Abstract
Stroke is a leading cause of disability with high morbidity and mortality worldwide. Of all strokes, 87% are ischemic. The only approved treatments for acute ischemic stroke are intravenous thrombolysis with alteplase within 4.5 h and thrombectomy within 8 h after symptom onset, which can be applied to just a few patients. During the past decades, ischemic preconditioning has been widely studied to confirm its neuroprotection against subsequent ischemia/reperfusion injury in the brain, including preconditioning in situ or in a remote organ (such as a limb) before onset of brain ischemia, the latter of which is termed as remote ischemic preconditioning. Because acute stroke is unpredicted, ischemic preconditioning is actually not suitable for clinical application. So remote ischemic conditioning performed during or after the ischemic duration of the brain was then designed to study its neuroprotection alone or in combination with alteplase in animals and patients, which is named as remote ischemic perconditioning or remote ischemic postconditioning. As expected, animal experiments and clinical trials both showed exciting results, indicating that an evolution in the treatment for acute ischemic stroke may not be far away. However, some problems or disputes still exist. This review summarizes the research progress and unresolved issues of remote ischemic conditioning (pre-, per-, and post-conditioning) in treating acute ischemic stroke, with the hope of advancing our understanding of this promising neuroprotective strategy for ischemic stroke in the near future.
Conflict of interest statement: The authors declare no conflict of interest.
References
Abu-Amara, M., Yang, S.Y., Quaglia, A., Rowley, P., de Mel, A., Tapuria, N., Seifalian, A., Davidson, B., and Fuller, B. (2011). Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury. Clin. Sci. (Lond.) 121, 257–266.10.1042/CS20100598Search in Google Scholar
Ates, E., Genc, E., Erkasap, N., Erkasap, S., Akman, S., Firat, P., Emre, S., and Kiper, H. (2002). Renal protection by brief liver ischemia in rats. Transplantation 74, 1247–1251.10.1097/00007890-200211150-00009Search in Google Scholar
Connolly, M., Bilgin-Freiert, A., Ellingson, B., Dusick, J.R., Liebeskind, D., Saver, J., and Gonzalez, N.R. (2013). Peripheral vascular disease as remote ischemic preconditioning, for acute stroke. Clin. Neurol. Neurosurg. 115, 2124–2129.10.1016/j.clineuro.2013.07.038Search in Google Scholar
Dave, K.R., Saul, I., Prado, R., Busto, R., and Perez-Pinzon, M.A. (2006). Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci. Lett. 404, 170–175.10.1016/j.neulet.2006.05.037Search in Google Scholar
Dezfulian, C., Garrett, M., and Gonzalez, N.R. (2013). Clinical application of preconditioning and postconditioning to achieve neuroprotection. Transl. Stroke Res. 4, 19–24.10.1007/s12975-012-0224-3Search in Google Scholar
Dirnagl, U., Becker, K., and Meisel, A. (2009). Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 8, 398–412.10.1016/S1474-4422(09)70054-7Search in Google Scholar
Fan, J., Zhang, Z., Chao, X., Gu, J., Cai, W., Zhou, W., Yin, G., and Li, Q. (2014). Ischemic preconditioning enhances autophagy but suppresses autophagy cell death in rat spinal neurons following ischemia-reperfusion. Brain Res. 1562, 76–86.10.1016/j.brainres.2014.03.019Search in Google Scholar
Feigin, V.L., Forouzanfar, M.H., Krishnamurthi, R., Mensah, G.A., Connor, M., Bennett, D.A., Moran, A.E., Sacco, R.L., Anderson, L., Truelsen, T., et al. (2014). Global and regional burden of stroke during 1990–2010: findings from the Global Burde of Disease Study 2010. Lancet 383, 245–254.10.1016/S0140-6736(13)61953-4Search in Google Scholar
Gateau-Roesch, O., Argaud, L., and Ovize, M. (2006). Mitochondrial permeability transition pore and postconditioning. Cardiovasc. Res. 70, 264–273.10.1016/j.cardiores.2006.02.024Search in Google Scholar PubMed
