Journal of Neuroscience Research 92:141–147 (2014)

Mini-Review Blood–Brain Barrier and Traumatic Brain Injury Jose Luıs Alves* Doctoral Programme in Health Sciences, Faculdade de Medicina da Universidade de Coimbra, Coimbra, Portugal

The blood–brain barrier (BBB) is an anatomical microstructural unit, with several different components playing key roles in normal brain physiological regulation. Formed by tightly connected cerebrovascular endothelial cells, its normal function depends on paracrine interactions between endothelium and closely related glia, with several recent reports stressing the need to consider the entire gliovascular unit in order to explain the underlying cellular and molecular mechanisms. Despite that, with regard to traumatic brain injury (TBI) and significant events in incidence and potential clinical consequences in pediatric and adult ages, little is known about the actual role of BBB disruption in its diverse pathological pathways. This Mini-Review addresses the current literature on possible factors affecting gliovascular units and contributing to posttraumatic BBB dysfunction, including neuroinflammation and disturbed transport mechanisms along with altered permeability and consequent posttraumatic edema. Key mechanisms and its components are described, and promising lines of basic and clinical research are identified, because further knowledge on BBB pathological interference should play a key role in understanding TBI and provide a basis for possible therapeutic targets in the near future, whether through restoration of normal BBB function after injury or delivering drugs in an increased permeability context, preventing secondary damage and improving functional outcome. VC 2013 Wiley Periodicals, Inc. Key words: blood–brain barrier; injury; glia; glial cells

Traumatic brain injury (TBI) is a common clinical condition, one of the most frequent traumatic situations in pediatric and adult ages, necessarily unforeseen and sudden in progress, with multiple causes (traffic accidents, falls, gunshot wounds) and possibly devastating consequences for the victim and a huge burden for the society, implying huge costs in public health care. Previous reports on humans (McAllister et al., 2012) and animal models (Dixon et al., 1999) have shown, along with major neurological deficits/symptoms (motor deficits, epilepsy), persistence of nonspecific complaints (namely, headaches) and minor cognitive deficits, C 2013 Wiley Periodicals, Inc. V

disturbed spatial orientation and memory, and diminished learning abilities and work performance, directly related to cortical and hippocampal disruption with neuronal loss (Smith et al., 1994). These symptoms, considered to be the most frequent in daily practice with minor TBI in children and adults, become obvious as early as 48 hr and last for as long as 2 weeks, in a transitory postconcussion syndrome, or even persist as traumatic sequelae for life, with obvious implications. TBI has also been associated with an increased risk for depression (Holsinger et al., 2002) and neurodegenerative diseases (Plassman et al., 2000). Emotional processing disturbances can also be attributed to hippocampal damage, according to recent theories on cognitive/mnesic mechanisms and complex emotional states. TBI is the cause of death in 30–50% of all deaths related to traumatic events (Jallo and Loftus, 2009), with a mortality rate of 18.1/100,000 inhabitants (period 1995–2001), according to the U.S. Centers for Disease Control (CDC; TBI Surveillance System). Even with low-energy trauma, representing the majority of TBIs, the risk for complications or progression of initial injury or cerebral edema poses a significant challenge for the neurosurgeon/neurointensivist. Despite the current sophistication and increasing accessibility to imaging and clinical–surgical protocols, there is an obvious need for simple and reliable clinical tools, able to guide the decision process and monitoring (Buki et al., 2009), along with effective therapeutic agents in delaying self-sustained pathological mechanisms. With this purpose, this Mini-Review addresses a significant event, posttraumatic blood–brain barrier (BBB) dysfunction. Key pathological pathways and their specific components are listed, and promising lines of research are identified, in order to categorize possible therapeutic targets in the near future. *Correspondence to: Jose Luıs Alves, Rua Ant onio Gonc¸alves, No. 59, 4D, Lote 18, 3000 Coimbra, Portugal. E - mail: [email protected] Received 30 March 2013; Revised 10 May 2013; Accepted 29 August 2013 Published online 21 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jnr.23300

