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Targeting the blood-spinal cord barrier: A therapeutic approach to spinal cord protection against ischemia-reperfusion injury
Life Sciences 158 (2016) 1–6
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Review article
Targeting the blood-spinal cord barrier: A therapeutic approach to spinal cord protection against ischemia-reperfusion injury Ji Hu a,⁎,1, Qijing Yu b,⁎,1, Lijie Xie a, Hongfei Zhu c a b c
Department of Anesthesiology, Liyuan Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430077, Hubei Province, China Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China Department of Anesthesiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China
a r t i c l e
i n f o
Article history: Received 24 March 2016 Received in revised form 15 June 2016 Accepted 17 June 2016 Available online 18 June 2016 Keywords: Blood-spinal cord barrier Spinal cord ischemia Reperfusion injury
a b s t r a c t One of the principal functions of physical barriers between the blood and central nervous system protects system (i.e., blood brain barrier and blood-spinal cord barrier) is the protection from toxic and pathogenic agents in the blood. Disruption of blood-spinal cord barrier (BSCB) plays a key role in spinal cord ischemia-reperfusion injury (SCIRI). Following SCIRI, the permeability of the BSCB increases. Maintaining the integrity of the BSCB alleviates the spinal cord injury after spinal cord ischemia. This review summarizes current knowledge of the structure and function of the BSCB and its changes following SCIRI, as well as the prevention and cure of SCIRI and the role of the BSCB. © 2016 Elsevier Inc. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Morphological structure and physiological function of BSCB. . . Morphological and functional changes in BSCB following SCIRI . 3.1. Morphological changes . . . . . . . . . . . . . . . . 3.2. Functional change . . . . . . . . . . . . . . . . . . 4. Prevention and treatment of SCIRI and the role of the BSCB . . . 4.1. Hypothermia treatment . . . . . . . . . . . . . . . 4.2. Ischemia preconditioning and ischemia post-conditioning 4.3. Drug intervention . . . . . . . . . . . . . . . . . . 4.3.1. Antioxidants . . . . . . . . . . . . . . . . 4.3.2. Anti-inflammatory drugs . . . . . . . . . . . 4.3.3. Anti-apoptotic agents . . . . . . . . . . . . 4.3.4. Traditional Chinese medicine . . . . . . . . . 4.4. BSCB treatment . . . . . . . . . . . . . . . . . . . 5. Conclusion and perspectives . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding authors. E-mail addresses: [email protected] (J. Hu), [email protected] (Q. Yu). 1 Ji Hu and Qijing Yu are co-first authors who contributed equally to this study.
http://dx.doi.org/10.1016/j.lfs.2016.06.018 0024-3205/© 2016 Elsevier Inc. All rights reserved.
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1. Introduction Spinal cord ischemia-reperfusion injury (SCIRI) is a devastating event that induces a series of complex cellular and molecular cascade events, sometimes converging to paralysis that physically and socially affects individuals. This condition is a serious complication of numerous pathophysiological states, such as hypotension, thoracoabdominal aortic aneurysm surgery, and thoracoabdominal aortic repair surgery [1, 2]. Blocking of the aorta for a certain period of time is often necessary in order to reduce bleeding and easily perform operations, especially in thoracoabdominal aortic aneurysm surgery and spinal operation. This procedure can cause spinal cord injury and even paralysis after restoring blood flow. The incidence of spinal cord injury after thoracic and thoracoabdominal aortic repair surgery is up to 32% [3]. With the development of medical technologies, the incidence rate of paraplegia following spinal cord injury decreased, while the incidence of paraplegia was still 5.1% following open thoracoabdominal aortic aneurysm repair surgery [4]. Reducing the SCIRI occurrence, as well as preventing and effectively taking care of patients with SCIRI, are key points that have attracted increasing research interests. Blood-spinal cord barrier (BSCB) is the diffusion barrier of physiological and metabolic molecules between the microvascular and surrounding tissues, which plays an important role in maintaining the stability of the central nervous system environment. Recently, several studies have demonstrated that the BSCB plays a vital role in SCIRI [5–7]. In fact maintaining the integrity of the BSCB can attenuate the spinal cord ischemia injury. Thus, the protection of the integrity of the BSCB is a promising tool to relieve spinal cord ischemia-reperfusion injury.
2. Morphological structure and physiological function of BSCB Similarly to the blood-brain barrier (BBB), the BSCB composition is based on specialized nonfenestrated endothelial cells, pericytes, end feet of astrocytic processes, and include some accessory structures, such as the tight junctions (TJs) and basal lamina (Fig. 1). TJs consist of several proteins, including occludin, claudins (claudin-1, claudin-3, and claudin-5), zonula occludens proteins (ZO-1, ZO-2, and ZO-3), and junctional adhesion molecules (JAMs) (Fig. 2). The orchestrated interaction of these building blocks makes possible the regulatory and protective functions of the BSCB [8,9]. One of the principal functions of the BSCB is to keep the homeostasis of the central nervous system. The barrier can selectively regulate the passage of water, ions, inflammatory factors, toxic metabolic substances, and inflammatory cells in the spinal cord tissue from the blood. Thus, the BSCB effectively protects the spinal cord [8]. The disruption of the barrier integrity leads to an increase in its permeability. As a consequence, many toxic substances can penetrate
Fig. 1. Schematic representation of the principal building blocks of the blood-spinal cord barrier (BSCB). A representative spinal cord capillary consists of nonfenestrated endothelial cells linked with tight junctions (TJs), basal lamina, pericytes, and astrocyte foot processes. The barrier provides a specialized mircroenviroment for the cellular constituents of the spinal cord.
Fig. 2. Endothelial cells are linked by tight junctions (TJs). A typical TJ consists of occludin, claudins, zona occludens (ZO-1, ZO-2, and ZO-3) proteins, and junctional adhesion molecules (JAMs). The paracellular diffusion pathway is severely restricted by TJs between individual endothelial cells.
