- Email: [email protected]
Advance in spinal cord ischemia reperfusion injury: Blood–spinal cord barrier and remote ischemic preconditioning
Life Sciences 154 (2016) 34–38
Contents lists available at ScienceDirect
Life Sciences journal homepage: www.elsevier.com/locate/lifescie
Review article
Advance in spinal cord ischemia reperfusion injury: Blood–spinal cord barrier and remote ischemic preconditioning Qijing Yu a, Jinxiu Huang b, Ji Hu b,⁎, Hongfei Zhu c a b c
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China Department of Anesthesiology, Liyuan Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430077, Hubei, China Department of Anesthesiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei, China
a r t i c l e
i n f o
Article history: Received 21 January 2016 Received in revised form 16 March 2016 Accepted 24 March 2016 Available online 07 April 2016 Keywords: Blood–spinal cord barrier Ischemia reperfusion injury Remote ischemic preconditioning
a b s t r a c t The blood–spinal cord barrier (BSCB) is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier plays a vital role in maintaining the microenvironment stability of the spinal cord. When the spinal cord is subjected to ischemia/reperfusion (I/R) injury, the structure and function of the BSCB is disrupted, further destroying the spinal cord homeostasis and ultimately leading to neurological deficit. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia is followed by reperfusion to tissues/organs to protect the distant target tissues/organs against subsequent lethal ischemic injuries. RIPC is an innovation of the treatment strategies that protect the organ from I/R injury. In this study, we review the morphological structure and function of the BSCB, the injury mechanism of BSCB resulting from spinal cord I/R, and the effect of RIPC on it. © 2016 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . Morphological structure and function of the BSCB . . . . . 2.1. Morphological structure of the BSCB . . . . . . . . 2.2. Function of each component element of BSCB . . . . 3. Injury mechanism of BSCB due to spinal cord I/R . . . . . . 3.1. Disruption of BSCB induced by MMPs. . . . . . . . 3.2. Disruption of BSCB induced by inflammatory reaction 3.3. Disruption of BSCB induced by oxidative stress . . . 3.4. The role of AQP-4. . . . . . . . . . . . . . . . . 4. Protection of RIPC for SCIRI. . . . . . . . . . . . . . . . 5. Problems and prospect . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
34 35 35 35 35 35 35 36 36 36 37 37 37
1. Introduction
Abbreviations: BSCB, Blood–spinal cord barrier; I/R, Ischemia/reperfusion; RIPC, Remote ischemic preconditioning; SCIRI, Spinal cord ischemia reperfusion injury; BBB, Blood–brain barrier; CNS, Central nervous system; TJ, Tight junction; NVU, Neurovascular unit; JAM, Junction adherence molecular; HO-1, Heme oxygenase-1; BDNF, Brain derived neurotrophic factor; MMPs, Matrix metalloproteinases; TLRs, Tolllike receptors; AQPs, Aquaporins. ⁎ Corresponding author. E-mail address: [email protected] (J. Hu).
http://dx.doi.org/10.1016/j.lfs.2016.03.046 0024-3205/© 2016 Elsevier Inc. All rights reserved.
Clinically, thoracoabdominal aortic aneurysm repair surgery can lead to spinal cord ischemia reperfusion injury (SCIRI), whose incidence is reported to range from 1% to 32%. However, a main, devastating, and unpredictable complication after spinal cord injury is paraplegia [1–2]. To date, various intervening measures, including hypothermia, improvement of surgical techniques, and pharmacologic adjuncts, have been used to protect the spinal cord from ischemic injury [3]; nonetheless, complications still cannot be prevented completely. Therefore, a
Q. Yu et al. / Life Sciences 154 (2016) 34–38
more effective strategy should be developed to protect the spinal cord against ischemia reperfusion (I/R) injury. The pathogenesis of SCIRI includes oxygen-free radical-induced lipid peroxidation, intracellular calcium overload, leukocyte activation, inflammatory response, and neuronal apoptosis. In addition, the disruption of the blood–spinal cord barrier (BSCB) is a major pathological change that can exacerbate spinal cord edema, increase leukocyte infiltration, as well as amplify inflammation and oxidative stress. Therefore, BSCB disruption plays a vital role in the evolution of SCIRI and further damage of neurons [4–6]. BSCB is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier strictly regulates the stability of the spinal cord microenvironment. The repairing of the BSCB should be performed as soon as possible after spinal cord injury because the normal function of neurons is based on the homeostasis of the spinal cord. In recent years, changes of the BSCB after spinal cord I/R and improvement of the neurological function through protecting BSCB integrity have drawn extensive attention from researchers. Clarifying the mechanism responsible for BSCB disruption and further using it as a therapeutic target is greatly significant to alleviate SCIRI. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia followed by reperfusion to a tissue/organ protect the distant target tissue/organ against subsequent lethal ischemic injuries, and the most convenient method induced by the upper or lower limb. It has a huge development prospect clinically as it is safe, simple, and easily accepted by doctors and patients. Certain studies have shown that RIPC can protect spinal cord against I/R injury [7–9], but the mechanism is not entirely clear yet. In the rat model of brain I/R injury, a researcher has found that remote ischemic postconditioning can alleviate permeability of the blood–brain barrier (BBB) and brain edema after brain ischemia, which reduces infarct volume and improves the neurological outcome as well [10–11]. Meanwhile, the possibility of RIPC alleviating the permeability of the BSCB in the model of spinal cord injury has not been reported. As both BSCB and BBB belong to the central nervous system (CNS) barrier, they are similar not only in structure but also in function, thus it is very likely that RIPC induces spinal cord ischemia tolerance through keeping BSCB intact. The present study will review the morphological structure and function of the BSCB, injury mechanism of BSCB due to spinal cord I/R, and the effect of RIPC on it.
2. Morphological structure and function of the BSCB 2.1. Morphological structure of the BSCB Similar to BBB, the basal components of BSCB include endothelial cells between spinal cord capillaries and tight junction (TJ) proteins, basal lamina, pericytes, and astrocytic end feet processes [12]. Endothelial cells, pericytes, astrocytes, neurons, and extracellular matrix are collectively known as the neurovascular unit (NVU) [13]. Endothelial cells of spinal cord capillaries, which are characterized by the absence of cell membrane fenestrations unlike those of peripheral circulation, contain a high number of cytosolic mitochondria, lack pinocytic vacuoles, and include a very weak activity of the pinocytosis [14]. TJs between endothelial cells are composed of some specific transmembrane proteins such as claudins (claudin-1, claudin-3, claudin-5, etc.), occludin, and junction adherence molecular (JAM). These transmembrane proteins are linked to cytoskeletal filaments by interactions with accessory proteins (ZO-1, ZO-2, ZO-3, etc.). The basal lamina surrounds capillary endothelial cells and engulfs pericytes. The major components of the basal lamina include collagen, fibronectin, laminin, and proteoglycans [16]. Astrocytes, which are one of the most numerous types of cells in the CNS, projects end feet processes to surround neural synapses, ranvier nodes, and blood vessels [17].