142

Alves

GENERAL PHYSIOLOGY The BBB is one of the main factors supporting the restricted, closely controlled environment necessary for the brain’s survival (Ballabh et al., 2004; Chodobski et al., 2011). Structurally, the BBB is composed of endothelial cells surrounded and supported by other cellular components, astrocytes, pericytes, and neurons. We should stress the importance of astrocytes for the BBB’s regular function, because astrocytic processes intimately contact endothelium of parenchymal microvessels. All these cells and the surrounding environment play a specific role in BBB differentiation and maintenance of functions (Chodobski et al., 2011), including differentiated transport mechanisms, constituting a true gliovascular unit (Abbott et al., 2006; Wolburg et al., 2009), with glial and endothelial cells functionally interacting in a paracrine manner. PATHOLOGY Translational research in TBI is increasingly focusing on broader functional aspects of brain response to injury, shifting from cell-oriented studies to experimental research on physiological concepts, such as the BBB. Preliminary data show immediate and delayed BBB/gliovascular unit dysfunction (Neuwelt et al., 2008) in TBI. Disrupted tight junctions and basal membrane lead to increased paracellular permeability. Proinflammatory status, causing oxidative stress and upregulated endothelial expression of cell adhesion molecules, promotes influx of inflammatory cells into the brain parenchyma, determining the progression of injury, including excitotoxicity and neuronal loss. On an ultrastructural level, by using light and electron microscopic analysis of rat cerebral cuts in an animal model of TBI (Dietrich et al., 1994), microscopic hemorrhagic contusions or petechia (more prominent in gray–white interface underlying somatosensory cortex and cisterna ambiens) were shown, demonstrating primary, shearing stress-derived vascular damage, which can be located away from initial injury site, implying protein leakage and extravasation of blood cells. Obviously, the degree of posttraumatic dysfunction of the BBB should affect time course and extent of neuronal repair, influencing long-term functional outcome. Disrupted walls in brain microvessels activate a coagulation cascade, leading to intravascular coagulation and thrombi formation in occluded venules and, to a lesser extent, arterioles (Stein et al., 2002; Schwarzmaier et al., 2010). Platelet- and leukocyte-derived aggregates were observed within pial and parenchymal venules (Schwarzmaier et al., 2010), playing their part in significantly reducing blood flow in pericontusional brain tissues (Schroder et al., 1998; von Oettingen et al., 2002) and therefore acting as a potential risk factor for secondary ischemic injury. OXIDATIVE STRESS As shown in several experimental and clinical reports on TBI, one can expect microglial activation, local migration of immune circulating cells, increased nitric oxide (NO)