into the spinal cord, causing spinal cord edema, neurons apoptosis, and death. 3. Morphological and functional changes in BSCB following SCIRI 3.1. Morphological changes The morphological structure of the BSCB is disrupted when spinal cord injury occurs. Matsushita et al. [7] showed ound that pericytes dissociate from endothelial cells after spinal cord injury and rapidly recover following intravenous infusion of bone marrow mesenchymal stem cells. Moreover, the matrix metalloproteinase-9(MMP-9) was found as increased in endothelial cells following spinal cord injury, while occludin and ZO-1 decreased in endothelial cells following hypoxia treatment [10]. Lee et al. [11] demonstrated that the expression of matrix metalloproteinase-3 (MMP-3) increased in endothelium after spinal cord injury and this result was related to the BSCB disruption. The expression of caveolin-1, the major structural protein required for the formation of caveolae, was detected as significantly increased in microvascular endothelial cell following SCIRI. In addition, the down-regulation of caveolin-1 expression could decrease the permeability of the BSCB [12]. Taken together, it is clear that changes in MMP-9, MMP-3 and caveolin-1 expression may affect the integrity of the BSCB following spinal cord injury. A study conducted in rats by Nordal and Wong [13] showed that the overexpression of the intercellular adhesion molecule-1 (ICAM-1) in the endothelium and astrocytes of the spinal cord induced the BSCB disruption after radiation injury. However, whether ICAM-1 expression increases in endothelium cells and astrocytes following SCIRI it is not clear and needs further investigation. Fang et al. [14,15] reported that the expression of MMP-9 was increased even in the astrocytes, along with the decrease in the expression of ZO-1 in endothelium cells; Moreover, they observed that the distribution of ZO-1 along microvasculatures became discontinuous. Among morphological changes occurring in BSCB, claudin-5, occludin, and ZO-1 levels increases after cerebral ischemia injury [16,17]. APQ-4 is a molecular water channel present in the brain and spinal cord, predominantly expressed in astrocytes and astrocytic end-feet processes and astrocytes. Similar changes have been observed after spinal cord injury [14, 18]. In summary, principal changes occurring in BSCB following spinal cord injury comprise the dissociation of the pericytes from endothelial cells, the increase of the expression of AQP-4, MMP-9, MMP-3 and caveolin-1 and the increase of claudin-5, occludin, and ZO-1 levels. The variation of basilemma after spinal cord injury and changes in ICAM-1 expression following SCIRI have not been elucidated and need further investigation.
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3.2. Functional change
4.1. Hypothermia treatment
Following SCIRI, the morphological structure of BSCB changes. As a consequence, its function is strongly affected. The primary functional change is the increased permeability of the BSCB. Unregulated passage of water, some ions, inflammatory factors and cells, and toxic metabolic substances infiltrates the spinal cord, leading to spinal cord edema, neurons death, and even paraplegia. More in detail, following SCIRI endothelial cells increases their permeability. Fang et al. [19] assessed the integrity of the BSCB by lanthanum nitrate extravasation tracing observed by electron microscopy. They found that lanthanum nitrate penetrates into basilemma, invading up to the parenchyma. Lanthanum ion is an electron-opaque tracer, which is widely used to examine the integrity of the BBB by transmission electron microscope. Another vascular tracer often used to detect the permeability by extravasation into brain or spinal parenchyma is the Evans blue (EB)·Compared with the normal spinal cord, the EB resulted markedly increased in the ischemia injury [19,20].One of the main reasons for the increased permeability of the BSCB is the reduction of the expression of claudins, occludin, and ZO-1, along with the increase in gaps between endothelial cells. This phenomenon results in inflammatory cells infiltration, such as neutrophils and macrophages into the spinal cord. These cells can release inflammatory factors, as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and cyclooxygenase (COX2), which can activate microglial cells. All these events aggravate spinal cord injury [5,10,21]. The matrix metalloproteinases (MMPs) can disrupt the basilemma structure and degrade TJ proteins, which mainly increases the permeability. Several studies confirmed a potential role for hypoxia, showing that this condition can induce the up-regulation of MMP-9 expression in the spinal cord tissue [22,23]. Among the MMPs, MMP-9 is the principal protein responsible of the disruption of the basilemma and the degradation TJ proteins. MMP-2 and MMP-3 can also affect the BSCB [10,24]. Fluoxetine, a selective serotonin reuptake inhibitor, which is commonly prescribed as anti-depressant, can suppress the expression of MMP-9 by down-regulating nuclear transcription factor-κB (NF-κB) and reducing the loss of occludin and ZO-1 in the endothelium after hypoxia/reoxygenation [10].This data thus indicates that NFκB signal pathway regulates the expression of MMP-9. The expression of NF-κB increases after spinal cord injury and combining bone marrow stromal cells with green tea polyphenols can downregulate the expression of NF-κB [25]. The down-regulation of the NF-κB expression can also reduce the level of MMP-9 in cerebral endothelium cells. We can infer that the NF-κB signal pathway indirectly regulates the integrity of BSCB. The distribution and low expression of TJ proteins in the endothelium increase the gap between endothelial cells. In a rabbit model of SCIRI, the expression of ZO-1 among endothelial cells was observed as decreased by using fluorescence microscopy [14]. Yang et al. reported that the decrease of the expression of claudin-5, occludin, and ZO-1 was related to an increase in the permeability of BBB [16]. Overall, the principal functional change of the BSCB is the increase in its permeability, with worsening of spinal cord injury. The main mechanism is related to the up-regulation of the MMP-9 expression and the down-regulation of TJ proteins.
Hypothermia can reduce the enzymes activity and energy metabolism levels. Low temperature can reduce lipid peroxidation and the release of excitatory and inflammatory amino acids. Hypothermia also plays an important role in reducing tissue edema. Thus, low temperature has a protective effect on SCIRI, as has been reported in rat model [26,27]. Recently, Zhu et al. [28] showed that hypothermia treatment can reduce neurons apoptosis and improve locomotion function after spinal cord ischemia injury in rats, and mechanisms underlying these effects are associated with the inhibition of the expression of Bcl-2 associated X (BAX) protein and the activation of B-cell lymphoma-2 (Bcl-2) protein, both crucial plyers Bcl-2 in cell apoptosis. It has been reported that low temperature treatment can protect the integrity of the BSCB. Yu et al. [29] found that a low temperature of 30 °C can reduce albumin, fibrinogen, and fiber adhesion proteins infiltrating into the spinal cord and protect the integrity of the BSCB in a rat model of spinal cord trauma. On the other hand, Tang et al. [30] reported that mild hypothermia can reduce the BBB disruption in mice after inducing experimental stroke. Local hypothermia can protect the integrity of BBB in rats, and the mechanism of action involves the up-regulation of claudin-5 and occludin expression and the down-regulation of TNF-α and IL-1β expression after intracerebral hemorrhage [31]. A recently study showed that local hypothermia can reduce protease activated receptor-1 (PAR1), MMP-9, and AQP-4 expression in rats, alleviating the disruption of the BBB and cerebral edema [32]. Thus, low temperature can protect the integrity of the BBB or the BSCB by down-regulating MMP-9 and AQP-4 expression and upregulating TJ proteins. Hypothermia treatment is a simple method easy to perform in clinical applications. For example, cooling blankets and cooling pads can implement surface cooling, and infusion of cold intravenous solution is an effective technique for rapid induction of hypothermia. Clinical studies conducted on human patients provided evidences that localized or systemic hypothermia may be applied safely and efficaciously in patients with brain and spinal cord injuries. Holzer et al. reported that therapeutic mild hypothermia (target temperature, 32 °C to 34 °C) increased the rate of a favorable neurologic outcome and reduced mortality in patients successfully resuscitated after cardiac arrest due to ventricular fibrillation [33]. The neurological outcome of patients with acute cervical spinal cord injury was improved by receiving modest (33 °C) intravascular hypothermia for 48 h [34]. Moreover, local deep cooling (dural temperature 6 °C) could improve the neurological outcome of patients with a neurologically complete spinal cord injury [35]. However, Beca et al. demonstrated that early therapeutic hypothermia ((32 °C to 33 °C) with a servocontrolled cooling blanket) in children with severe traumatic brain injury did not improve outcome and should not be used outside a clinical trial [36]. Thus, there some controversial about the effect and the clinical efficacy of hypothermia, and be further investigations are required.