Ginsberg, M.D. (2009). Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke 40, S111–S114.10.1161/STROKEAHA.108.528877Search in Google Scholar PubMed PubMed Central
Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., Larrue, V., Lees, K.R., Medeghri, Z., Machnig, T., et al. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 359, 1317–1329.10.1056/NEJMoa0804656Search in Google Scholar PubMed
Hahn, C.D., Manlhiot, C., Schmidt, M.R., Nielsen, T.T., and Redington, A.N. (2011). Remote ischemic per-conditioning: a novel therapy for acute stroke? Stroke 42, 2960–2962.10.1161/STROKEAHA.111.622340Search in Google Scholar PubMed
Hausenloy, D.J. and Yellon, D.M. (2008). Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc. Res. 79, 377–386.10.1093/cvr/cvn114Search in Google Scholar PubMed
Henninger, N. and Fisher, M. (2007). Stimulating circle of wills nerve fibers preserves the diffusion-perfusion mismatch in experimental stroke. Stroke 38, 2779–2786.10.1161/STROKEAHA.107.485581Search in Google Scholar PubMed
Heusch, G., Musiolik, J., Kottenberg, E., Peters, J., Jakob, H., and Thielmann, M. (2012). STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ. Res. 110, 111–115.10.1161/CIRCRESAHA.111.259556Search in Google Scholar PubMed
Hess, D.C., Hoda, M.N., and Bhatia, K. (2013). Remote limb perconditioning and postconditioning. Will it translate into a promising treatment for acute stroke? Stroke 44, 1191–1197.10.1161/STROKEAHA.112.678482Search in Google Scholar PubMed
Hoda, M.N., Siddiqui, S., Herberg, S., Periyasamy-Thandavan, S., Bhatia, K., Hafez, S.S., Johnson MH, Hill, W.D., Ergul, A., Fagan, S.C., et al. (2012). Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke. Stroke 43, 2794–2799.10.1161/STROKEAHA.112.660373Search in Google Scholar PubMed PubMed Central
Hoda, M.N., Bhatia,.K, Hafez, S.S., Johnson, M.H., Siddiqui, S., Ergul, A., Zaidi, S.K., Fagan, S.C., and Hess, D.C. (2014). Remote ischemic perconditioning is effective after embolic stroke in ovariectomized female mice. Transl. Stroke Res. 5, 484–490.10.1007/s12975-013-0318-6Search in Google Scholar PubMed PubMed Central
Hougaard, K.D., Hjort, N., Zeidler, D., Sørensen, L., Nørgaard, A., Hansen, T.M., von Weitzel-Mudersbach, P., Simonsen, C.Z., Damgaard, D., Gottrup, H., et al. (2014). Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial. Stroke 45, 159–167.10.1161/STROKEAHA.113.001346Search in Google Scholar PubMed
Hu, S., Dong, H., Zhang, H., Wang, S., Hou, L., Chen, S., Zhang, J., and Xiong, L. (2012). Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats. Brain Res. 1459, 81–90.10.1016/j.brainres.2012.04.017Search in Google Scholar PubMed
Jensen, H.A., Loukogeorgakis, S., Yannopoulos, F., Rimpiläinen, E., Petzold, A., Tuominen, H., Lepola, P., Macallister, R.J., Deanfield, J.E., Mäkelä, T., et al. (2011). Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. Circulation 123, 714–721.10.1161/CIRCULATIONAHA.110.986497Search in Google Scholar PubMed
Jovin, T.G., Chamorro, A., Cobo, E., de Miquel, M.A., Molina, C.A., Rovira, A., Román, L.S., Serena, J., Abilleira, S., Ribó, M., et al. (2015). Thrombectomy within 8 hours after symptom onset in ischemic stroke. N. Engl. J. Med. 372, 2296–2306.10.1056/NEJMoa1503780Search in Google Scholar PubMed
Kanoria, S.R., Jalan, R., Seifalian, A.M., Williams, R., and Davidson, B.R. (2007). Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury. Transplantation 84, 445–458.10.1097/01.tp.0000228235.55419.e8Search in Google Scholar PubMed
Kerendi, F., Kin, H., Halkos, M.E., Jiang, R., Zatta, A.J., Zhao, Z.Q., Guyton, R.A., and Vinten-Johansen, J. (2005). Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res. Cardiol. 100, 404–412.10.1007/s00395-005-0539-2Search in Google Scholar PubMed