35
2.2. Function of each component element of BSCB Endothelial cells of spinal cord capillaries, as the most important part of BSCB, strictly restrict free transcellular flow of blood-borne molecules, and a high number of cytosolic mitochondria provides high energy for selective active transport and calcium homeostasis. In addition, heme oxygenase-1 (HO-1) and brain derived neurotrophic factor (BDNF) can be expressed and secreted by endothelial cells, which contribute to recovery of the neural function [18–19]. The paracellular diffusion pathway is severely restricted by TJs between individual endothelial cells. Claudin-5, occludin, and ZO-1 are the main proteins of TJs, which are also considered as the sensitive markers no matter when the CNS barrier is normal or damaged. Moreover, ZO proteins can not only act as the scaffold for multiple signal pathways within cells but also involve in the regulating function of TJs [15,20]. Pericytes are small-vessel wall-associated cells that are separated from endothelial cells by the basal lamina. Capillary pericytes and endothelial cells communicate with each other in several ways, including gap junctions and soluble factors. Furthermore, pericytes play a significant regulatory role in endothelial cell proliferation, migration, and differentiation [21]. Astrocytes can be stimulated by neuronal activity and can regulate vascular function, thus further adjusting blood flow to neuronal activity in specific regions [22–23]. In addition, astrocytic end feet processes express a high concentration of water channel aquaporin 4 (AQP-4), which is involved in the volume regulation of CNS [24]. 3. Injury mechanism of BSCB due to spinal cord I/R 3.1. Disruption of BSCB induced by MMPs Matrix metalloproteinases (MMPs) comprise a large family of extracellular zinc endopeptidases that can degrade and remodel basal lamina proteins, tight junction proteins, and many other extracellular matrices [25]. MMPs can be expressed by various cells in the brain, including endothelial cells, microglia, neurons, astrocytes, and infiltrating inflammatory cells during cerebral ischemia [26]. MMPs are secreted as inactive zymogens, and their expression and activation can be strongly promoted by the overproduction of reactive oxygen species and proinflammatory cytokines (TNF-α, IL-1β, etc.) during the I/R process [27]. MMP-9 is the most widely researched among all types of MMPs, and has been demonstrated to play a critical role in regulating BBB during cerebral ischemia. A considerable number of studies have shown that MMP-9 can degrade claudin-5, occludin, and ZO-1 in cultured brain endothelial cells in vitro and in vivo ischemia model. Moreover, knockout mice that lack MMP-9 have shown a significant protective effect on BBB [28–30]. In the SCIRI model, Fang Bo et al. found that the permeability of the BSCB was increased and the expression of MMP-9 was up-regulated in microglia, neuron, and astrocyte. In addition, MMP-9 was also involved in the infiltration and migration of microglia and in the increased production of proinflammatory cytokines and chemokine, which amplified the inflammation and further exacerbated BSCB disruption and neuronal apoptosis [31–32]. Some studies have indicated that dexmedetomidine or sevoflurane preconditioning or intrathecal transplantation of bone marrow stromal cells can down-regulated MMP-9 expression after spinal cord I/R, thus maintaining the integrity of the BSCB and improving the neurological outcome [31–33]. The above-mentioned research results indicate that MMP-9 could destroy the BSCB, and play an important part in the development and progression of inflammatory reaction. Consequently, taking some interventions to inhibit MMP-9 expression will contribute to the stability of the BSCB structure and alleviation of SCIRI. 3.2. Disruption of BSCB induced by inflammatory reaction Inflammatory cytokines are one of the most pivotal factors for BSCB disruption in SCIRI; they lead to the dissociation of ZO-1 from the
36
Q. Yu et al. / Life Sciences 154 (2016) 34–38
cytoskeletal complex and up-regulation expression of MMPs and TNFα, which are frequently associated with BSCB permeability increase. Nevertheless, BSCB disruption in turn exacerbates inflammatory reaction, resulting in an irreversible damage of the spinal cord [4,34]. Recently, Toll-like receptors (TLRs), especially TLR4, have attracted broad attention for their critical role in inflammatory response after spinal cord I/ R. TLR4, which is recognized as a LPS ligand, is a group of membranespanning proteins that regulate innate immune response and is significantly expressed in the microglial membrane [35]. Research has shown that early and sustained microglial activation can be induced in the course of SCIRI, and its membrane-bound receptor TLR4 is also over expressed. Once TLR4 binds to its ligand, NF-κB relocates to the nucleus and regulates the expression of target inflammatory genes IL-1β. The TLR4-microglia-NF-κB/IL-1β pathway as a positive feedback loop in the SCIRI, is capable of exacerbating inflammatory reaction and BSCB dysfunction [6]. Furthermore, researchers have found that TLR4 induces NF-κB activation by interacting with its downstream receptors, namely, MyD88 and TRIF. The early phase of SCIRI in the spinal cord was found to be largely TLR4/MyD88-dependent and the following late phase was found to be mainly reliant on TLR4/TRIF activation, which was amplified by the MyD88 pathway [5]. Subsequently, these researchers discovered that MiR-27a could ameliorate inflammatory damage to BSCB after SCIRI by down-regulating TICAM-2 of the TLR4 signaling pathway and then inhibiting the NF-κB/IL-1β pathway [36]. Both inflammatory reaction and BSCB disruption are significant physiopathologic mechanisms of SCIRI. Inflammatory reaction can break down BSCB, whereas the opening of the BSCB in turn increases infiltrating leukocytes, which form a vicious cycle to amplify inflammatory response and exacerbate spinal cord injury. 3.3. Disruption of BSCB induced by oxidative stress Under physiological conditions, a dynamic balance exists between the oxidation system and antioxidation system in vivo; small amounts of oxygen radicals produced by an organism can be removed by superoxide dismutase, glutathione, and some other antioxidant enzymes. However, overproduction of reactive oxygen species due to massive infiltrating leukocytes upsets the balance during SCIRI. Some studies reported that increased levels of superoxide contribute to BBB endothelial dysfunction [37]. Peroxynitrite, which is formed by the conjugation of superoxide and NO, can cause significant injury to cerebral microvessels through lipid peroxidation, consumption of endogeneous antioxidants, and induction of mitochondrial failure [38], ultimately resulting in BBB dysfunction. Some reports have shown that oxidative stress promotes redistribution and/or down-regulation of critical tight junction proteins such as claudin-5, occludin, ZO-1, and JAM-1 [37,39]. Meanwhile, MMP9 can be activated by NO, reactive oxygen species, and peroxynitrite [40–41], which lead to the degradation of TJs and basal lamina. Subsequently, increased BBB permeability results in the genesis and development of vasogenic brain edema. Therefore, some interventions that reduce reactive oxygen specie production or enhance spinal cord antioxidant ability during spinal cord I/R will help stabilize the BSCB structure and function. Lately, studies have reported that some drugs or compounds can up-regulate ZO-1 and occludin expression by increasing antioxidant HO-1, thus keeping the BSCB integrity and protecting the spinal cord from stress damage [42–44]. In addition, remote limb ischemic postconditioning up-regulates the expression of HO-1 via activating the Nrf2-ARE pathway, and then protects the brain against cerebral I/ R injury [45]. In conclusion, the HO-1 signaling pathway critically stabilizes the BBB/BSCB structure and function in the oxidative stress state. 3.4. The role of AQP-4 The aquaporins (AQPs) are a family of transmembrane proteins that function as “water channels”, which provide water passive transport
across the membrane where they reside. All AQPs are expressed in areas of high water flow where the cell membranes are not sufficient to provide adequate speed. Among them, AQP-4 is the most abundant in the CNS and has the highest expression levels in spinal cord tissue. In the CNS, AQP-4 is expressed mostly by astrocytic end feet around capillaries, and its normal function is to enable fast water influx or efflux, driven by osmotic or hydrostatic pressures. In addition, it is responsible for the evolution of cytotoxic and vasogenic edema [46–47]. Research has shown that the AQP-4 expression is significantly increased in the hippocampal CA1 and cortex after cerebral I/R, and is responsible for cerebral edema [48]. Moreover, a study in adult knockout mice has shown that the deletion of AQP-4 diminishes cytotoxic edema formation and improves neurological outcomes [49]. Remote ischemic postconditioning could also enhance neurological function by AQP4 downregulation in astrocytes [50]. Similarly, AQP-4 is also significant in regulating the water balance of the spinal cord tissue. Some investigators found that the expression of AQP-4 is positive correlated with spinal cord edema [51–52]. Certain pharmacological preconditioning methods can alleviate spinal cord edema by down-regulating AQP4 in the course of spinal cord I/R [53–54]. 4. Protection of RIPC for SCIRI RIPC is a treatment strategy in which alternate cycles of preconditioning ischemia followed by reperfusion are delivered to a remote organ which protects the remote organ against subsequent lethal ischemic injury. RIPC is an innovation among various kinds of strategies that protect the organ from I/R injury. In fundamental experiments, scholars found that the RIPC of the arteries, such as cerebral, mesenteric, intestinal, renal, abdominal aorta, and skeletal muscle, protects myocardium against I/R injury in various animals like rats, mice, and rabbits [55]. However, these approaches may not be directly translated in clinical settings. Clinically, the best utilized way is rendering the forelimb ischemic by applying blood pressure cuff on the upper arm. The advantages of this method are its non-invasiveness, simplicity, convenience, repeatability, and cost-effectiveness features. In addition, the upper limb is more resistant to ischemic insult. This limb RIPC method has been demonstrated in the brain, heart, kidney, liver, intestines, lung, and other organs in many animal I/R models [56]. At present, the most widely used RIPC protocol is inflating the blood pressure cuff tied on the upper arm 20 mm Hg greater than systolic arterial pressure, rendering the forearm ischemia for 5 min, and followed by a 5 min intermittent reperfusion, with this cycle possibly repeated for 3 to 5 consecutive periods [57]. A large amount of clinical evidence has indicated that RIPC can produce a protective effect for many organ surgeries such as coronary bypass surgeries, percutaneous coronary interventions, selective cervical decompressions, kidney transplantations, and abdominal aortic aneurysm surgeries [55]. In the last few years, certain animal experiments have shown that RIPC can protect the spinal cord against I/R injury. In a rabbit experiment, Dong Hailong et al. found that before the rabbits were subjected to spinal cord ischemia by aortic occlusion, RIPC, which was achieved by bilateral femoral artery occlusion (10 min ischemia/10 min reperfusion, two cycles), obviously improved neurological outcomes and relieved spinal cord tissue injury. They also found that in rat models, spinal cord ischemic tolerance was induced by limb RIPC achieved by 3 cycles of right femoral artery and 3 min ischemia/3 min reperfusion [8–9]. In addition, research has shown that in rats, RIPC can reduce spinal cord damage in the course of spinal cord I/R [58] via occluding the right femoral artery with a tourniquet for 3 cycles of 10 min ischemia/ 10 min reperfusion. Recently, an experimental study on the pocrine model indicated that RIPC achieved by the transient ischemia of left hind limb protected the spinal cord against ischemic insult [7]. Furthermore, in a clinical experiment, the protection of RIPC for spinal cords has also been confirmed. Xiong Lize et al. facilitated an experiment in which patients undergoing elective decompression surgery were subjected to