4. Prevention and treatment of SCIRI and the role of the BSCB The prevention and treatment of SCIRI remains a hotspot issue. Principal preventive measures of SCIRI include hypothermia treatment, ischemic preconditioning and post-conditioning, and drug intervention. Mechanisms mainly involved in these methods may include anti-oxidation, anti-inflammatory and anti-apoptosis responses. Although these treatments acquired a certain therapeutic effect, the paraplegia induced by SCIRI is still a threat for patients.
4.2. Ischemia preconditioning and ischemia post-conditioning Ischemic preconditioning is the exposure to brief periods of circulatory occlusion and reperfusion to protect local or systemic organs against subsequent ischemia-reperfusion injury. Mechanisms of underlying ischemia preconditioning are extremely complicated. They include the increase of the expression of anti-oxidant enzymes and brain-derived neurotrophic factors and the decrease of the production of reactive oxygen species, among others [37,38]. Liang et al. [39] proposed that ischemia preconditioning can improve hind limb movement function and protect motor neurons after SCIRI in rats. Other studies also confirmed that ischemia preconditioning has a protective effect on SCIRI [14,18]. This procedure can maintain the integrity of BSCB, mainly through the up-regulation of ZO-1 expression and down-regulation of MMP-9, TNF-α, and AQP-4 levels. These events lead to a decrease in the permeability of the BSCB, alleviating the spinal cord tissue edema. Ischemia post-conditioning is defined as a procedure of rapid
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intermittent periods of reperfusion and ischemia in the early phase of reperfusion after long ischemia. Ischemia post-conditioning and ischemia preconditioning possess similar protective mechanisms. Song et al. [37] found that ischemia post-conditioning can protect spinal cord by increasing endogenous antioxidant enzyme levels in a rabbit model of SCIRI. Ischemia preconditioning and ischemia post-conditioning are difficult to perform in a clinical setting and it remains unclear the real contribution in clinical benefit. By contrast, remote ischemic preconditioning (RIRC) and post-conditioning (RIPoC) are easy to perform, and their protective effects have been confirmed in cerebral and spinal cord ischemia injuries [40]. RIPC consists of cycles of transient nonfatal ischemia in one tissue to enhance the toleration of a subsequent prolonged fatal ischemia in distant organs. On the other hand, RIPoC refers to transient episodes of peripheral ischemia (e.g. limb ischemia) at the beginning of reperfusion, and can enhance the toleration of a subsequent prolonged fatal ischemia in distant organs. Several studies [41– 43] have showed that RIPC and RIPoC can really reduce myocardial ischemia injury and brain ischemia injury. Li et al. [44] found that RIPoC can maintain the integrity of BBB and reduce cerebral edema by down-regulating AQP-4 expression in rats. In addition, Ren et al. [45] found that RIPC can alleviate the permeability of the BBB and cerebral edema still in rats. A study realized on human cohort by Hong et al. [46] reported that RIPC with RIPoC by transient upper limb ischemia did not improve clinical outcome in patients underwent cardiac surgery. Overall, ischemia preconditioning and post-conditioning may have significant protective effects on the BBB and the BSCB, but the clinical effects need to be deeply evaluated through further studies. 4.3. Drug intervention To date, many drugs have been used to treat SCIRI, but the curative effect is not satisfactory. These drugs are as follows. 4.3.1. Antioxidants Antioxidants are able to clear away oxygen free radicals induced by spinal cord ischemia. Representative drugs include vitamin C, glutathione peptide, and superoxide dismutase [47–49].These drugs could relief spinal cord ischemia injury by intraperitoneal administration to animal before ischemia surgery or several times in a few days after ischemia injury. However, the protective effect of antioxidant in vivo in human patients has not been confirmed and needs further researches. 4.3.2. Anti-inflammatory drugs Inflammation plays a crucial role in SCIRI, and suppressing the inflammatory reaction can alleviate spinal cord injury. Currently, diltiazem, ibuprofen, minocycline and methylprednisolone have been used to treat spinal cord injury. Fansa et al. [50] found that in a rabbit model, the intravenous infusion of diltiazem 10 min before ischemia induction can reduce IL-6 levels, leading to reduce spinal cord injury. The effect of ibuprofen was assessed by using a rat model. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord injury, rats recovered walking function. This was connected with the protection of tissues, the stimulation of axonal sprouting, and the degree of raphespinal regeneration [51]. However, another study showed that ibuprofen could not improve functional and histological outcomes after spinal cord injury in rats. In this case, ibuprofen was administrated subcutaneously every 12 h, starting 30 min after the spinal cord injury, and continued for 42 days [52]. Boyaci et al. [53] demonstrated that methylprednisolone (30 mg/kg) can reduce spinal cord ischemia reperfusion injury in rabbits. Diltiazem, minocycline, and methylprednisolone are drugs commonly used in clinical. Unfortunately clinical studies about their protective effects for spinal cord injury are rare. Minocycline given intravenously within 12 h of spinal cord injury and for 7 days could improve the neurological and functional outcomes compared with placebo in patients with spinal cord injury, but need to warrant further formal investigation of efficacy [54]. Evaniew et al.
