Kim HJ (2010) AMPK attenuates bupivacaine-induced neurotoxicity. J Dent Res 89(8):797–801. https://doi.org/10.1177/0022034510366823
Levine C, Bayer R (1989) The ethics of screening for early intervention in HIV disease. Am J Public Health 79(12):1661–1667
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(5):595–601
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91
Manwani B, McCullough LD (2013) Function of the master energy regulator adenosine monophosphate-activated protein kinase in stroke. J Neurosci Res 91(8):1018–1029. https://doi.org/10.1002/jnr.23207
Nakatsu Y, Kotake Y, Hino A, Ohta S (2008) Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death. Toxicol Appl Pharmacol 230(3):358–363. https://doi.org/10.1016/j.taap.2008.03.021
Niu X, Chen J, Wang P, Zhou H, Li S, Zhang M (2014) The effects of hispidulin on bupivacaine-induced neurotoxicity: role of AMPK signaling pathway. Cell Biochem Biophys 70(1):241–249. https://doi.org/10.1007/s12013-014-9888-5
Park SY, Jin ML, Ko MJ, Park G, Choi YW (2016) Anti-neuroinflammatory effect of emodin in LPS-stimulated microglia: involvement of AMPK/Nrf2 activation. Neurochem Res 41(11):2981–2992. https://doi.org/10.1007/s11064-016-2018-6
Salazar JD, Wityk RJ, Grega MA, Borowicz LM, Doty JR, Petrofski JA, Baumgartner WA (2001) Stroke after cardiac surgery: short- and long-term outcomes. Ann Thorac Surg 72(4):1195–1201 discussion 1201-1192
Song JS, Kim EK, Choi YW, Oh WK, Kim YM (2016) Hepatocyte-protective effect of nectandrin B, a nutmeg lignan, against oxidative stress: role of Nrf2 activation through ERK phosphorylation and AMPK-dependent inhibition of GSK-3beta. Toxicol Appl Pharmacol 307:138–149. https://doi.org/10.1016/j.taap.2016.08.003
Sudlow CL, Warlow CP (1997) Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 28(3):491–499
Tan RX, Lu H, Wolfender JL, Yu TT, Zheng WF, Yang L, Gafner S, Hostettmann K (1999) Mono- and sesquiterpenes and antifungal constituents from Artemisia species. Planta Med 65(1):64–67
Tian Y, Guo S, Wu X, Ma L, Zhao X (2015) Minocycline alleviates sevoflurane-induced cognitive impairment in aged rats. Cell Mol Neurobiol 35(4):585–594. https://doi.org/10.1007/s10571-014-0154-6
Urakawa S, Hida H, Masuda T, Misumi S, Kim TS, Nishino H (2007) Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats. Neuroscience 144(3):920–933. https://doi.org/10.1016/j.neuroscience.2006.10.038
Venugopal R, Jaiswal AK (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17(24):3145–3156. https://doi.org/10.1038/sj.onc.1202237
Vereczki V, Martin E, Rosenthal RE, Hof PR, Hoffman GE, Fiskum G (2006) Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death. J Cereb Blood Flow Metab 26(6):821–835. https://doi.org/10.1038/sj.jcbfm.9600234
Wang P, Xu TY, Guan YF, Tian WW, Viollet B, Rui YC, Zhai QW, Su DF, Miao CY (2011) Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. Ann Neurol 69(2):360–374. https://doi.org/10.1002/ana.22236
Wang R, Tu J, Zhang Q, Zhang X, Zhu Y, Ma W, Cheng C, Brann DW, Yang F (2013) Genistein attenuates ischemic oxidative damage and behavioral deficits via eNOS/Nrf2/HO-1 signaling. Hippocampus 23(7):634–647. https://doi.org/10.1002/hipo.22126
Wang J, Luo B, Xie Y, Hu HY, Feng L, Li ZN (2014) Evaluation methods on the nutritional status of stroke patients. Eur Rev Med Pharmacol Sci 18(24):3902–3907
Yin Y, Gong FY, Wu XX, Sun Y, Li YH, Chen T, Xu Q (2008) Anti-inflammatory and immunosuppressive effect of flavones isolated from Artemisia vestita. J Ethnopharmacol 120(1):1–6. https://doi.org/10.1016/j.jep.2008.07.029
Young AR, Ali C, Duretete A, Vivien D (2007) Neuroprotection and stroke: time for a compromise. J Neurochem 103(4):1302–1309. https://doi.org/10.1111/j.1471-4159.2007.04866.x
Zhu J, Aja S, Kim EK, Park MJ, Ramamurthy S, Jia J, Hu X, Geng P, Ronnett GV (2012) Physiological oxygen level is critical for modeling neuronal metabolism in vitro. J Neurosci Res 90(2):422–434. https://doi.org/10.1002/jnr.22765
Acknowledgements
The study was supported by Shandong Province Chinese Medicine Science and Technology Development Project (2017-321) and Qingdao medical scientific research guidance program (2016-WJZD024).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The experimental protocol was approved by the Medical Ethics Committee of The Affiliated Qingdao Hiser Hospital of Qingdao University.
Conflict of Interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
ESM 1
(GIF 36 kb)
Rights and permissions
About this article
Cite this article
An, P., Wu, T., Yu, H. et al. Hispidulin Protects Against Focal Cerebral Ischemia Reperfusion Injury in Rats. J Mol Neurosci 65, 203–212 (2018). https://doi.org/10.1007/s12031-018-1086-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-018-1086-2