Kim, Y.H., Yoon, D.W., Kim, J.H., Lee, J.H., and Lim, C.H. (2014). Effect of remote ischemic post-conditioning on systemic inflammatory response and survival rate in lipopolysaccharide-induced systemic inflammation model. J. Inflamm. (Lond.) 11, 16.10.1186/1476-9255-11-16Search in Google Scholar PubMed PubMed Central
Koch, S., Katsnelson, M., Dong, C., and Perez-Pinzon, M. (2011). Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke 42, 1387–1391.10.1161/STROKEAHA.110.605840Search in Google Scholar PubMed PubMed Central
Konstantinov, I.E., Arab, S., Kharbanda, R.K., Li, J., Cheung, M.M., Cherepanov, V., Downey, G.P., Liu, P.P., Cukerman, E., Coles, J.G., et al. (2004). The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol. Genomics 19, 143–150.10.1152/physiolgenomics.00046.2004Search in Google Scholar PubMed
Konstantinov, I.E., Arab, S., Li, J., Coles, J.G., Boscarino, C., Mori, A., Cukerman, E., Dawood, F., Cheung, M,M., Shimizu, M., et al. (2005). The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J. Thorac. Cardiovasc. Surg. 130, 1326–1332.10.1016/j.jtcvs.2005.03.050Search in Google Scholar PubMed
Li, S., Hu, X., Zhang, M., Zhou, F., Lin, N., Xia, Q., Zhou, Y., Qi, W., Zong, Y., Yang, H., et al. (2015). Remote ischemic post-conditioning improves neurological function by AQP4 down-regulation in astrocytes. Behav. Brain Res. 289, 1–8.10.1016/j.bbr.2015.04.024Search in Google Scholar PubMed
Lim, S.Y. and Hausenloy, D.J. (2012). Remote ischemic conditioning: from bench to bedside. Front. Physiol. 3, 27.10.3389/fphys.2012.00027Search in Google Scholar PubMed PubMed Central
Lim, S.Y., Yellon, D.M., and Hausenloy, D.J. (2010). The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res. Cardiol. 105, 651–655.10.1007/s00395-010-0099-ySearch in Google Scholar PubMed
Liu, M., Liang, Y., Chigurupati, S., Lathia, J.D., Pletnikov, M., Sun, Z., Crow, M., Ross, C.A., Mattson, M.P., and Rabb, H. (2008). Acute kidney injury leads to inflammation and functional changes in the brain. J. Am. Soc. Nephrol. 19, 1360–1370.10.1681/ASN.2007080901Search in Google Scholar PubMed PubMed Central
Liu, X., Sha, O., and Cho, E.Y. (2013). Remote ischemic postconditioning promotes the survival of retinal ganglion cells after optic nerve injury. J. Mol. Neurosci. 51, 639–646.10.1007/s12031-013-0036-2Search in Google Scholar PubMed
Liu, Z.J., Chen, C., Li, X.R., Ran, Y.Y., Xu, T., Zhang, Y., Geng, X.K., Zhang, Y., Du, H.S., Leak, R.K., et al. (2015). Remote ischemic preconditioning-mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci. Ther. doi: 10.1111/cns.12448.10.1111/cns.12448Search in Google Scholar PubMed PubMed Central
Loukogeorgakis, S.P., Panagiotidou, A.T., Broadhead, M.W., Donald, A., Deanfield, J.E., and MacAllister, R.J. (2005). Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system. J. Am. Coll. Cardiol. 46, 450–456.10.1016/j.jacc.2005.04.044Search in Google Scholar PubMed
Malhotra, S., Naggar, I., Stewart, M., and Rosenbaum, D.M. (2011). Neurogenic pathway mediated remote preconditioning protects the brain from transient focal ischemic injury. Brain Res. 1386, 184–190.10.1016/j.brainres.2011.02.032Search in Google Scholar PubMed
Mastitskaya, S., Marina, N., Gourine, A., Gilbey, M.P., Spyer, K.M., Teschemacher, A.G., Kasparov, S., Trapp, S., Ackland, G.L., and Gourine, A.V. (2012). Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal preganglionic neurons. Cardiovasc. Res. 95, 487–494.10.1093/cvr/cvs212Search in Google Scholar PubMed PubMed Central
Meng, R., Asmaro, K., Meng, L., Liu, Y. Ma, C., Xi, C., Li, G., Ren, C., Luo, Y., Ling, F., et al. (2012). Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 79, 1853–1861.10.1212/WNL.0b013e318271f76aSearch in Google Scholar PubMed