demonstrated that methylprednisolone did not improve motor score recovery in patients with acute traumatic spinal cord injuries in either the cervical or thoracic spine. In addition, they found that there was a significantly higher rate of total complications in the methylprednisolone group [55]. 4.3.3. Anti-apoptotic agents Reducing neuron apoptosis can ameliorate hind limb motor function and spinal cord injury. Anti-apoptotic agents mainly includes ginsenoside Rd, bosentan and erythropoietin. Rats receiving intraperitoneal injection of ginsenoside Rd every days for up to 7 days after SCIRI showed an inhibition of neuron apoptosis [56]. Even bosentan has been showed as able to decrease apoptosis rate after ischemia injury in spinal cord in rats [57]. Celik et al. [58] found that intravenously administration of recombinant human erythropoietin immediately after onset of the reperfusion can prevent motor neuron apoptosis in a rabbit model of SCIRI. However there is no literature reporting that anti-apoptotic agents could prevent neuron apoptosis in human SCIRI patients. Although the administration of selegiline, a selective monoamine oxidase type B inhibitor, with anti-apoptotic properties, in the subacute phase can promote cognitive functioning in stroke patients, this was assessed only by neuropsychological characterization, without apoptosis assessment [59]. 4.3.4. Traditional Chinese medicine Curcumin and Ginkgo biloba are natural products belonging to traditional Chinese medicine. The protective effect of curcumin and Ginkgo biloba has been evaluated in animal models of spinal cord ischemia. In a rabbit model of SCIRI, the intraperitoneal administration of curcumin just after the onset of reperfusion has been proved to relief the spinal cord ischemia injury [60]. Kurt et al. [61] indicated that in a rat model of SCIRI the treatment withn 100 mg/kg/day orogastric dose of Ginkgo biloba extract for 3 days pre-surgery and 2 days post-surgery, which led to attenuate spinal cord ischemia injury. However, even if several studies aimed to verify the protective effect of traditional Chinese medicine have been conducted on murine, rat and rabbit models, the analysis of these effects on human cohort is lacking. Recently, it has been shown that the treatment with several drugs, ghrelin, melatonin, fluoxetine, and salvianolic acid B can effectively protect the integrity of the BBB and the BSCB following spinal cord and cerebral injury [62–65].It is clear that the production of novel drugs that can effectively protect BSCB may be helpful for treating SCIRI. However, more clinical researches need to be performed to better understand mechanisms and effects of such drugs. 4.4. BSCB treatment As discussed above, the BSCB is well-known to play a vital role in the pathological process of SCIRI. If the integrity of the BSCB is disrupted, the permeability will increase and the spinal cord injury will be more severe. Maintaining the integrity of BSCB through different methods has good preventive and therapeutic effects on SCIRI and thus attracting always more researchers. Bone marrow stromal stem cells, dexmedetomidine, ischemia, and sevoflurane preconditioning can downregulate MMP-9 expression and upregulate TJ proteins levels. This response can maintain the integrity of the BSCB and protect spinal cord [14,15,19,66]. MMP-9 is one of the main destructive factors for the BSCB. Reducing MMP-9 expression can alleviate brain or spinal cord injury. For example, Asahi et al. [67] reported in knockout mice for MMP-9 gene the BBB was more intact than that wild-type mice. MMP-9 inhibitors, such as TIMPs and BB-1101, can clearly ameliorate the permeability of the BBB [68]. Understand how to maintain the integrity of BSCB following spinal cord ischemia injury is a worthy research field to analyze in depth.
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5. Conclusion and perspectives Paraplegia induced by SCIRI not only threatens physical health but also causes heavy economic burden to the families and society. Unfortunately, although many adjunctive therapies have been used to protect spinal cord, this complication still cannot be completely prevented. The permeability of the BSCB is disrupted following spinal cord ischemia and a secondary progressive increase in the BSCB disruption after reperfusion, which leads to spinal cord edema and inflammatory events, exacerbates the spinal cord injury. The protection of the integrity of the BSCB can significantly attenuate SCIRI, as confirmed by several studies. However, the most effective protective measures for the integrity of the BSCB after SCIRI are worth to explore. The combination of multiple drugs and methods, along with a deeper understanding of cellular mechanisims will be an efficient tool to presevre the integrity of the BSCB [25,69–72], which represents a BSCB treatment is a promising prevention and cure of SCIRI. Author contributions Ji Hu and Lijie Xie wrote the manuscript, and Qijing Yu and Hongfei Zhu have carefully revised the manuscript. Ji Hu and Qijing Yu are cofirst authors who contributed equally to this study. All authors have approved the final version of this paper. Conflicts of interest None declared. Acknowledgments This work was supported by grants from the Nature Science Foundation of Hubei Province (No.2013CFB086 to Ji Hu), the Hubei Province health and family planning scientific research project (No. WJ2015MB023 to Qijing Yu) and the Science and Technology Department of Hubei province (project of scientific research condition and resource research development) fund (No. 2015BCE099 to Hongfei Zhu). References [1] A. Katsargyris, K. Oikonomou, G. Kouvelos, et al., Spinal cord ischemia after endovascular repair of thoracoabdominal aortic aneurysms with fenestrated and branched stent grafts, J. Vasc. Surg. 62 (6) (2015) 1450–1455. [2] M. Kato, M. Motoki, T. Isaji, et al., Spinal cord injury after endovascular treatment for thoracoabdominal aneurysm or dissection, Eur. J. Cardiothorac. Surg. 48 (4) (2015) 571–577. [3] N. Panthee, M. Ono, Spinal cord injury following thoracic and thoracoabdominal aortic repairs, Asian Cardiovasc. Thorac. Ann. 23 (2) (2015) 235–246. [4] S.A. Lemaire, M.D. Price, S.Y. Green, S. Zarda, J.S. Coselli, Results of open thoracoabdominal aortic aneurysm repair, Ann. Cardiothorac Surg. 1 (3) (2012) 286–292. [5] 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. [6] 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. [7] T. Matsushita, K.L. Lankford, E.J. Arroyo, M. Sasaki, M. Neyazi, C. Radtke, J.D. Kocsis, Diffuse and persistent blood–spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells, Exp. Neurol. 267 (2015) 152–164. [8] B. Aube, S.A. Levesque, A. Pare, E. Chamma, H. Kebir, R. Gorina, M. Lecuyer, J.I. Alvarez, Y. De Koninck, B. Engelhardt, A. Prat, D. Cote, S. Lacroix, Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases, J. Immunol. 193 (2014) 2438–2454. [9] V. Bartanusz, D. Jezova, B. Alajajian, M. Digicaylioglu, The blood-spinal cord barrier: morphology and clinical implications, Ann. Neurol. 70 (2011) 194–206. [10] J.Y. Lee, H.S. Kim, H.Y. Choi, T.H. Oh, T.Y. Yune, Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury, Brain 135 (2012) 2375–2389. [11] J.Y. Lee, H.Y. Choi, H. Ahn, B. Ju, T. Yune, Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury, Am. J. Pathol. 184 (11) (2014) 2985–3000.