Q. Yu et al. / Life Sciences 154 (2016) 34–38
limb RIPC by performing 3 cycles of 5 min ischemia/5 min reperfusion of the upper limb, and they discovered that the early recovery of the patients' neurological functions after surgery was improved [59]. However, clinical evidence of RIPC protection for SCIRI is still deficient, and large-scale samples, multicenter, randomized controlled trials, and the best RIPC protocol are still needed to be studied further in the future. Although many studies have verified the protection of RIPC for SCIRI, the potential mechanism remains unclear. The humoral pathway may be involved in the RIPC protective effect. As previous studies have reported, the heat shock protein, endocannabinoid, and antioxidant pathway are triggered by reactive oxygen species involved in RIPC protection for spinal cord ischemia injury [8–9,58]. The role of BSCB in SCIRI has been the focus of attention in recent years. Ischemic preconditioning was reported to possibly alleviate BSCB disruption induced by SCIRI, thus improving neurological outcomes [4,10–11]. Fang Bo et al. found that in rabbit models, the ischemic preconditioning group, which was achieved by abdominal aorta occlusion (5 min ischemia/5 min reperfusion, 3 cycles), had better pathological outcomes in the spinal cord ischemic segments as compared with the model group. In the ischemic preconditioning group, the degree of spinal cord edema was lighter, the BSCB permeability was lower, the expression of ZO-1 was increased, and MMP-9 and TNF-α were reduced [4]. In the rat model, Changhong Ren et al. discovered that RIPC can alleviate the permeability of BBB and brain edema, thus reducing infarct volume after brain ischemia [11]. Lately, Shuai Li et al. revealed that the remote ischemic postconditioning could relieve the permeability of BBB and brain edema and down-regulate the AQP4 expression in astrocytes as well; thus speculating that the remote ischemia post-conditioning improved the neurological function by AQP4 down-regulation [10]. Although both BSCB and BBB belong to the CNS barrier, they are similar not only in structure but also in function. The possibility of RIPC protecting the spinal cord against ischemia insult by keeping the integrity of BSCB still needs to be further confirmed. 5. Problems and prospect Although some factors contributing to BSCB disruption after spinal cord I/R have been investigated extensively, whether there are other factors involved and how are these factors cross-talking are largely unknown. For instance, as mentioned above, MMPs, inflammatory reaction, oxidative stress, and AQP4 may induce BSCB disruption after spinal cord I/R. Whether there are other factors? Are these factors interrelating and influencing each other? Which one plays the most dominant role? These problems need to be further investigated. RIPC is an innovative strategy to protect organs from I/R injury and has aroused extensive attention from global scholars. However, the underlying mechanism remains to be elucidated. The RIPC protocol is not uniform, neither in various animal models, nor in clinical trials. A proper RIPC protocol for clinic has not been carried out. On the other hand, clinical evidence of RIPC protection for SCIRI is still scarce. Studies with large-scale samples, multicenter, and randomized controlled trials are needed in the future. Previous studies have demonstrated that RIPC can alleviate the permeability of BBB and brain edema, however, whether this mechanism happened on BSCB needs to be further confirmed. What kinds of signals are produced in the remote organs after RIPC? How these signals are delivered to BBB/BSCB? Whether via a neural pathway or humoral pathway? These questions are eager to be answered. HO-1 pathway has been reported to protect cerebral ischemia post-remote limb ischemia conditioning. Investigating if this pathway is also suitable for spinal protection post-RIPC is greatly significant to reveal the mechanism of RIPC. Acknowledgments This work was supported by grants from the Hubei Province Health and Family Planning Scientific Research Project (No. WJ2015MB023 to
37
Qijing Yu) and Science and Technology Department of Hubei Province (project of scientific research condition and resource research development) fund (No. 2015BCE099 to Hongfei Zhu).
References [1] N. Panthee, M. Ono, Spinal cord injury following thoracic and thoracoabdominal aortic repairs, Asian Cardiovasc. Thorac. Ann. 23 (2) (2015) 235–246. [2] D.C. Etz, M. Luehr, K.V. Aspern, M. Misfeld, S. Gudehus, J. Ender, T. Koelbel, E.S. Debus, F.W. Mohr, Spinal cord ischemia in open and endovascular thoracoabdominal aortic aneurysm repair: new concepts, J. Cardiovasc. Surg. 55 (2) (2014) 159–168. [3] M.M. Wynn, C.W. Acher, A modern theory of spinal cord ischemia injury in thoracoabdominal aortic surgery and its implications for prevention of paralysis, J. Cardiothorac. Vasc. Anesth. 28 (4) (2014) 1088–1099. [4] B. Fang, X.M. Li, X.J. Sun, N.R. Bao, X.Y. Ren, H.W. Lv, H. Ma, Ischemic preconditioning protects against spinal cord ischemia-reperfusion injury in rabbits by attenuating blood spinal cord barrier disruption, Int. J. Mol. Sci. 14 (5) (2013) 10343–10354. [5] X.Q. Li, H.W. Lv, W.F. Tan, B. Fang, H. Wang, H. Ma, Role of the TLR4 pathway in blood–spinal cord barrier dysfunction during the bimodal stage after ischemia/reperfusion injury in rats, J. Neuroinflammation 11 (2014) 62. [6] X.Q. Li, J. Wang, B. Fang, W.F. Tan, H. Ma, Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats, Mol. Brain 7 (2014) 28. [7] H. Haapanen, J. Herajärvi, O. Arvola, T. Anttila, T. Starck, M. Kallio, V. Anttila, H. Tuominen, K. Kiviluoma, T. Juvonen, Remote ischemic preconditioning protects the spinal cord against ischemic insult: an experimental study in a pocrin model, J. Thorac. Cardiovasc. Surg. (2015), http://dx.doi.org/10.1016/j.jtcvs.2015.07.036. [8] H.L. Dong, Y. Zhang, B.X. Su, Z.H. Zhu, Q.H. Gu, H.F. Sang, L. Xiong, Limb remote ischemic preconditioning protects the spinal cord from ischemia-reperfusion injury: a newly identified nonneuronal but reactive oxygrn species-dependent pathway, Anesthesiology 112 (4) (2010) 881–891. [9] B. Su, H. Dong, R. Ma, X. Zhang, Q. Ding, L. Xiong, Cannabioid 1 receptor mmediation of spinal cord ischemic tolerance induced by limb remote ischemia preconditioning in rats, J. Thorac. Cardiovasc. Surg. 138 (6) (2009) 1409–1416. [10] S. Li, X. Hu, M. Zhang, F. Zhou, N. Lin, Q. Xia, Y. Zhou, W. Qi, Y. Zong, H. Yang, T. Wang, Remote ischemic post-conditioning improves neurological function by AQP4 downregulation in astrocytes, Behav. Brain Res. 289 (2015) 1–8. [11] C. Ren, M. Gao, D. Dornbos III, Y. Ding, X. Zeng, Y. Luo, X. Ji, Remote ischemic postconditioning reduced brain damage in experimental ischemia/reperfusion injury, Neurol. Res. 33 (5) (2011) 514–519. [12] P. Ballabh, A. Braun, M. Nedergaard, The blood–brain barrier: an overview: structure, regulation, and clinical implications, Neurobiol. Dis. 16 (1) (2004) 1–13. [13] R. Daneman, The blood–brain barrier in health and disease, Ann. Neurol. 72 (5) (2012) 648–672. [14] J. Bernacki, A. Dobrowolska, K. Nierwiñska, A. Maecki, Physiology and pharmacological role of the blood–brain barrier, Pharmacol. Rep. 60 (2008) 600–622. [15] H.C. Bauer, I.A. Krizbai, H. Bauer, A. Traweger, “You Shall Not Pass”—tight junctions of the blood brain barrier, Front. Neurosci. 8 (2014) 392. [16] F.L. Cardoso, O. Brites, M.A. Brito, Looking at the blood–brain barrier: molecular anatomy and possible investigation approaches, Brain Res. Rev. 64 (2) (2010) 328–363. [17] Y. Zhang, B.A. Barres, Astrocytes heterogeneity: an underappreciated topic in neurobiology, Curr. Opin. Neurobiol. 20 (5) (2010) 588–594. [18] N. Wang, G. Wang, J. Hao, J. Ma, Y. Wang, X. Jiang, H. Jiang, Cur ameliorates hydrogen peroxide-induced epithelial barrier disruption by upregulating heme oxygenase-1 expression in human intestinal epithelial cells, Dig. Dis. Sci. 57 (7) (2012) 1792–1801. [19] Y. Béjot, A. Prigent-Tessier, C. Cachia, M. Giroud, C. Mossiat, N. Bertrand, P. Garnier, C. Marie, Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats, Neurochem. Int. 58 (1) (2011) 102–111. [20] E. Candelario-Jalil, Y. Yang, G.A. Rosenberg, Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia, Neuroscience 158 (3) (2009) 983–994. [21] V. Bartanusz, D. Jezova, B. Alajajian, M. Diqicaylioqlu, The blood–spinal cord barrier: morphology and clinical implications, Ann. Neurol. 70 (2) (2011) 194–206. [22] D. Attwell, A.M. Buchan, S. Charpak, M. Lauritzen, B.A. Macvicar, E.A. Newman, Glial and neuronal control of brain blood flow, Nature 468 (2010) 232–243. [23] G.C. Petzold, V.N. Murthy, Role of astrocytes in neurovascular coupling, Neuron 71 (5) (2011) 782–797. [24] N.N. Haj-Yasein, G.F. Vindedal, M. Eilert-Olsen, G.A. Gundersen, Ø. Skare, P. Laake, A. Kiungland, A.E. Thorén, J.M. Burkhardt, O.P. Ottersen, E.A. Nagelhus, Glialconditional deletion of aquaporin-4 (AQP-4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet, Proc. Natl. Acad. Sci. U. S. A. 108 (43) (2011) 17815–17820. [25] Rong Jin, Guojun Yang, Guohong Li, Molecular insights and therapeutic targets for blood–brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator, Neurobiol. Dis. 38 (3) (2010) 376–385. [26] R. Jin, G. Yang, G. Li, Inflammatory mechanisms in ischemic stroke: role of inflammatory cells, J. Leukoc. Biol. 87 (5) (2010) 779–789. [27] E. Dejonckheere, R.E. Vandenbrouche, C. Libert, Matrix metalloproteinases as drug targets in ischemia/reperfusion injury, Drug Discov. Today 16 (17–18) (2011) 762–778.