release, and production of reactive oxygen species (ROS) and inflammatory mediators; all of these phenomena are capable of interfering with the BBB, as previously described (Perez-Asensio et al., 2005; Briones et al., 2011; Xiong et al., 2012). One consequence of oxidative stress, peroxidation of membrane polyunsaturated fatty acids induced by ROS, may affect BBB function, by giving rise to active aldehydes, such as 4-hydroxynonenal (4-HNE), significantly increasing endothelial monolayer permeability in experimental studies (Chodobski et al., 2011, citing other studies). As a key occurrence in posttraumatic events (Globus et al., 2002; Perez-Asensio, 2005) leading to increased BBB permeability, oxidative stress is associated with depletion of the endogenous antioxidant glutathione and increased paracellular permeability of BBB, although only to low-molecular-weight markers (Agarwal and Shukla, 1999; Mertsch et al., 2011). On the other hand, hydrogen peroxide was shown to increase permeability on endothelial monolayers, requiring the ERK signal transduction pathway (Fischer et al., 2005), along with occludin and tight junction-associated proteins (zonula occludens 1 and 2) redistribution. However, as with many other clinical trials on TBI, antioxidant therapeutic agents, although promising (Choi et al., 2012), have yet to be shown as truly beneficial for patients, stressing the importance of focused translational research protocols on high-energy oxidants as mediators of secondary damage associated with TBI. INFLAMMATION Although not an inflammatory disease per se, post-TBI cerebral cytokines expression is significantly increased, namely, interleukin (IL)21b, IL-6, and tumor necrosis factor-a (TNF-a), produced by supporting microglia and astroglial cells, neurons, and endothelial cells (Hopkins and Rothwell, 1995; Brown and Neher, 2010). These major proinflammatory molecules (Ye et al., 2013), should play a supplementary role in BBB disruption (Mark et al., 2001), as demonstrated in experimental animal models, showing increased IL-1b-dependent BBB permeability related to occludin/ZO-1 loss and tight junction redistribution (Bolton et al., 1998). Other inflammatory agents, including matrix metalloproteinases (MMPs; Rosenberg, 2009) and bradykinins (Walker et al., 1995), included in a cascade-like response to trauma, should also promote BBB disruption and diminished function. Proinflammatory cytokine (TNF-a, IL-1) expression by activated microglia is increased in posttraumatic brain tissue (Kinoshita et al., 2002; SzmydyngerChodobska et al., 2009) and contributes to neuronal damage, namely, by eliciting TNF-a-induced neurodegeneration through caspase-dependent cascades and stimulating microglial glutamate release (Takeuchi et al., 2006; Ye et al., 2013). A possible contribution to BBB increased permeability (Mark et al., 2001; Sakon et al., 2003), in part by downregulating occludin expression Journal of Neuroscience Research

Blood–Brain Barrier and Brain Injury

(Mankertz et al., 2000), has also been discussed. However, some authors argue that its main role is to induce endothelial and astrocytic chemokine synthesis (SzmydyngerChodobska et al., 2010), promoting inflammatory cells recruitment (Bajetto et al., 2002; Middleton et al., 2002) and increasing expression of the cell adhesion molecules E-selectin, ICAM1, vascular cell adhesion molecule-1 (VCAM1; Hess et al., 1994; Hopkins and Rothwell, 1995; Wong and Dorovini-Zis, 1995). After experimental TBI in rodent models, a significant influx of neutrophils and monocytes takes place (Schoettle et al., 1990; Szmydynger-Chodobska et al., 2010; Nimer et al., 2013), with implications for brain edema and extent of parenchymal damage. Neutrophils show neuronal toxicity properties, especially in a hypoxic–hypoglucidic context (Dinkel et al., 2004), while increasing endothelial barrier permeability (DiStasi and Ley, 2009; Nimer et al., 2013), generating ROS, proteolytic enzymes, and proinflammatory cytokines. As previously mentioned, increased levels of MMPs have also been observed (MMP-2, -3, -9; Paul et al., 1998; Truettner et al., 2005; Vilalta et al., 2008; Rosenberg, 2009), produced in different cellular types, including vascular endothelium, astrocytes, microglia, and neurons (Rosenberg et al., 2001), and even from invading leukocytes, disrupting basal lamina proteins and degrading tight junction complexes (Mun-Bryce and Rosenberg, 1998; Cunningham et al., 2005; Yang et al., 2007). A neuropeptide in the family of neurokinins, substance P (SP), is a promoter of neuroinflammation as a response to various noxious stimuli (Poncet et al., 1996; Richardson and Vasko, 2002; Zacest et al., 2010), acting on neurokinin 1 receptors (NK1r) and disturbing the normal BBB, leading to increased vascular permeability and interstitial accumulation of osmotically active molecules and water, culminating in the so-called early vasogenic edema (Bosaller et al., 1992; Donkin et al., 2009). SP increase is documented immediately after initial trauma, diminishing in the next hours (Armstead et al., 2005; Donkin et al., 2011; Song et al., 2012). Many other peptides, such as calcitonin gene-related peptide (CGRP), play similar roles in complex cerebral blood flow selfregulation (Vink et al., 2004; Psen and Gulati, 2010). These studies led to early reports of experimental and clinical trials using SP as a biomarker and/or therapeutic target (Vink et al., 2004; Donkin and Vink, 2010; Vink and van den Heuvel, 2010), with specific antagonists (n-acetyl tryptophan, cannabinoid receptors type 2) showing promising results with regard to functional outcome in animal models. SP antagonist agents, namely, n-acetyl tryptophan, seem to promote magnesium cerebral replacement (Vink et al., 2004) and attenuate vasogenic edema (Donkin and Vink, 2010). However, transposition of results from animal models to clinical trials is yet to be satisfactory. The myriad agents and intersecting pathways in neuroinflammation, while posing a significant challenge, represent a unique and vast group of potential therapeutic targets, with synergistic effects. Journal of Neuroscience Research