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Review article
Targeting the blood-spinal cord barrier: A therapeutic approach to spinal cord protection against ischemia-reperfusion injury Ji Hu a,⁎,1, Qijing Yu b,⁎,1, Lijie Xie a, Hongfei Zhu c a b c
Department of Anesthesiology, Liyuan Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430077, Hubei Province, China Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China Department of Anesthesiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China
a r t i c l e
i n f o
Article history: Received 24 March 2016 Received in revised form 15 June 2016 Accepted 17 June 2016 Available online 18 June 2016 Keywords: Blood-spinal cord barrier Spinal cord ischemia Reperfusion injury
a b s t r a c t One of the principal functions of physical barriers between the blood and central nervous system protects system (i.e., blood brain barrier and blood-spinal cord barrier) is the protection from toxic and pathogenic agents in the blood. Disruption of blood-spinal cord barrier (BSCB) plays a key role in spinal cord ischemia-reperfusion injury (SCIRI). Following SCIRI, the permeability of the BSCB increases. Maintaining the integrity of the BSCB alleviates the spinal cord injury after spinal cord ischemia. This review summarizes current knowledge of the structure and function of the BSCB and its changes following SCIRI, as well as the prevention and cure of SCIRI and the role of the BSCB. © 2016 Elsevier Inc. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Morphological structure and physiological function of BSCB. . . Morphological and functional changes in BSCB following SCIRI . 3.1. Morphological changes . . . . . . . . . . . . . . . . 3.2. Functional change . . . . . . . . . . . . . . . . . . 4. Prevention and treatment of SCIRI and the role of the BSCB . . . 4.1. Hypothermia treatment . . . . . . . . . . . . . . . 4.2. Ischemia preconditioning and ischemia post-conditioning 4.3. Drug intervention . . . . . . . . . . . . . . . . . . 4.3.1. Antioxidants . . . . . . . . . . . . . . . . 4.3.2. Anti-inflammatory drugs . . . . . . . . . . . 4.3.3. Anti-apoptotic agents . . . . . . . . . . . . 4.3.4. Traditional Chinese medicine . . . . . . . . . 4.4. BSCB treatment . . . . . . . . . . . . . . . . . . . 5. Conclusion and perspectives . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding authors. E-mail addresses: [email protected] (J. Hu), [email protected] (Q. Yu). 1 Ji Hu and Qijing Yu are co-first authors who contributed equally to this study.
http://dx.doi.org/10.1016/j.lfs.2016.06.018 0024-3205/© 2016 Elsevier Inc. All rights reserved.
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1. Introduction Spinal cord ischemia-reperfusion injury (SCIRI) is a devastating event that induces a series of complex cellular and molecular cascade events, sometimes converging to paralysis that physically and socially affects individuals. This condition is a serious complication of numerous pathophysiological states, such as hypotension, thoracoabdominal aortic aneurysm surgery, and thoracoabdominal aortic repair surgery [1, 2]. Blocking of the aorta for a certain period of time is often necessary in order to reduce bleeding and easily perform operations, especially in thoracoabdominal aortic aneurysm surgery and spinal operation. This procedure can cause spinal cord injury and even paralysis after restoring blood flow. The incidence of spinal cord injury after thoracic and thoracoabdominal aortic repair surgery is up to 32% [3]. With the development of medical technologies, the incidence rate of paraplegia following spinal cord injury decreased, while the incidence of paraplegia was still 5.1% following open thoracoabdominal aortic aneurysm repair surgery [4]. Reducing the SCIRI occurrence, as well as preventing and effectively taking care of patients with SCIRI, are key points that have attracted increasing research interests. Blood-spinal cord barrier (BSCB) is the diffusion barrier of physiological and metabolic molecules between the microvascular and surrounding tissues, which plays an important role in maintaining the stability of the central nervous system environment. Recently, several studies have demonstrated that the BSCB plays a vital role in SCIRI [5–7]. In fact maintaining the integrity of the BSCB can attenuate the spinal cord ischemia injury. Thus, the protection of the integrity of the BSCB is a promising tool to relieve spinal cord ischemia-reperfusion injury.
2. Morphological structure and physiological function of BSCB Similarly to the blood-brain barrier (BBB), the BSCB composition is based on specialized nonfenestrated endothelial cells, pericytes, end feet of astrocytic processes, and include some accessory structures, such as the tight junctions (TJs) and basal lamina (Fig. 1). TJs consist of several proteins, including occludin, claudins (claudin-1, claudin-3, and claudin-5), zonula occludens proteins (ZO-1, ZO-2, and ZO-3), and junctional adhesion molecules (JAMs) (Fig. 2). The orchestrated interaction of these building blocks makes possible the regulatory and protective functions of the BSCB [8,9]. One of the principal functions of the BSCB is to keep the homeostasis of the central nervous system. The barrier can selectively regulate the passage of water, ions, inflammatory factors, toxic metabolic substances, and inflammatory cells in the spinal cord tissue from the blood. Thus, the BSCB effectively protects the spinal cord [8]. The disruption of the barrier integrity leads to an increase in its permeability. As a consequence, many toxic substances can penetrate
Fig. 1. Schematic representation of the principal building blocks of the blood-spinal cord barrier (BSCB). A representative spinal cord capillary consists of nonfenestrated endothelial cells linked with tight junctions (TJs), basal lamina, pericytes, and astrocyte foot processes. The barrier provides a specialized mircroenviroment for the cellular constituents of the spinal cord.
Fig. 2. Endothelial cells are linked by tight junctions (TJs). A typical TJ consists of occludin, claudins, zona occludens (ZO-1, ZO-2, and ZO-3) proteins, and junctional adhesion molecules (JAMs). The paracellular diffusion pathway is severely restricted by TJs between individual endothelial cells.