38
Q. Yu et al. / Life Sciences 154 (2016) 34–38
[28] F. Chen, N. Ohashi, W. Li, C. Eckman, J.H. Nguyen, Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure, Hepatology 50 (6) (2009) 1914–1923. [29] A.T. Bauer, H.F. Bürgers, T. Rabie, H.H. Marti, Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement, J. Cereb. Blood Flow Metab. 30 (4) (2010) 837–848. [30] M. Asahi, X. Wang, T. Mori, T. Sumii, J.C. Jung, M.A. Moskowitz, M.E. Fini, E.H. Lo, Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood– brain barrier and white matter components after cerebral ischemia, J. Neurosci. 21 (19) (2001) 7724–7732. [31] X.Q. Li, X.Z. Cao, J. Wang, B. Fang, W.F. Tan, H. Ma, Sevoflurane preconditioning ameliorates neuronal deficits by inhibiting microglial MMP-9 expression after spinal cord ischemia/reperfusion in rats, Mol. Brain 7 (2014) 69. [32] B. Fang, X.Q. Li, B. Bi, W.F. Tan, G. Liu, Y. Zhang, H. Ma, Dexmedetomidine attenuates blood–spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rats, Cell. Physiol. Biochem. 36 (1) (2015) 373–383. [33] B. Fang, H. Wang, X.J. Sun, X.Q. Li, C.Y. Ai, W.F. Tan, P.F. White, H. Ma, Intrathecal transplantation of bone marrow stromal cells attenuates blood spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rabbits, J. Vasc. Surg. 58 (4) (2013) 1043–1052. [34] G.R. Ding, L.B. Qiu, X.W. Wang, K.C. Li, Y.C. Zhou, Y. Zhou, J. Zhang, J.X. Zhou, Y.R. Li, G.Z. Guo, EMP-induced alterations of tight junction protein expression and disruption of the blood–brain barrier, Toxicol. Lett. 196 (3) (2010) 154–160. [35] M.T. Bell, F. Puskas, V.A. Agoston, J.C. Cleveland Jr., K.A. Freeman, F. Gamboni, P.S. Herson, X. Meng, P.D. Smith, M.J. Weyant, D.A. Fullerton, T.B. Reece, Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury, Circulation 128 (2013) S152–S156. [36] X.Q. Li, H.W. Lv, Z.L. Wang, W.F. Tan, B. Fang, H. Ma, MiR-27a ameliorates inflammatory damage to the blood–spinal cord barrier after spinal cord ischemia: reperfusion injury in rats by downregulating TICAM-2 of the TLR4 signaling pathway, J. Neuroinflammation 12 (2015) 25. [37] J.J. Lochhead, G. McCaffrey, C.E. Quigley, J. Finch, K.M. DeMarco, N. Nametz, T.P. Davis, Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation, J. Cereb. Blood Flow Metab. 30 (9) (2010) 1625–1636. [38] B.J. Thompson, P.T. Ronaldson, Drug delivery to the ischemic brain, Adv. Pharmacol. 71 (2014) 165–202. [39] G. Schreibelt, G. Kooij, A. Reijerkerk, R. van Doorn, S.I. Gringhuis, S. van der PoI, B.B. Weksler, I.A. Romero, P.O. Couraud, J. Piontek, I.E. Blasig, C.D. Dijkstra, E. Ronken, H.E. de Vries, Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling, FASEB J. 21 (13) (2007) 3666–3676. [40] T. Okamoto, T. Akaike, T. Sawa, Y. Miyamoto, A. van der Vliet, H. Maeda, Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation, J. Biol. Chem. 276 (31) (2001) 29596–29602. [41] Z.Z. Gu, M. Kaul, B.X. Yan, S.J. Kridel, J.K. Cui, A. Strongin, J.W. Smith, R.C. Liddington, S.A. Lipton, S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death, Science 297 (5584) (2002) 1186–1190. [42] Z.W. Chen, X.X. Mao, A.M. Liu, X.Y. Gao, X.H. Chen, M.Z. Ye, J.T. Ye, P.Q. Liu, S.W. Xu, J.X. Liu, W. He, Q.S. Lian, R.B. Pi, Osthole, a natural coumarin improves cognitive impairments and BBB dysfunction after transient global brain ischemia in C57 BL/6J mice: involvement of Nrf2 pathway, Neurochem. Res. 40 (1) (2015) 186–194. [43] Y. Zhao, B.S. Fu, X.J. Zhang, T. Zhao, L.Y. Chen, J. Zhang, X.L. Wang, Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice, Brain Res. Bull. 109 (2014) 61–67.
[44] D.S. Yu, Y. Cao, X.F. Mei, Y.F. Wang, Z.K. Fan, Y.S. Wang, G. Lv, Curcumin improves the integrity of blood–spinal cord barrier after compressive spinal cord injury in rats, J. Neurol. Sci. 346 (1–2) (2014) 51–59. [45] P. Li, L. Su, X. Li, W. Di, X. Zhang, C. Zhang, T. He, X. Zhu, Y. Zhang, Y. Li, Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1 and NQO-1 in mice, Int. J. Neurosci. (2015), http://dx.doi.org/10.3109/00207454.2015.1042973. [46] K. Aqhayev, E. Bal, T. Rahimli, M. Mut, S. Balci, F. Vrionis, N. Akalan, Expression of water channel aquaporin-4 during experimental syringomyelia: laboratory investigation, J. Neurosurg. Spine 15 (4) (2011) 428–432. [47] O. Nesic, J.D. Guest, D. Zivadinovic, P.A. Narayana, J.J. Herrera, R.J. Grill, V.U. Mokkapati, B.B. Gelman, J. Lee, Aquaporins in spinal cord injury: the janus face of aquaporin-4, Neuroscience 168 (4) (2010) 1019–1035. [48] X. Zhang, L. Chen, X. Dang, J. Liu, Y. Ito, W. Sun, Neuroprotective effects of total steroid saponins on cerebral ischemia injuries in an animal model of focal ischemia/ reperfusion, Planta Med. 80 (8–9) (2014) 637–644. [49] G. Akdemir, J. Ratelade, N. Asavapanumas, A.S. Verkman, Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion, Neurosci. Lett. 574 (2014) 70–75. [50] S. Li, X. Hu, M. Zhang, F. Zhou, N. Lin, Q. Xia, Y. Zhou, W. Qi, Y. Zong, H. Yang, T. Wang, Remote ischemic post-conditioning improves neurological function by AQP4 downregulation in astrocytes, Behav. Brain Res. 289 (2015) 1–8. [51] K. Oshio, D.K. Bingder, B. Yang, S. Schecter, A.S. Verkman, G.T. Manley, Expression of aquaporin water channels in mouse spinal cord, Neuroscience 127 (3) (2004) 685–693. [52] H. Qiang, C. Zhang, Z. Shi, M. Ling, Neuroprotective effects of recombinant adenoassociated virus expressing vascular endothelial growth factor on rat traumatic spinal cord injury and its mechanism, Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 26 (6) (2012) 724–730. [53] N. Ning, X. Dang, C. Bai, C. Zhang, K. Wang, Panax notoginsenoside produces neuroprotective effects in rat model of acute spinal cord ischemia-reperfusion injury, J. Ethnopharmacol. 139 (2) (2012) 504–512. [54] C. Zhang, J. Ma, L. Fan, Y. Zou, X. Dang, K. Wang, J. Song, Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating, Tissue Cell 47 (3) (2015) 291–300. [55] P.K. Randhawa, A. Bali, A.S. Jaggi, RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms, Eur. J. Pharmacol. 746 (2015) 317–332. [56] L. Candilio, A. Malik, D.J. Hausenloy, Protection of organs than the heart by remote ischemic conditioning, J. Cardiovasc. Med. 14 (3) (2013) 193–205. [57] S.N. Heyman, D. Leibowitz, I. Mor-Yosef Levi, A. Liberman, A. Eisenkraft, R. Elcalai, M. Khamaisi, Rosenberger, Adaptive response to hypoxia and remote ischemia preconditioning: a new HIF era in clinical medicine, Acta Physiol. (2015), http://dx.doi.org/ 10.1111/apha.12613. [58] O. Selimoglu, M. Ugurlucan, M. Basaran, F. Gungor, M. Banach, O. Cucu, L.L. Ong, A.Y. Gasparyan, D. Mikhailidis, T.N. Ogus, Efficacy of remote ischaemic preconditioning for spinal cord protection against ischaemic injury: association with heat shock protein expression, Folia Neuropathol. 46 (3) (2008) 204–212. [59] S. Hu, H.L. Dong, Y.Z. Li, Z.J. Luo, L. Sun, Q.Z. Yang, L.F. Yang, L.Z. Xiong, Effects of remote ischemic preconditioning on biochemical markers and neurologic outcomes in patients undergoing elective cervical decompression surgery: a prospective randomized controlled trial, J. Neurosurg. Anesthesiol. 22 (1) (2010) 46–52.