Mozaffarian, D., Benjamin, E.J., Go, A.S., Arnett, D.K., Blaha, M.J., Cushman, M., de Ferranti, S., Després, J.P., Fullerton, H.J., Howard, V.J., et al. (2015). Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 131, e29–322.10.1161/CIR.0000000000000152Search in Google Scholar PubMed
Oosterlinck, W., Dresselaers, T., Geldhof, V., Nevelsteen, I., Janssens, S., Himmelreich, U., and Herijgers, P. (2013). Diabetes mellitus and the metabolic syndrome do not abolish, but might reduce, the cardioprotective effect of ischemic postconditioning. J. Thorac. Cardiovasc. Surg. 145, 1595–1602.10.1016/j.jtcvs.2013.02.016Search in Google Scholar PubMed
Peng, B., Guo, Q.L., He, Z.J., Ye, Z., Yuan, Y.J., Wang, N., and Zhou, J. (2012). Remote ischemic postconditioning protects the brain from global cerebral ischemia/reperfusion injury by up-regulating endothelial nitric oxide synthase through the PI3K/Akt pathway. Brain Res. 1445, 92–102.10.1016/j.brainres.2012.01.033Search in Google Scholar PubMed
Pignataro, G., Esposito, E., Sirabella, R., Vinciguerra, A., Cuomo, O., Di, Renzo, G., and Annunziato, L. (2013). nNOS and p-ERK involvement in the neuroprotection exerted by remote postconditioning in rats subjected to transient middle cerebral artery occlusion. Neurobiol. Dis. 54, 105–114.10.1016/j.nbd.2013.02.008Search in Google Scholar PubMed
Przyklenk, K., Bauer, B., Ovize, M., Kloner, R.A., and Whittaker, P. (1993). Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87, 893–899.10.1161/01.CIR.87.3.893Search in Google Scholar PubMed
Qi, Z., Dong, W., Shi, W., Wang, R., Zhang, C., Zhao, Y., Ji, X., Liu, K.J., and Luo, Y. (2015). Bcl-2 phosphorylation triggers autophagy switch and reduces mitochondrial damage in limb remote ischemic conditioned rats after ischemic stroke. Transl. Stroke Res. 6, 198–206.10.1007/s12975-015-0393-ySearch in Google Scholar PubMed
Redington, K.L., Disenhouse, T., Strantzas, S.C., Gladstone, R., Wei, C., Tropak, M.B., Dai, X., Manlhiot, C., Li, J., and Redington, A.N. (2012). Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res. Cardiol. 107, 241.10.1007/s00395-011-0241-5Search in Google Scholar PubMed
Rehni, A.K., Shri, R., and Singh, M. (2007). Remote ischaemic preconditioning and prevention of cerebral injury. Indian J. Exp. Biol. 45, 247–252.Search in Google Scholar
Ren, C., Gao, X., Steinberg, G.K., and Zhao, H. (2008). Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience 151, 1099–1103.10.1016/j.neuroscience.2007.11.056Search in Google Scholar PubMed PubMed Central
Ren, C., Yan, Z., Wei, D., Gao, X., Chen, X., and Zhao, H. (2009). Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res. 1288, 88–94.10.1016/j.brainres.2009.07.029Search in Google Scholar PubMed PubMed Central
Ren, C., Gao, M., Dornbos, D. 3rd, Ding, Y., Zeng, X., Luo, Y., and Ji, X. (2011). Remote ischemic post-conditioning reduced brain damage in experimental ischemia/reperfusion injury. Neurol. Res. 33, 514–519.10.1179/016164111X13007856084241Search in Google Scholar PubMed
Ren, C., Wang, P., Wang, B., Li, N., Li, W., Zhang, C., Jin, K., and Ji, X. (2015). Limb remote ischemic per-conditioning in combination with post-conditioning reduces brain damage and promotes neuroglobin expression in the rat brain after ischemic stroke. Restor. Neurol. Neurosci. 33, 369–379.10.3233/RNN-140413Search in Google Scholar PubMed PubMed Central
Saxena, P., Newman, M.A., Shehatha, J.S., Redington, A.N., and Konstantinov, I.E. (2010). Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical application. J. Card. Surg. 25, 127–134.10.1111/j.1540-8191.2009.00820.xSearch in Google Scholar PubMed
Schmidt, M.R., Smerup, M., Konstantinov, I.E., Shimizu, M., Li, J., Cheung, M., White, P.A., Kristiansen, S.B., Sorensen, K., Dzavik, V., et al. (2007). Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am. J. Physiol. Heart Circ. Physiol. 292, H1883–H1890.10.1152/ajpheart.00617.2006Search in Google Scholar PubMed