into the spinal cord, causing spinal cord edema, neurons apoptosis, and death. 3. Morphological and functional changes in BSCB following SCIRI 3.1. Morphological changes The morphological structure of the BSCB is disrupted when spinal cord injury occurs. Matsushita et al. [7] showed ound that pericytes dissociate from endothelial cells after spinal cord injury and rapidly recover following intravenous infusion of bone marrow mesenchymal stem cells. Moreover, the matrix metalloproteinase-9(MMP-9) was found as increased in endothelial cells following spinal cord injury, while occludin and ZO-1 decreased in endothelial cells following hypoxia treatment [10]. Lee et al. [11] demonstrated that the expression of matrix metalloproteinase-3 (MMP-3) increased in endothelium after spinal cord injury and this result was related to the BSCB disruption. The expression of caveolin-1, the major structural protein required for the formation of caveolae, was detected as significantly increased in microvascular endothelial cell following SCIRI. In addition, the down-regulation of caveolin-1 expression could decrease the permeability of the BSCB [12]. Taken together, it is clear that changes in MMP-9, MMP-3 and caveolin-1 expression may affect the integrity of the BSCB following spinal cord injury. A study conducted in rats by Nordal and Wong [13] showed that the overexpression of the intercellular adhesion molecule-1 (ICAM-1) in the endothelium and astrocytes of the spinal cord induced the BSCB disruption after radiation injury. However, whether ICAM-1 expression increases in endothelium cells and astrocytes following SCIRI it is not clear and needs further investigation. Fang et al. [14,15] reported that the expression of MMP-9 was increased even in the astrocytes, along with the decrease in the expression of ZO-1 in endothelium cells; Moreover, they observed that the distribution of ZO-1 along microvasculatures became discontinuous. Among morphological changes occurring in BSCB, claudin-5, occludin, and ZO-1 levels increases after cerebral ischemia injury [16,17]. APQ-4 is a molecular water channel present in the brain and spinal cord, predominantly expressed in astrocytes and astrocytic end-feet processes and astrocytes. Similar changes have been observed after spinal cord injury [14, 18]. In summary, principal changes occurring in BSCB following spinal cord injury comprise the dissociation of the pericytes from endothelial cells, the increase of the expression of AQP-4, MMP-9, MMP-3 and caveolin-1 and the increase of claudin-5, occludin, and ZO-1 levels. The variation of basilemma after spinal cord injury and changes in ICAM-1 expression following SCIRI have not been elucidated and need further investigation.
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3.2. Functional change
4.1. Hypothermia treatment
Following SCIRI, the morphological structure of BSCB changes. As a consequence, its function is strongly affected. The primary functional change is the increased permeability of the BSCB. Unregulated passage of water, some ions, inflammatory factors and cells, and toxic metabolic substances infiltrates the spinal cord, leading to spinal cord edema, neurons death, and even paraplegia. More in detail, following SCIRI endothelial cells increases their permeability. Fang et al. [19] assessed the integrity of the BSCB by lanthanum nitrate extravasation tracing observed by electron microscopy. They found that lanthanum nitrate penetrates into basilemma, invading up to the parenchyma. Lanthanum ion is an electron-opaque tracer, which is widely used to examine the integrity of the BBB by transmission electron microscope. Another vascular tracer often used to detect the permeability by extravasation into brain or spinal parenchyma is the Evans blue (EB)·Compared with the normal spinal cord, the EB resulted markedly increased in the ischemia injury [19,20].One of the main reasons for the increased permeability of the BSCB is the reduction of the expression of claudins, occludin, and ZO-1, along with the increase in gaps between endothelial cells. This phenomenon results in inflammatory cells infiltration, such as neutrophils and macrophages into the spinal cord. These cells can release inflammatory factors, as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and cyclooxygenase (COX2), which can activate microglial cells. All these events aggravate spinal cord injury [5,10,21]. The matrix metalloproteinases (MMPs) can disrupt the basilemma structure and degrade TJ proteins, which mainly increases the permeability. Several studies confirmed a potential role for hypoxia, showing that this condition can induce the up-regulation of MMP-9 expression in the spinal cord tissue [22,23]. Among the MMPs, MMP-9 is the principal protein responsible of the disruption of the basilemma and the degradation TJ proteins. MMP-2 and MMP-3 can also affect the BSCB [10,24]. Fluoxetine, a selective serotonin reuptake inhibitor, which is commonly prescribed as anti-depressant, can suppress the expression of MMP-9 by down-regulating nuclear transcription factor-κB (NF-κB) and reducing the loss of occludin and ZO-1 in the endothelium after hypoxia/reoxygenation [10].This data thus indicates that NFκB signal pathway regulates the expression of MMP-9. The expression of NF-κB increases after spinal cord injury and combining bone marrow stromal cells with green tea polyphenols can downregulate the expression of NF-κB [25]. The down-regulation of the NF-κB expression can also reduce the level of MMP-9 in cerebral endothelium cells. We can infer that the NF-κB signal pathway indirectly regulates the integrity of BSCB. The distribution and low expression of TJ proteins in the endothelium increase the gap between endothelial cells. In a rabbit model of SCIRI, the expression of ZO-1 among endothelial cells was observed as decreased by using fluorescence microscopy [14]. Yang et al. reported that the decrease of the expression of claudin-5, occludin, and ZO-1 was related to an increase in the permeability of BBB [16]. Overall, the principal functional change of the BSCB is the increase in its permeability, with worsening of spinal cord injury. The main mechanism is related to the up-regulation of the MMP-9 expression and the down-regulation of TJ proteins.
Hypothermia can reduce the enzymes activity and energy metabolism levels. Low temperature can reduce lipid peroxidation and the release of excitatory and inflammatory amino acids. Hypothermia also plays an important role in reducing tissue edema. Thus, low temperature has a protective effect on SCIRI, as has been reported in rat model [26,27]. Recently, Zhu et al. [28] showed that hypothermia treatment can reduce neurons apoptosis and improve locomotion function after spinal cord ischemia injury in rats, and mechanisms underlying these effects are associated with the inhibition of the expression of Bcl-2 associated X (BAX) protein and the activation of B-cell lymphoma-2 (Bcl-2) protein, both crucial plyers Bcl-2 in cell apoptosis. It has been reported that low temperature treatment can protect the integrity of the BSCB. Yu et al. [29] found that a low temperature of 30 °C can reduce albumin, fibrinogen, and fiber adhesion proteins infiltrating into the spinal cord and protect the integrity of the BSCB in a rat model of spinal cord trauma. On the other hand, Tang et al. [30] reported that mild hypothermia can reduce the BBB disruption in mice after inducing experimental stroke. Local hypothermia can protect the integrity of BBB in rats, and the mechanism of action involves the up-regulation of claudin-5 and occludin expression and the down-regulation of TNF-α and IL-1β expression after intracerebral hemorrhage [31]. A recently study showed that local hypothermia can reduce protease activated receptor-1 (PAR1), MMP-9, and AQP-4 expression in rats, alleviating the disruption of the BBB and cerebral edema [32]. Thus, low temperature can protect the integrity of the BBB or the BSCB by down-regulating MMP-9 and AQP-4 expression and upregulating TJ proteins. Hypothermia treatment is a simple method easy to perform in clinical applications. For example, cooling blankets and cooling pads can implement surface cooling, and infusion of cold intravenous solution is an effective technique for rapid induction of hypothermia. Clinical studies conducted on human patients provided evidences that localized or systemic hypothermia may be applied safely and efficaciously in patients with brain and spinal cord injuries. Holzer et al. reported that therapeutic mild hypothermia (target temperature, 32 °C to 34 °C) increased the rate of a favorable neurologic outcome and reduced mortality in patients successfully resuscitated after cardiac arrest due to ventricular fibrillation [33]. The neurological outcome of patients with acute cervical spinal cord injury was improved by receiving modest (33 °C) intravascular hypothermia for 48 h [34]. Moreover, local deep cooling (dural temperature 6 °C) could improve the neurological outcome of patients with a neurologically complete spinal cord injury [35]. However, Beca et al. demonstrated that early therapeutic hypothermia ((32 °C to 33 °C) with a servocontrolled cooling blanket) in children with severe traumatic brain injury did not improve outcome and should not be used outside a clinical trial [36]. Thus, there some controversial about the effect and the clinical efficacy of hypothermia, and be further investigations are required.