Contents lists available at ScienceDirect
Life Sciences journal homepage: www.elsevier.com/locate/lifescie
Review article
Advance in spinal cord ischemia reperfusion injury: Blood–spinal cord barrier and remote ischemic preconditioning Qijing Yu a, Jinxiu Huang b, Ji Hu b,⁎, Hongfei Zhu c a b c
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China Department of Anesthesiology, Liyuan Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430077, Hubei, China Department of Anesthesiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei, China
a r t i c l e
i n f o
Article history: Received 21 January 2016 Received in revised form 16 March 2016 Accepted 24 March 2016 Available online 07 April 2016 Keywords: Blood–spinal cord barrier Ischemia reperfusion injury Remote ischemic preconditioning
a b s t r a c t The blood–spinal cord barrier (BSCB) is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier plays a vital role in maintaining the microenvironment stability of the spinal cord. When the spinal cord is subjected to ischemia/reperfusion (I/R) injury, the structure and function of the BSCB is disrupted, further destroying the spinal cord homeostasis and ultimately leading to neurological deficit. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia is followed by reperfusion to tissues/organs to protect the distant target tissues/organs against subsequent lethal ischemic injuries. RIPC is an innovation of the treatment strategies that protect the organ from I/R injury. In this study, we review the morphological structure and function of the BSCB, the injury mechanism of BSCB resulting from spinal cord I/R, and the effect of RIPC on it. © 2016 Elsevier Inc. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . Morphological structure and function of the BSCB . . . . . 2.1. Morphological structure of the BSCB . . . . . . . . 2.2. Function of each component element of BSCB . . . . 3. Injury mechanism of BSCB due to spinal cord I/R . . . . . . 3.1. Disruption of BSCB induced by MMPs. . . . . . . . 3.2. Disruption of BSCB induced by inflammatory reaction 3.3. Disruption of BSCB induced by oxidative stress . . . 3.4. The role of AQP-4. . . . . . . . . . . . . . . . . 4. Protection of RIPC for SCIRI. . . . . . . . . . . . . . . . 5. Problems and prospect . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
. . . . . . . . . . . . .
34 35 35 35 35 35 35 36 36 36 37 37 37
1. Introduction
Abbreviations: BSCB, Blood–spinal cord barrier; I/R, Ischemia/reperfusion; RIPC, Remote ischemic preconditioning; SCIRI, Spinal cord ischemia reperfusion injury; BBB, Blood–brain barrier; CNS, Central nervous system; TJ, Tight junction; NVU, Neurovascular unit; JAM, Junction adherence molecular; HO-1, Heme oxygenase-1; BDNF, Brain derived neurotrophic factor; MMPs, Matrix metalloproteinases; TLRs, Tolllike receptors; AQPs, Aquaporins. ⁎ Corresponding author. E-mail address: [email protected] (J. Hu).
http://dx.doi.org/10.1016/j.lfs.2016.03.046 0024-3205/© 2016 Elsevier Inc. All rights reserved.
Clinically, thoracoabdominal aortic aneurysm repair surgery can lead to spinal cord ischemia reperfusion injury (SCIRI), whose incidence is reported to range from 1% to 32%. However, a main, devastating, and unpredictable complication after spinal cord injury is paraplegia [1–2]. To date, various intervening measures, including hypothermia, improvement of surgical techniques, and pharmacologic adjuncts, have been used to protect the spinal cord from ischemic injury [3]; nonetheless, complications still cannot be prevented completely. Therefore, a
Q. Yu et al. / Life Sciences 154 (2016) 34–38
more effective strategy should be developed to protect the spinal cord against ischemia reperfusion (I/R) injury. The pathogenesis of SCIRI includes oxygen-free radical-induced lipid peroxidation, intracellular calcium overload, leukocyte activation, inflammatory response, and neuronal apoptosis. In addition, the disruption of the blood–spinal cord barrier (BSCB) is a major pathological change that can exacerbate spinal cord edema, increase leukocyte infiltration, as well as amplify inflammation and oxidative stress. Therefore, BSCB disruption plays a vital role in the evolution of SCIRI and further damage of neurons [4–6]. BSCB is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier strictly regulates the stability of the spinal cord microenvironment. The repairing of the BSCB should be performed as soon as possible after spinal cord injury because the normal function of neurons is based on the homeostasis of the spinal cord. In recent years, changes of the BSCB after spinal cord I/R and improvement of the neurological function through protecting BSCB integrity have drawn extensive attention from researchers. Clarifying the mechanism responsible for BSCB disruption and further using it as a therapeutic target is greatly significant to alleviate SCIRI. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia followed by reperfusion to a tissue/organ protect the distant target tissue/organ against subsequent lethal ischemic injuries, and the most convenient method induced by the upper or lower limb. It has a huge development prospect clinically as it is safe, simple, and easily accepted by doctors and patients. Certain studies have shown that RIPC can protect spinal cord against I/R injury [7–9], but the mechanism is not entirely clear yet. In the rat model of brain I/R injury, a researcher has found that remote ischemic postconditioning can alleviate permeability of the blood–brain barrier (BBB) and brain edema after brain ischemia, which reduces infarct volume and improves the neurological outcome as well [10–11]. Meanwhile, the possibility of RIPC alleviating the permeability of the BSCB in the model of spinal cord injury has not been reported. As both BSCB and BBB belong to the central nervous system (CNS) barrier, they are similar not only in structure but also in function, thus it is very likely that RIPC induces spinal cord ischemia tolerance through keeping BSCB intact. The present study will review the morphological structure and function of the BSCB, injury mechanism of BSCB due to spinal cord I/R, and the effect of RIPC on it.
2. Morphological structure and function of the BSCB 2.1. Morphological structure of the BSCB Similar to BBB, the basal components of BSCB include endothelial cells between spinal cord capillaries and tight junction (TJ) proteins, basal lamina, pericytes, and astrocytic end feet processes [12]. Endothelial cells, pericytes, astrocytes, neurons, and extracellular matrix are collectively known as the neurovascular unit (NVU) [13]. Endothelial cells of spinal cord capillaries, which are characterized by the absence of cell membrane fenestrations unlike those of peripheral circulation, contain a high number of cytosolic mitochondria, lack pinocytic vacuoles, and include a very weak activity of the pinocytosis [14]. TJs between endothelial cells are composed of some specific transmembrane proteins such as claudins (claudin-1, claudin-3, claudin-5, etc.), occludin, and junction adherence molecular (JAM). These transmembrane proteins are linked to cytoskeletal filaments by interactions with accessory proteins (ZO-1, ZO-2, ZO-3, etc.). The basal lamina surrounds capillary endothelial cells and engulfs pericytes. The major components of the basal lamina include collagen, fibronectin, laminin, and proteoglycans [16]. Astrocytes, which are one of the most numerous types of cells in the CNS, projects end feet processes to surround neural synapses, ranvier nodes, and blood vessels [17].
