Abstract
Remote ischemic conditioning (RIC), as an emerging protective method, might be used clinically to prevent ischemia–reperfusion injury (IRI) in ischemic stroke. In this study, we aim to investigate whether RIC performed either during brain ischemia or after reperfusion has a protective effect and further explore the mechanistic basis for the protective effects of RIC against IRI in an aged rat model. We investigated brain IRI in 16–18 months old SD rats. Animals underwent: (i) sham laparotomy, (ii) brain IRI, (iii) brain IRI + RIC during ischemia (IRI + RIperC), or (iv) brain IRI + RIC after reperfusion (IRI + RIpostC). RIC consists of three cycles of 10 min of hind limb ischemia followed by 10 min reperfusion. After 24 h of reperfusion, the infarct size, neurological deficit scores and brain oedema were assessed in all groups. The levels of IL-1β, IL-6, TNF-α were measured by ELISA. The mRNA and protein expressions of TLR4, MyD88, TRAF6 and NF-κB were detected by RT-PCR and western blot. Both RIperC and RIpostC treatment attenuated the IRI-induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores and brain oedema. RIperC and RIpostC also can decrease the concentration of IL-1β, IL-6, TNF-α in IRI. From the results of RT-PCR and western blot, we found that RIC decreased the mRNA and protein expression of TLR4, MyD88, TRAF6 and NF-κB compared to that in the IRI group. The present study suggested that RIC protected aged rats against IRI, and this protective effect might be mediated by inhibiting the TLR-4/MyD88/TRAF-6/NF-κB signaling pathway.
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References
Ahmad A, Crupi R, Campolo M, Genovese T, Esposito E, Cuzzocrea S (2013) Absence of TLR4 reduces neurovascular unit and secondary inflammatory process after traumatic brain injury in mice. PLoS ONE 8:e57208. https://doi.org/10.1371/journal.pone.0057208
An JQ et al (2020) Safety and efficacy of remote ischemic postconditioning after thrombolysis in patients with stroke. Neurology 95:e3355–e3363. https://doi.org/10.1212/WNL.0000000000010884
An Y, Chen Q, Quan N (2011) Interleukin-1 exerts distinct actions on different cell types of the brain in vitro. J Inflamm Res 2011:11–20. https://doi.org/10.2147/JIR.S15357
Arango-Davila CA et al (2015) Soluble or soluble/membrane TNF-alpha inhibitors protect the brain from focal ischemic injury in rats. Int J Neurosci 125:936–940. https://doi.org/10.3109/00207454.2014.980906
Caso JR, Moro MA, Lorenzo P, Lizasoain I, Leza JC (2007) Involvement of IL-1beta in acute stress-induced worsening of cerebral ischaemia in rats Eur Neuropsychopharmacol 17:600–607 doi:https://doi.org/10.1016/j.euroneuro.2007.02.009
Che R et al (2019) rt-PA with remote ischemic postconditioning for acute ischemic stroke. Ann Clin Transl Neurol 6:364–372. https://doi.org/10.1002/acn3.713
Chen G, Thakkar M, Robinson C, Dore S (2018) Limb remote ischemic conditioning: mechanisms. Anesth Potential Expand Ther Options Front Neurol 9:40. https://doi.org/10.3389/fneur.2018.00040
Cheng Z, Li L, Mo X, Zhang L, Xie Y, Guo Q, Wang Y (2014) Non-invasive remote limb ischemic postconditioning protects rats against focal cerebral ischemia by upregulating STAT3 and reducing apoptosis. Int J Mol Med 34:957–966. https://doi.org/10.3892/ijmm.2014.1873
Fusella F, Secli L, Cannata C, Brancaccio M (2020) The one thousand and one chaperones of the NF-kappaB pathway. Cell Mol Life Sci 77:2275–2288. https://doi.org/10.1007/s00018-019-03402-z
Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66:232–245. https://doi.org/10.1016/j.surneu.2005.12.028
Jung GB, Kang SW, Lee GJ, Kim D (2018) Biochemical characterization of the brain hippocampal areas after cerebral ischemia-reperfusion using Raman spectroscopy. Appl Spectrosc 72:1479–1486. https://doi.org/10.1177/0003702818776627