4. Prevention and treatment of SCIRI and the role of the BSCB The prevention and treatment of SCIRI remains a hotspot issue. Principal preventive measures of SCIRI include hypothermia treatment, ischemic preconditioning and post-conditioning, and drug intervention. Mechanisms mainly involved in these methods may include anti-oxidation, anti-inflammatory and anti-apoptosis responses. Although these treatments acquired a certain therapeutic effect, the paraplegia induced by SCIRI is still a threat for patients.
4.2. Ischemia preconditioning and ischemia post-conditioning Ischemic preconditioning is the exposure to brief periods of circulatory occlusion and reperfusion to protect local or systemic organs against subsequent ischemia-reperfusion injury. Mechanisms of underlying ischemia preconditioning are extremely complicated. They include the increase of the expression of anti-oxidant enzymes and brain-derived neurotrophic factors and the decrease of the production of reactive oxygen species, among others [37,38]. Liang et al. [39] proposed that ischemia preconditioning can improve hind limb movement function and protect motor neurons after SCIRI in rats. Other studies also confirmed that ischemia preconditioning has a protective effect on SCIRI [14,18]. This procedure can maintain the integrity of BSCB, mainly through the up-regulation of ZO-1 expression and down-regulation of MMP-9, TNF-α, and AQP-4 levels. These events lead to a decrease in the permeability of the BSCB, alleviating the spinal cord tissue edema. Ischemia post-conditioning is defined as a procedure of rapid
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intermittent periods of reperfusion and ischemia in the early phase of reperfusion after long ischemia. Ischemia post-conditioning and ischemia preconditioning possess similar protective mechanisms. Song et al. [37] found that ischemia post-conditioning can protect spinal cord by increasing endogenous antioxidant enzyme levels in a rabbit model of SCIRI. Ischemia preconditioning and ischemia post-conditioning are difficult to perform in a clinical setting and it remains unclear the real contribution in clinical benefit. By contrast, remote ischemic preconditioning (RIRC) and post-conditioning (RIPoC) are easy to perform, and their protective effects have been confirmed in cerebral and spinal cord ischemia injuries [40]. RIPC consists of cycles of transient nonfatal ischemia in one tissue to enhance the toleration of a subsequent prolonged fatal ischemia in distant organs. On the other hand, RIPoC refers to transient episodes of peripheral ischemia (e.g. limb ischemia) at the beginning of reperfusion, and can enhance the toleration of a subsequent prolonged fatal ischemia in distant organs. Several studies [41– 43] have showed that RIPC and RIPoC can really reduce myocardial ischemia injury and brain ischemia injury. Li et al. [44] found that RIPoC can maintain the integrity of BBB and reduce cerebral edema by down-regulating AQP-4 expression in rats. In addition, Ren et al. [45] found that RIPC can alleviate the permeability of the BBB and cerebral edema still in rats. A study realized on human cohort by Hong et al. [46] reported that RIPC with RIPoC by transient upper limb ischemia did not improve clinical outcome in patients underwent cardiac surgery. Overall, ischemia preconditioning and post-conditioning may have significant protective effects on the BBB and the BSCB, but the clinical effects need to be deeply evaluated through further studies. 4.3. Drug intervention To date, many drugs have been used to treat SCIRI, but the curative effect is not satisfactory. These drugs are as follows. 4.3.1. Antioxidants Antioxidants are able to clear away oxygen free radicals induced by spinal cord ischemia. Representative drugs include vitamin C, glutathione peptide, and superoxide dismutase [47–49].These drugs could relief spinal cord ischemia injury by intraperitoneal administration to animal before ischemia surgery or several times in a few days after ischemia injury. However, the protective effect of antioxidant in vivo in human patients has not been confirmed and needs further researches. 4.3.2. Anti-inflammatory drugs Inflammation plays a crucial role in SCIRI, and suppressing the inflammatory reaction can alleviate spinal cord injury. Currently, diltiazem, ibuprofen, minocycline and methylprednisolone have been used to treat spinal cord injury. Fansa et al. [50] found that in a rabbit model, the intravenous infusion of diltiazem 10 min before ischemia induction can reduce IL-6 levels, leading to reduce spinal cord injury. The effect of ibuprofen was assessed by using a rat model. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord injury, rats recovered walking function. This was connected with the protection of tissues, the stimulation of axonal sprouting, and the degree of raphespinal regeneration [51]. However, another study showed that ibuprofen could not improve functional and histological outcomes after spinal cord injury in rats. In this case, ibuprofen was administrated subcutaneously every 12 h, starting 30 min after the spinal cord injury, and continued for 42 days [52]. Boyaci et al. [53] demonstrated that methylprednisolone (30 mg/kg) can reduce spinal cord ischemia reperfusion injury in rabbits. Diltiazem, minocycline, and methylprednisolone are drugs commonly used in clinical. Unfortunately clinical studies about their protective effects for spinal cord injury are rare. Minocycline given intravenously within 12 h of spinal cord injury and for 7 days could improve the neurological and functional outcomes compared with placebo in patients with spinal cord injury, but need to warrant further formal investigation of efficacy [54]. Evaniew et al.