35
2.2. Function of each component element of BSCB Endothelial cells of spinal cord capillaries, as the most important part of BSCB, strictly restrict free transcellular flow of blood-borne molecules, and a high number of cytosolic mitochondria provides high energy for selective active transport and calcium homeostasis. In addition, heme oxygenase-1 (HO-1) and brain derived neurotrophic factor (BDNF) can be expressed and secreted by endothelial cells, which contribute to recovery of the neural function [18–19]. The paracellular diffusion pathway is severely restricted by TJs between individual endothelial cells. Claudin-5, occludin, and ZO-1 are the main proteins of TJs, which are also considered as the sensitive markers no matter when the CNS barrier is normal or damaged. Moreover, ZO proteins can not only act as the scaffold for multiple signal pathways within cells but also involve in the regulating function of TJs [15,20]. Pericytes are small-vessel wall-associated cells that are separated from endothelial cells by the basal lamina. Capillary pericytes and endothelial cells communicate with each other in several ways, including gap junctions and soluble factors. Furthermore, pericytes play a significant regulatory role in endothelial cell proliferation, migration, and differentiation [21]. Astrocytes can be stimulated by neuronal activity and can regulate vascular function, thus further adjusting blood flow to neuronal activity in specific regions [22–23]. In addition, astrocytic end feet processes express a high concentration of water channel aquaporin 4 (AQP-4), which is involved in the volume regulation of CNS [24]. 3. Injury mechanism of BSCB due to spinal cord I/R 3.1. Disruption of BSCB induced by MMPs Matrix metalloproteinases (MMPs) comprise a large family of extracellular zinc endopeptidases that can degrade and remodel basal lamina proteins, tight junction proteins, and many other extracellular matrices [25]. MMPs can be expressed by various cells in the brain, including endothelial cells, microglia, neurons, astrocytes, and infiltrating inflammatory cells during cerebral ischemia [26]. MMPs are secreted as inactive zymogens, and their expression and activation can be strongly promoted by the overproduction of reactive oxygen species and proinflammatory cytokines (TNF-α, IL-1β, etc.) during the I/R process [27]. MMP-9 is the most widely researched among all types of MMPs, and has been demonstrated to play a critical role in regulating BBB during cerebral ischemia. A considerable number of studies have shown that MMP-9 can degrade claudin-5, occludin, and ZO-1 in cultured brain endothelial cells in vitro and in vivo ischemia model. Moreover, knockout mice that lack MMP-9 have shown a significant protective effect on BBB [28–30]. In the SCIRI model, Fang Bo et al. found that the permeability of the BSCB was increased and the expression of MMP-9 was up-regulated in microglia, neuron, and astrocyte. In addition, MMP-9 was also involved in the infiltration and migration of microglia and in the increased production of proinflammatory cytokines and chemokine, which amplified the inflammation and further exacerbated BSCB disruption and neuronal apoptosis [31–32]. Some studies have indicated that dexmedetomidine or sevoflurane preconditioning or intrathecal transplantation of bone marrow stromal cells can down-regulated MMP-9 expression after spinal cord I/R, thus maintaining the integrity of the BSCB and improving the neurological outcome [31–33]. The above-mentioned research results indicate that MMP-9 could destroy the BSCB, and play an important part in the development and progression of inflammatory reaction. Consequently, taking some interventions to inhibit MMP-9 expression will contribute to the stability of the BSCB structure and alleviation of SCIRI. 3.2. Disruption of BSCB induced by inflammatory reaction Inflammatory cytokines are one of the most pivotal factors for BSCB disruption in SCIRI; they lead to the dissociation of ZO-1 from the
36
Q. Yu et al. / Life Sciences 154 (2016) 34–38
cytoskeletal complex and up-regulation expression of MMPs and TNFα, which are frequently associated with BSCB permeability increase. Nevertheless, BSCB disruption in turn exacerbates inflammatory reaction, resulting in an irreversible damage of the spinal cord [4,34]. Recently, Toll-like receptors (TLRs), especially TLR4, have attracted broad attention for their critical role in inflammatory response after spinal cord I/ R. TLR4, which is recognized as a LPS ligand, is a group of membranespanning proteins that regulate innate immune response and is significantly expressed in the microglial membrane [35]. Research has shown that early and sustained microglial activation can be induced in the course of SCIRI, and its membrane-bound receptor TLR4 is also over expressed. Once TLR4 binds to its ligand, NF-κB relocates to the nucleus and regulates the expression of target inflammatory genes IL-1β. The TLR4-microglia-NF-κB/IL-1β pathway as a positive feedback loop in the SCIRI, is capable of exacerbating inflammatory reaction and BSCB dysfunction [6]. Furthermore, researchers have found that TLR4 induces NF-κB activation by interacting with its downstream receptors, namely, MyD88 and TRIF. The early phase of SCIRI in the spinal cord was found to be largely TLR4/MyD88-dependent and the following late phase was found to be mainly reliant on TLR4/TRIF activation, which was amplified by the MyD88 pathway [5]. Subsequently, these researchers discovered that MiR-27a could ameliorate inflammatory damage to BSCB after SCIRI by down-regulating TICAM-2 of the TLR4 signaling pathway and then inhibiting the NF-κB/IL-1β pathway [36]. Both inflammatory reaction and BSCB disruption are significant physiopathologic mechanisms of SCIRI. Inflammatory reaction can break down BSCB, whereas the opening of the BSCB in turn increases infiltrating leukocytes, which form a vicious cycle to amplify inflammatory response and exacerbate spinal cord injury. 3.3. Disruption of BSCB induced by oxidative stress Under physiological conditions, a dynamic balance exists between the oxidation system and antioxidation system in vivo; small amounts of oxygen radicals produced by an organism can be removed by superoxide dismutase, glutathione, and some other antioxidant enzymes. However, overproduction of reactive oxygen species due to massive infiltrating leukocytes upsets the balance during SCIRI. Some studies reported that increased levels of superoxide contribute to BBB endothelial dysfunction [37]. Peroxynitrite, which is formed by the conjugation of superoxide and NO, can cause significant injury to cerebral microvessels through lipid peroxidation, consumption of endogeneous antioxidants, and induction of mitochondrial failure [38], ultimately resulting in BBB dysfunction. Some reports have shown that oxidative stress promotes redistribution and/or down-regulation of critical tight junction proteins such as claudin-5, occludin, ZO-1, and JAM-1 [37,39]. Meanwhile, MMP9 can be activated by NO, reactive oxygen species, and peroxynitrite [40–41], which lead to the degradation of TJs and basal lamina. Subsequently, increased BBB permeability results in the genesis and development of vasogenic brain edema. Therefore, some interventions that reduce reactive oxygen specie production or enhance spinal cord antioxidant ability during spinal cord I/R will help stabilize the BSCB structure and function. Lately, studies have reported that some drugs or compounds can up-regulate ZO-1 and occludin expression by increasing antioxidant HO-1, thus keeping the BSCB integrity and protecting the spinal cord from stress damage [42–44]. In addition, remote limb ischemic postconditioning up-regulates the expression of HO-1 via activating the Nrf2-ARE pathway, and then protects the brain against cerebral I/ R injury [45]. In conclusion, the HO-1 signaling pathway critically stabilizes the BBB/BSCB structure and function in the oxidative stress state. 3.4. The role of AQP-4 The aquaporins (AQPs) are a family of transmembrane proteins that function as “water channels”, which provide water passive transport
across the membrane where they reside. All AQPs are expressed in areas of high water flow where the cell membranes are not sufficient to provide adequate speed. Among them, AQP-4 is the most abundant in the CNS and has the highest expression levels in spinal cord tissue. In the CNS, AQP-4 is expressed mostly by astrocytic end feet around capillaries, and its normal function is to enable fast water influx or efflux, driven by osmotic or hydrostatic pressures. In addition, it is responsible for the evolution of cytotoxic and vasogenic edema [46–47]. Research has shown that the AQP-4 expression is significantly increased in the hippocampal CA1 and cortex after cerebral I/R, and is responsible for cerebral edema [48]. Moreover, a study in adult knockout mice has shown that the deletion of AQP-4 diminishes cytotoxic edema formation and improves neurological outcomes [49]. Remote ischemic postconditioning could also enhance neurological function by AQP4 downregulation in astrocytes [50]. Similarly, AQP-4 is also significant in regulating the water balance of the spinal cord tissue. Some investigators found that the expression of AQP-4 is positive correlated with spinal cord edema [51–52]. Certain pharmacological preconditioning methods can alleviate spinal cord edema by down-regulating AQP4 in the course of spinal cord I/R [53–54]. 4. Protection of RIPC for SCIRI RIPC is a treatment strategy in which alternate cycles of preconditioning ischemia followed by reperfusion are delivered to a remote organ which protects the remote organ against subsequent lethal ischemic injury. RIPC is an innovation among various kinds of strategies that protect the organ from I/R injury. In fundamental experiments, scholars found that the RIPC of the arteries, such as cerebral, mesenteric, intestinal, renal, abdominal aorta, and skeletal muscle, protects myocardium against I/R injury in various animals like rats, mice, and rabbits [55]. However, these approaches may not be directly translated in clinical settings. Clinically, the best utilized way is rendering the forelimb ischemic by applying blood pressure cuff on the upper arm. The advantages of this method are its non-invasiveness, simplicity, convenience, repeatability, and cost-effectiveness features. In addition, the upper limb is more resistant to ischemic insult. This limb RIPC method has been demonstrated in the brain, heart, kidney, liver, intestines, lung, and other organs in many animal I/R models [56]. At present, the most widely used RIPC protocol is inflating the blood pressure cuff tied on the upper arm 20 mm Hg greater than systolic arterial pressure, rendering the forearm ischemia for 5 min, and followed by a 5 min intermittent reperfusion, with this cycle possibly repeated for 3 to 5 consecutive periods [57]. A large amount of clinical evidence has indicated that RIPC can produce a protective effect for many organ surgeries such as coronary bypass surgeries, percutaneous coronary interventions, selective cervical decompressions, kidney transplantations, and abdominal aortic aneurysm surgeries [55]. In the last few years, certain animal experiments have shown that RIPC can protect the spinal cord against I/R injury. In a rabbit experiment, Dong Hailong et al. found that before the rabbits were subjected to spinal cord ischemia by aortic occlusion, RIPC, which was achieved by bilateral femoral artery occlusion (10 min ischemia/10 min reperfusion, two cycles), obviously improved neurological outcomes and relieved spinal cord tissue injury. They also found that in rat models, spinal cord ischemic tolerance was induced by limb RIPC achieved by 3 cycles of right femoral artery and 3 min ischemia/3 min reperfusion [8–9]. In addition, research has shown that in rats, RIPC can reduce spinal cord damage in the course of spinal cord I/R [58] via occluding the right femoral artery with a tourniquet for 3 cycles of 10 min ischemia/ 10 min reperfusion. Recently, an experimental study on the pocrine model indicated that RIPC achieved by the transient ischemia of left hind limb protected the spinal cord against ischemic insult [7]. Furthermore, in a clinical experiment, the protection of RIPC for spinal cords has also been confirmed. Xiong Lize et al. facilitated an experiment in which patients undergoing elective decompression surgery were subjected to