Labus J, Hackel S, Lucka L, Danker K (2014) Interleukin-1beta induces an inflammatory response and the breakdown of the endothelial cell layer in an improved human THBMEC-based in vitro blood-brain barrier model. J Neurosci Methods 228:35–45. https://doi.org/10.1016/j.jneumeth.2014.03.002
Lambertsen KL, Finsen B, Clausen BH (2019) Post-stroke inflammation-target or tool for therapy? Acta Neuropathol 137:693–714. https://doi.org/10.1007/s00401-018-1930-z
Lee KM, Kim JM, Baik EJ, Ryu JH, Lee SH (2015) Isobavachalcone attenuates lipopolysaccharide-induced ICAM-1 expression in brain endothelial cells through blockade of toll-like receptor 4 signaling pathways. Eur J Pharmacol 754:11–18. https://doi.org/10.1016/j.ejphar.2015.02.013
Li J et al (2014) MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res Cardiol 109:423. https://doi.org/10.1007/s00395-014-0423-z
Lin HC, Lee TK, Tsai CC, Lai IR, Lu KS (2012) Ischemic postconditioning protects liver from ischemia-reperfusion injury by modulating mitochondrial permeability transition. Transplantation 93:265–271. https://doi.org/10.1097/TP.0b013e31823ef335
Lin TN, He YY, Wu G, Khan M, Hsu CY (1993) Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24:117–121. https://doi.org/10.1161/01.str.24.1.117
Liu KX, Li YS, Huang WQ, Chen SQ, Wang ZX, Liu JX, Xia Z (2009) Immediate postconditioning during reperfusion attenuates intestinal injury. Intensive Care Med 35:933–942. https://doi.org/10.1007/s00134-009-1428-1
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91. https://doi.org/10.1161/01.str.20.1.84
O’Neill S et al (2015) Heat shock protein 90 inhibition abrogates TLR4-mediated NF-kappaB activity and reduces renal ischemia-reperfusion injury. Sci Rep 5:12958. https://doi.org/10.1038/srep12958
Qi W et al (2016) Remote ischemic postconditioning protects ischemic brain from injury in rats with focal cerebral ischemia/reperfusion associated with suppression of TLR4 and NF-small ka, CyrillicB expression. NeuroReport 27:469–475. https://doi.org/10.1097/WNR.0000000000000553
Rahimifard M et al (2017) Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev 36:11–19. https://doi.org/10.1016/j.arr.2017.02.004
Sun M et al (2015) Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation. Sci Rep 5:11445. https://doi.org/10.1038/srep11445
Vartanian K, Stenzel-Poore M (2010) Toll-like receptor tolerance as a mechanism for neuroprotection. Transl Stroke Res 1:252–260. https://doi.org/10.1007/s12975-010-0033-5
Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, Zhang S (2008) Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke 39:2362–2369. https://doi.org/10.1161/STROKEAHA.107.507939
Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579-588. https://doi.org/10.1152/ajpheart.01064.2002
Zhu L, Ye T, Tang Q, Wang Y, Wu X, Li H, Jiang Y (2016) Exercise preconditioning regulates the toll-like receptor 4/nuclear factor-kappab signaling pathway and reduces cerebral ischemia/reperfusion inflammatory injury: a study in rats. J Stroke Cerebrovasc Dis 25:2770–2779. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.07.033
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This study was supported by a grant from the Qingdao Municipal Science and Technology Bureau, China (no. 14-2-3-14-nsh).
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Communicated by Sreedharan Sajikumar.
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Lv, J., Yan, W., Zhou, J. et al. Per- and post-remote ischemic conditioning attenuates ischemic brain injury via inhibition of the TLR4/MyD88 signaling pathway in aged rats. Exp Brain Res 239, 2561–2567 (2021). https://doi.org/10.1007/s00221-021-06150-4
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DOI: https://doi.org/10.1007/s00221-021-06150-4