demonstrated that methylprednisolone did not improve motor score recovery in patients with acute traumatic spinal cord injuries in either the cervical or thoracic spine. In addition, they found that there was a significantly higher rate of total complications in the methylprednisolone group [55]. 4.3.3. Anti-apoptotic agents Reducing neuron apoptosis can ameliorate hind limb motor function and spinal cord injury. Anti-apoptotic agents mainly includes ginsenoside Rd, bosentan and erythropoietin. Rats receiving intraperitoneal injection of ginsenoside Rd every days for up to 7 days after SCIRI showed an inhibition of neuron apoptosis [56]. Even bosentan has been showed as able to decrease apoptosis rate after ischemia injury in spinal cord in rats [57]. Celik et al. [58] found that intravenously administration of recombinant human erythropoietin immediately after onset of the reperfusion can prevent motor neuron apoptosis in a rabbit model of SCIRI. However there is no literature reporting that anti-apoptotic agents could prevent neuron apoptosis in human SCIRI patients. Although the administration of selegiline, a selective monoamine oxidase type B inhibitor, with anti-apoptotic properties, in the subacute phase can promote cognitive functioning in stroke patients, this was assessed only by neuropsychological characterization, without apoptosis assessment [59]. 4.3.4. Traditional Chinese medicine Curcumin and Ginkgo biloba are natural products belonging to traditional Chinese medicine. The protective effect of curcumin and Ginkgo biloba has been evaluated in animal models of spinal cord ischemia. In a rabbit model of SCIRI, the intraperitoneal administration of curcumin just after the onset of reperfusion has been proved to relief the spinal cord ischemia injury [60]. Kurt et al. [61] indicated that in a rat model of SCIRI the treatment withn 100 mg/kg/day orogastric dose of Ginkgo biloba extract for 3 days pre-surgery and 2 days post-surgery, which led to attenuate spinal cord ischemia injury. However, even if several studies aimed to verify the protective effect of traditional Chinese medicine have been conducted on murine, rat and rabbit models, the analysis of these effects on human cohort is lacking. Recently, it has been shown that the treatment with several drugs, ghrelin, melatonin, fluoxetine, and salvianolic acid B can effectively protect the integrity of the BBB and the BSCB following spinal cord and cerebral injury [62–65].It is clear that the production of novel drugs that can effectively protect BSCB may be helpful for treating SCIRI. However, more clinical researches need to be performed to better understand mechanisms and effects of such drugs. 4.4. BSCB treatment As discussed above, the BSCB is well-known to play a vital role in the pathological process of SCIRI. If the integrity of the BSCB is disrupted, the permeability will increase and the spinal cord injury will be more severe. Maintaining the integrity of BSCB through different methods has good preventive and therapeutic effects on SCIRI and thus attracting always more researchers. Bone marrow stromal stem cells, dexmedetomidine, ischemia, and sevoflurane preconditioning can downregulate MMP-9 expression and upregulate TJ proteins levels. This response can maintain the integrity of the BSCB and protect spinal cord [14,15,19,66]. MMP-9 is one of the main destructive factors for the BSCB. Reducing MMP-9 expression can alleviate brain or spinal cord injury. For example, Asahi et al. [67] reported in knockout mice for MMP-9 gene the BBB was more intact than that wild-type mice. MMP-9 inhibitors, such as TIMPs and BB-1101, can clearly ameliorate the permeability of the BBB [68]. Understand how to maintain the integrity of BSCB following spinal cord ischemia injury is a worthy research field to analyze in depth.
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5. Conclusion and perspectives Paraplegia induced by SCIRI not only threatens physical health but also causes heavy economic burden to the families and society. Unfortunately, although many adjunctive therapies have been used to protect spinal cord, this complication still cannot be completely prevented. The permeability of the BSCB is disrupted following spinal cord ischemia and a secondary progressive increase in the BSCB disruption after reperfusion, which leads to spinal cord edema and inflammatory events, exacerbates the spinal cord injury. The protection of the integrity of the BSCB can significantly attenuate SCIRI, as confirmed by several studies. However, the most effective protective measures for the integrity of the BSCB after SCIRI are worth to explore. The combination of multiple drugs and methods, along with a deeper understanding of cellular mechanisims will be an efficient tool to presevre the integrity of the BSCB [25,69–72], which represents a BSCB treatment is a promising prevention and cure of SCIRI. Author contributions Ji Hu and Lijie Xie wrote the manuscript, and Qijing Yu and Hongfei Zhu have carefully revised the manuscript. Ji Hu and Qijing Yu are cofirst authors who contributed equally to this study. All authors have approved the final version of this paper. Conflicts of interest None declared. Acknowledgments This work was supported by grants from the Nature Science Foundation of Hubei Province (No.2013CFB086 to Ji Hu), the Hubei Province health and family planning scientific research project (No. WJ2015MB023 to Qijing Yu) and the Science and Technology Department of Hubei province (project of scientific research condition and resource research development) fund (No. 2015BCE099 to Hongfei Zhu). References [1] A. Katsargyris, K. Oikonomou, G. Kouvelos, et al., Spinal cord ischemia after endovascular repair of thoracoabdominal aortic aneurysms with fenestrated and branched stent grafts, J. Vasc. Surg. 62 (6) (2015) 1450–1455. [2] M. Kato, M. Motoki, T. Isaji, et al., Spinal cord injury after endovascular treatment for thoracoabdominal aneurysm or dissection, Eur. J. Cardiothorac. Surg. 48 (4) (2015) 571–577. [3] N. Panthee, M. Ono, Spinal cord injury following thoracic and thoracoabdominal aortic repairs, Asian Cardiovasc. Thorac. Ann. 23 (2) (2015) 235–246. [4] S.A. Lemaire, M.D. Price, S.Y. Green, S. Zarda, J.S. Coselli, Results of open thoracoabdominal aortic aneurysm repair, Ann. Cardiothorac Surg. 1 (3) (2012) 286–292. [5] 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. [6] 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. [7] T. Matsushita, K.L. Lankford, E.J. Arroyo, M. Sasaki, M. Neyazi, C. Radtke, J.D. Kocsis, Diffuse and persistent blood–spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells, Exp. Neurol. 267 (2015) 152–164. [8] B. Aube, S.A. Levesque, A. Pare, E. Chamma, H. Kebir, R. Gorina, M. Lecuyer, J.I. Alvarez, Y. De Koninck, B. Engelhardt, A. Prat, D. Cote, S. Lacroix, Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases, J. Immunol. 193 (2014) 2438–2454. [9] V. Bartanusz, D. Jezova, B. Alajajian, M. Digicaylioglu, The blood-spinal cord barrier: morphology and clinical implications, Ann. Neurol. 70 (2011) 194–206. [10] J.Y. Lee, H.S. Kim, H.Y. Choi, T.H. Oh, T.Y. Yune, Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury, Brain 135 (2012) 2375–2389. [11] J.Y. Lee, H.Y. Choi, H. Ahn, B. Ju, T. Yune, Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury, Am. J. Pathol. 184 (11) (2014) 2985–3000.
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