Q. Yu et al. / Life Sciences 154 (2016) 34–38
limb RIPC by performing 3 cycles of 5 min ischemia/5 min reperfusion of the upper limb, and they discovered that the early recovery of the patients' neurological functions after surgery was improved [59]. However, clinical evidence of RIPC protection for SCIRI is still deficient, and large-scale samples, multicenter, randomized controlled trials, and the best RIPC protocol are still needed to be studied further in the future. Although many studies have verified the protection of RIPC for SCIRI, the potential mechanism remains unclear. The humoral pathway may be involved in the RIPC protective effect. As previous studies have reported, the heat shock protein, endocannabinoid, and antioxidant pathway are triggered by reactive oxygen species involved in RIPC protection for spinal cord ischemia injury [8–9,58]. The role of BSCB in SCIRI has been the focus of attention in recent years. Ischemic preconditioning was reported to possibly alleviate BSCB disruption induced by SCIRI, thus improving neurological outcomes [4,10–11]. Fang Bo et al. found that in rabbit models, the ischemic preconditioning group, which was achieved by abdominal aorta occlusion (5 min ischemia/5 min reperfusion, 3 cycles), had better pathological outcomes in the spinal cord ischemic segments as compared with the model group. In the ischemic preconditioning group, the degree of spinal cord edema was lighter, the BSCB permeability was lower, the expression of ZO-1 was increased, and MMP-9 and TNF-α were reduced [4]. In the rat model, Changhong Ren et al. discovered that RIPC can alleviate the permeability of BBB and brain edema, thus reducing infarct volume after brain ischemia [11]. Lately, Shuai Li et al. revealed that the remote ischemic postconditioning could relieve the permeability of BBB and brain edema and down-regulate the AQP4 expression in astrocytes as well; thus speculating that the remote ischemia post-conditioning improved the neurological function by AQP4 down-regulation [10]. Although both BSCB and BBB belong to the CNS barrier, they are similar not only in structure but also in function. The possibility of RIPC protecting the spinal cord against ischemia insult by keeping the integrity of BSCB still needs to be further confirmed. 5. Problems and prospect Although some factors contributing to BSCB disruption after spinal cord I/R have been investigated extensively, whether there are other factors involved and how are these factors cross-talking are largely unknown. For instance, as mentioned above, MMPs, inflammatory reaction, oxidative stress, and AQP4 may induce BSCB disruption after spinal cord I/R. Whether there are other factors? Are these factors interrelating and influencing each other? Which one plays the most dominant role? These problems need to be further investigated. RIPC is an innovative strategy to protect organs from I/R injury and has aroused extensive attention from global scholars. However, the underlying mechanism remains to be elucidated. The RIPC protocol is not uniform, neither in various animal models, nor in clinical trials. A proper RIPC protocol for clinic has not been carried out. On the other hand, clinical evidence of RIPC protection for SCIRI is still scarce. Studies with large-scale samples, multicenter, and randomized controlled trials are needed in the future. Previous studies have demonstrated that RIPC can alleviate the permeability of BBB and brain edema, however, whether this mechanism happened on BSCB needs to be further confirmed. What kinds of signals are produced in the remote organs after RIPC? How these signals are delivered to BBB/BSCB? Whether via a neural pathway or humoral pathway? These questions are eager to be answered. HO-1 pathway has been reported to protect cerebral ischemia post-remote limb ischemia conditioning. Investigating if this pathway is also suitable for spinal protection post-RIPC is greatly significant to reveal the mechanism of RIPC. Acknowledgments This work was supported by grants from the Hubei Province Health and Family Planning Scientific Research Project (No. WJ2015MB023 to
37
Qijing Yu) and Science and Technology Department of Hubei Province (project of scientific research condition and resource research development) fund (No. 2015BCE099 to Hongfei Zhu).
References [1] N. Panthee, M. Ono, Spinal cord injury following thoracic and thoracoabdominal aortic repairs, Asian Cardiovasc. Thorac. Ann. 23 (2) (2015) 235–246. [2] D.C. Etz, M. Luehr, K.V. Aspern, M. Misfeld, S. Gudehus, J. Ender, T. Koelbel, E.S. Debus, F.W. Mohr, Spinal cord ischemia in open and endovascular thoracoabdominal aortic aneurysm repair: new concepts, J. Cardiovasc. Surg. 55 (2) (2014) 159–168. [3] M.M. Wynn, C.W. Acher, A modern theory of spinal cord ischemia injury in thoracoabdominal aortic surgery and its implications for prevention of paralysis, J. Cardiothorac. Vasc. Anesth. 28 (4) (2014) 1088–1099. [4] B. Fang, X.M. Li, X.J. Sun, N.R. Bao, X.Y. Ren, H.W. Lv, H. Ma, Ischemic preconditioning protects against spinal cord ischemia-reperfusion injury in rabbits by attenuating blood spinal cord barrier disruption, Int. J. Mol. Sci. 14 (5) (2013) 10343–10354. [5] X.Q. Li, H.W. Lv, W.F. Tan, B. Fang, H. Wang, H. Ma, Role of the TLR4 pathway in blood–spinal cord barrier dysfunction during the bimodal stage after ischemia/reperfusion injury in rats, J. Neuroinflammation 11 (2014) 62. [6] X.Q. Li, J. Wang, B. Fang, W.F. Tan, H. Ma, Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats, Mol. Brain 7 (2014) 28. [7] H. Haapanen, J. Herajärvi, O. Arvola, T. Anttila, T. Starck, M. Kallio, V. Anttila, H. Tuominen, K. Kiviluoma, T. Juvonen, Remote ischemic preconditioning protects the spinal cord against ischemic insult: an experimental study in a pocrin model, J. Thorac. Cardiovasc. Surg. (2015), http://dx.doi.org/10.1016/j.jtcvs.2015.07.036. [8] H.L. Dong, Y. Zhang, B.X. Su, Z.H. Zhu, Q.H. Gu, H.F. Sang, L. Xiong, Limb remote ischemic preconditioning protects the spinal cord from ischemia-reperfusion injury: a newly identified nonneuronal but reactive oxygrn species-dependent pathway, Anesthesiology 112 (4) (2010) 881–891. [9] B. Su, H. Dong, R. Ma, X. Zhang, Q. Ding, L. Xiong, Cannabioid 1 receptor mmediation of spinal cord ischemic tolerance induced by limb remote ischemia preconditioning in rats, J. Thorac. Cardiovasc. Surg. 138 (6) (2009) 1409–1416. [10] S. Li, X. Hu, M. Zhang, F. Zhou, N. Lin, Q. Xia, Y. Zhou, W. Qi, Y. Zong, H. Yang, T. Wang, Remote ischemic post-conditioning improves neurological function by AQP4 downregulation in astrocytes, Behav. Brain Res. 289 (2015) 1–8. [11] C. Ren, M. Gao, D. Dornbos III, Y. Ding, X. Zeng, Y. Luo, X. Ji, Remote ischemic postconditioning reduced brain damage in experimental ischemia/reperfusion injury, Neurol. Res. 33 (5) (2011) 514–519. [12] P. Ballabh, A. Braun, M. Nedergaard, The blood–brain barrier: an overview: structure, regulation, and clinical implications, Neurobiol. Dis. 16 (1) (2004) 1–13. [13] R. Daneman, The blood–brain barrier in health and disease, Ann. Neurol. 72 (5) (2012) 648–672. [14] J. Bernacki, A. Dobrowolska, K. Nierwiñska, A. Maecki, Physiology and pharmacological role of the blood–brain barrier, Pharmacol. Rep. 60 (2008) 600–622. [15] H.C. Bauer, I.A. Krizbai, H. Bauer, A. Traweger, “You Shall Not Pass”—tight junctions of the blood brain barrier, Front. Neurosci. 8 (2014) 392. [16] F.L. Cardoso, O. Brites, M.A. Brito, Looking at the blood–brain barrier: molecular anatomy and possible investigation approaches, Brain Res. Rev. 64 (2) (2010) 328–363. [17] Y. Zhang, B.A. Barres, Astrocytes heterogeneity: an underappreciated topic in neurobiology, Curr. Opin. Neurobiol. 20 (5) (2010) 588–594. [18] N. Wang, G. Wang, J. Hao, J. Ma, Y. Wang, X. Jiang, H. Jiang, Cur ameliorates hydrogen peroxide-induced epithelial barrier disruption by upregulating heme oxygenase-1 expression in human intestinal epithelial cells, Dig. Dis. Sci. 57 (7) (2012) 1792–1801. [19] Y. Béjot, A. Prigent-Tessier, C. Cachia, M. Giroud, C. Mossiat, N. Bertrand, P. Garnier, C. Marie, Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats, Neurochem. Int. 58 (1) (2011) 102–111. [20] E. Candelario-Jalil, Y. Yang, G.A. Rosenberg, Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia, Neuroscience 158 (3) (2009) 983–994. [21] V. Bartanusz, D. Jezova, B. Alajajian, M. Diqicaylioqlu, The blood–spinal cord barrier: morphology and clinical implications, Ann. Neurol. 70 (2) (2011) 194–206. [22] D. Attwell, A.M. Buchan, S. Charpak, M. Lauritzen, B.A. Macvicar, E.A. Newman, Glial and neuronal control of brain blood flow, Nature 468 (2010) 232–243. [23] G.C. Petzold, V.N. Murthy, Role of astrocytes in neurovascular coupling, Neuron 71 (5) (2011) 782–797. [24] N.N. Haj-Yasein, G.F. Vindedal, M. Eilert-Olsen, G.A. Gundersen, Ø. Skare, P. Laake, A. Kiungland, A.E. Thorén, J.M. Burkhardt, O.P. Ottersen, E.A. Nagelhus, Glialconditional deletion of aquaporin-4 (AQP-4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet, Proc. Natl. Acad. Sci. U. S. A. 108 (43) (2011) 17815–17820. [25] Rong Jin, Guojun Yang, Guohong Li, Molecular insights and therapeutic targets for blood–brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator, Neurobiol. Dis. 38 (3) (2010) 376–385. [26] R. Jin, G. Yang, G. Li, Inflammatory mechanisms in ischemic stroke: role of inflammatory cells, J. Leukoc. Biol. 87 (5) (2010) 779–789. [27] E. Dejonckheere, R.E. Vandenbrouche, C. Libert, Matrix metalloproteinases as drug targets in ischemia/reperfusion injury, Drug Discov. Today 16 (17–18) (2011) 762–778.