Shimizu, M., Tropak, M., Diaz, R.J., Suto, F., Surendra, H., Kuzmin, E., Li J, Gross, G., Wilson, G.J., Callahan, J., et al. (2009). Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin. Sci. (Lond.) 117, 191–200.10.1042/CS20080523Search in Google Scholar PubMed
Shimizu, M., Saxena, P., Konstantinnov, I.E., Cherepanov, V., Cheung, M.M., Wearden, P., Zhangdong H, Schmidt, M., Downey, G.P., and Redington, A.N. (2010). Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J. Surg. Res. 158, 155–161.10.1016/j.jss.2008.08.010Search in Google Scholar PubMed
Silacev, D.N., Isaev, N.K., Pevzner, I.B., Zorova, L.D., Stelmashook, E.V., Novikova, S.V., Plotnikov, E.Y., Skulachev, V.P., and Zoro,v D.B. (2012). The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk. PLoS One 7, e51553.10.1371/journal.pone.0051553Search in Google Scholar PubMed PubMed Central
Singh, D. and Chopra, K. (2004). Evidence of the role of angiotensin AT (1) receptors in remote renal preconditioning of myocardium. Methods Find. Exp. Clin. Pharmacol. 26, 117–122.10.1358/mf.2004.26.2.800064Search in Google Scholar PubMed
Steensrud, T., Li, J., Dai, X., Manlhiot, C., Kharbanda, R.K., Tropak, M., and Redington, A. (2010). Pretreatment with the nitric oxide donor SNAP or nerve transaction blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am. J. Physiol. Heart Circ. Physiol. 299, H1598–H1603.10.1152/ajpheart.00396.2010Search in Google Scholar PubMed
Sun, J., Tong, L., Luan, Q., Deng, J., Li, Y., Li, Z., Dong, H., and Xiong, L. (2012a). Protective effect of delayed remote limb ischemic postconditioning: role of mitochondrial K(ATP) channels in a rat model of focal cerebral ischemic reperfusion injury. J. Cereb. Blood Flow Metab. 32, 851–859.10.1038/jcbfm.2011.199Search in Google Scholar PubMed PubMed Central
Sun, Z., Baker, W., Hiraki, T., and Greenberg, J.H. (2012b). The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat. Brain Stimul. 5, 1–10.10.1016/j.brs.2011.01.009Search in Google Scholar PubMed PubMed Central
Szijártó, A., Czigány, Z., Turóczi, Z., and Harsányi, L. (2012). Remote ischemic preconditioning – a simple, low-risk method to decrease ischemic reperfusion injury: models, protocols and mechanistic background. A review. J. Surg. Res. 178, 797–806.10.1016/j.jss.2012.06.067Search in Google Scholar PubMed
Veighey, K. and Macallister, R.J. (2012). Clinical applications of remote ischemic pre-conditioning. Cardiol. Res. Pract. 2012, 620681.10.1155/2012/620681Search in Google Scholar PubMed PubMed Central
Wang, J., Ning, X., Yang, L., Tu, J., Gu, H., Zhan, C., Zhang, W., Su, T.C. (2014). Sex differences in trends of incidence and mortality of first-ever stroke in rural tianjin, China, from 1992 to 2012. Stroke 45, 1626–1631.10.1161/STROKEAHA.113.003899Search in Google Scholar PubMed
Weber, C. (2010). Far from the heart: receptor cross-talk in remote conditioning. Nat. Med. 16, 760–762.10.1038/nm0710-760Search in Google Scholar PubMed
Wegener, S., Gottschalk, B., Jovanovic, V., Knab, R., Fiebach, J.B., Schellinger, P.D., Kucinski, T., Jungehülsing, G.J., Brunecker, P., Müller, B., et al. (2004). Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke 35, 616–621.10.1161/01.STR.0000115767.17923.6ASearch in Google Scholar PubMed
Wei, D., Ren, C., Chen, X., and Zhao, H. (2012). The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS One 7, e30892.10.1371/journal.pone.0030892Search in Google Scholar PubMed PubMed Central
Zeynalove, E., Shah, Z.A., Li, R.C., and Doré, S. (2009). Heme oxygenase 1 is associated with ischemic preconditioning-induced protection against brain ischemia. Neurobiol. Dis. 35, 264–269.10.1016/j.nbd.2009.05.010Search in Google Scholar PubMed PubMed Central
©2016 by De Gruyter