38
Q. Yu et al. / Life Sciences 154 (2016) 34–38
[28] F. Chen, N. Ohashi, W. Li, C. Eckman, J.H. Nguyen, Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure, Hepatology 50 (6) (2009) 1914–1923. [29] A.T. Bauer, H.F. Bürgers, T. Rabie, H.H. Marti, Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement, J. Cereb. Blood Flow Metab. 30 (4) (2010) 837–848. [30] M. Asahi, X. Wang, T. Mori, T. Sumii, J.C. Jung, M.A. Moskowitz, M.E. Fini, E.H. Lo, Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood– brain barrier and white matter components after cerebral ischemia, J. Neurosci. 21 (19) (2001) 7724–7732. [31] X.Q. Li, X.Z. Cao, J. Wang, B. Fang, W.F. Tan, H. Ma, Sevoflurane preconditioning ameliorates neuronal deficits by inhibiting microglial MMP-9 expression after spinal cord ischemia/reperfusion in rats, Mol. Brain 7 (2014) 69. [32] B. Fang, X.Q. Li, B. Bi, W.F. Tan, G. Liu, Y. Zhang, H. Ma, Dexmedetomidine attenuates blood–spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rats, Cell. Physiol. Biochem. 36 (1) (2015) 373–383. [33] B. Fang, H. Wang, X.J. Sun, X.Q. Li, C.Y. Ai, W.F. Tan, P.F. White, H. Ma, Intrathecal transplantation of bone marrow stromal cells attenuates blood spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rabbits, J. Vasc. Surg. 58 (4) (2013) 1043–1052. [34] G.R. Ding, L.B. Qiu, X.W. Wang, K.C. Li, Y.C. Zhou, Y. Zhou, J. Zhang, J.X. Zhou, Y.R. Li, G.Z. Guo, EMP-induced alterations of tight junction protein expression and disruption of the blood–brain barrier, Toxicol. Lett. 196 (3) (2010) 154–160. [35] M.T. Bell, F. Puskas, V.A. Agoston, J.C. Cleveland Jr., K.A. Freeman, F. Gamboni, P.S. Herson, X. Meng, P.D. Smith, M.J. Weyant, D.A. Fullerton, T.B. Reece, Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury, Circulation 128 (2013) S152–S156. [36] X.Q. Li, H.W. Lv, Z.L. Wang, W.F. Tan, B. Fang, H. Ma, MiR-27a ameliorates inflammatory damage to the blood–spinal cord barrier after spinal cord ischemia: reperfusion injury in rats by downregulating TICAM-2 of the TLR4 signaling pathway, J. Neuroinflammation 12 (2015) 25. [37] J.J. Lochhead, G. McCaffrey, C.E. Quigley, J. Finch, K.M. DeMarco, N. Nametz, T.P. Davis, Oxidative stress increases blood–brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation, J. Cereb. Blood Flow Metab. 30 (9) (2010) 1625–1636. [38] B.J. Thompson, P.T. Ronaldson, Drug delivery to the ischemic brain, Adv. Pharmacol. 71 (2014) 165–202. [39] G. Schreibelt, G. Kooij, A. Reijerkerk, R. van Doorn, S.I. Gringhuis, S. van der PoI, B.B. Weksler, I.A. Romero, P.O. Couraud, J. Piontek, I.E. Blasig, C.D. Dijkstra, E. Ronken, H.E. de Vries, Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling, FASEB J. 21 (13) (2007) 3666–3676. [40] T. Okamoto, T. Akaike, T. Sawa, Y. Miyamoto, A. van der Vliet, H. Maeda, Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation, J. Biol. Chem. 276 (31) (2001) 29596–29602. [41] Z.Z. Gu, M. Kaul, B.X. Yan, S.J. Kridel, J.K. Cui, A. Strongin, J.W. Smith, R.C. Liddington, S.A. Lipton, S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death, Science 297 (5584) (2002) 1186–1190. [42] Z.W. Chen, X.X. Mao, A.M. Liu, X.Y. Gao, X.H. Chen, M.Z. Ye, J.T. Ye, P.Q. Liu, S.W. Xu, J.X. Liu, W. He, Q.S. Lian, R.B. Pi, Osthole, a natural coumarin improves cognitive impairments and BBB dysfunction after transient global brain ischemia in C57 BL/6J mice: involvement of Nrf2 pathway, Neurochem. Res. 40 (1) (2015) 186–194. [43] Y. Zhao, B.S. Fu, X.J. Zhang, T. Zhao, L.Y. Chen, J. Zhang, X.L. Wang, Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice, Brain Res. Bull. 109 (2014) 61–67.
[44] D.S. Yu, Y. Cao, X.F. Mei, Y.F. Wang, Z.K. Fan, Y.S. Wang, G. Lv, Curcumin improves the integrity of blood–spinal cord barrier after compressive spinal cord injury in rats, J. Neurol. Sci. 346 (1–2) (2014) 51–59. [45] P. Li, L. Su, X. Li, W. Di, X. Zhang, C. Zhang, T. He, X. Zhu, Y. Zhang, Y. Li, Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1 and NQO-1 in mice, Int. J. Neurosci. (2015), http://dx.doi.org/10.3109/00207454.2015.1042973. [46] K. Aqhayev, E. Bal, T. Rahimli, M. Mut, S. Balci, F. Vrionis, N. Akalan, Expression of water channel aquaporin-4 during experimental syringomyelia: laboratory investigation, J. Neurosurg. Spine 15 (4) (2011) 428–432. [47] O. Nesic, J.D. Guest, D. Zivadinovic, P.A. Narayana, J.J. Herrera, R.J. Grill, V.U. Mokkapati, B.B. Gelman, J. Lee, Aquaporins in spinal cord injury: the janus face of aquaporin-4, Neuroscience 168 (4) (2010) 1019–1035. [48] X. Zhang, L. Chen, X. Dang, J. Liu, Y. Ito, W. Sun, Neuroprotective effects of total steroid saponins on cerebral ischemia injuries in an animal model of focal ischemia/ reperfusion, Planta Med. 80 (8–9) (2014) 637–644. [49] G. Akdemir, J. Ratelade, N. Asavapanumas, A.S. Verkman, Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion, Neurosci. Lett. 574 (2014) 70–75. [50] S. Li, X. Hu, M. Zhang, F. Zhou, N. Lin, Q. Xia, Y. Zhou, W. Qi, Y. Zong, H. Yang, T. Wang, Remote ischemic post-conditioning improves neurological function by AQP4 downregulation in astrocytes, Behav. Brain Res. 289 (2015) 1–8. [51] K. Oshio, D.K. Bingder, B. Yang, S. Schecter, A.S. Verkman, G.T. Manley, Expression of aquaporin water channels in mouse spinal cord, Neuroscience 127 (3) (2004) 685–693. [52] H. Qiang, C. Zhang, Z. Shi, M. Ling, Neuroprotective effects of recombinant adenoassociated virus expressing vascular endothelial growth factor on rat traumatic spinal cord injury and its mechanism, Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 26 (6) (2012) 724–730. [53] N. Ning, X. Dang, C. Bai, C. Zhang, K. Wang, Panax notoginsenoside produces neuroprotective effects in rat model of acute spinal cord ischemia-reperfusion injury, J. Ethnopharmacol. 139 (2) (2012) 504–512. [54] C. Zhang, J. Ma, L. Fan, Y. Zou, X. Dang, K. Wang, J. Song, Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating, Tissue Cell 47 (3) (2015) 291–300. [55] P.K. Randhawa, A. Bali, A.S. Jaggi, RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms, Eur. J. Pharmacol. 746 (2015) 317–332. [56] L. Candilio, A. Malik, D.J. Hausenloy, Protection of organs than the heart by remote ischemic conditioning, J. Cardiovasc. Med. 14 (3) (2013) 193–205. [57] S.N. Heyman, D. Leibowitz, I. Mor-Yosef Levi, A. Liberman, A. Eisenkraft, R. Elcalai, M. Khamaisi, Rosenberger, Adaptive response to hypoxia and remote ischemia preconditioning: a new HIF era in clinical medicine, Acta Physiol. (2015), http://dx.doi.org/ 10.1111/apha.12613. [58] O. Selimoglu, M. Ugurlucan, M. Basaran, F. Gungor, M. Banach, O. Cucu, L.L. Ong, A.Y. Gasparyan, D. Mikhailidis, T.N. Ogus, Efficacy of remote ischaemic preconditioning for spinal cord protection against ischaemic injury: association with heat shock protein expression, Folia Neuropathol. 46 (3) (2008) 204–212. [59] S. Hu, H.L. Dong, Y.Z. Li, Z.J. Luo, L. Sun, Q.Z. Yang, L.F. Yang, L.Z. Xiong, Effects of remote ischemic preconditioning on biochemical markers and neurologic outcomes in patients undergoing elective cervical decompression surgery: a prospective randomized controlled trial, J. Neurosurg. Anesthesiol. 22 (1) (2010) 46–52.