143

SIGNALLING AND BLOOD-BORNE FACTORS Another phenomenon with possible influence in TBI’s pathogenic pathways involving BBB disruption is nonselective entrance of blood-borne factors, such as albumin and fibrinogen, possible only after mechanical vascular disruption and/or increased permeability (Chodobski et al., 2011). These blood-borne factors should play a key role in directing movement of microglial processes toward the site of injury, as shown in studies using two-photon confocal microscopy (Nimmerjahn et al., 2005), while not inducing any evident astrocytic response. As a result of intravascular coagulation, newly formed thrombin (following factor X-activated prothrombin cleavage) seems to play a significant role in TBI pathophysiology, depending on its concentration (Xi et al., 2003), inducing apoptosis of astrocytes and neurons through rho activation (Donovan et al., 1997), increasing [Ca21] in microglial cells, and promoting astrogliosis in injured brain (Nicole et al., 2005). Being able to stimulate proinflammatory cytokines production (TNF-a, IL-6, IL-12, neutrophil chemoattractants), thrombin might be one factor initiating the posttraumatic brain inflammatory response. Several other blood-borne factors or cellular components also play a key role in microglial activation, neuroinflammation, and BBB upset. For example, fibrinogen has been shown to promote microglial cytoskeleton rearrangement, an increase in cell size, and phagocytic activity (Adams et al., 2007). Albumin, a major plasma protein normally excluded from contact with the brain, directly increases [Ca21] in microglial cells and promotes microglial proliferation (Hooper et al., 2005), activating microtubuleassociated protein kinase (MAPK) pathways, increasing NO production by the ERK signaling pathway (Hooper et al., 2009), and inducing IL-1 synthesis (Ralay et al., 2010). The posttraumatic increase in BBB permeability to albumin and other macromolecules (Kelley et al., 2007), as a probable consequence of increased paracellular permeability and unbalanced expression/distribution/ function of tight junction proteins (Chodobski et al., 2011), is therefore a significant component of complex BBB–microglia interactions and the posttraumatic global cerebral response. Transforming growth factor-b (TGF-b) is an important regulator of cellular functions, including differentiation and proliferation. Although it is stored in platelets in its latent form (Pircher et al., 1986), requiring its activation for release, some authors argue that large amounts of TGF-b should be expected after mechanical damage of vascular walls (Dietrich et al., 1994; Schwarzmeier et al., 2010). TGF-b can also be produced by brain parenchymal cells (astrocytes, microglia), contributing to its rapid increase (cortical and hippocampal) after experimental brain injury (Cook et al., 1998). More importantly, cell culture studies have shown dose-dependent upregulation of endothelial paracellular permeability by TGF-b (Shen et al., 2011), possibly resulting from

144

Alves

increased tyrosine phosphorylation and reduced expression of the tight junction protein claudin-5 (CLDN5) and the adherence junction protein VE-cadherin (Garcia et al., 2004; Piontek et al., 2008). As regulators of many cellular functions, including proliferation, differentiation, and survival, in various cell types, the signaling factors briefly mentioned above should explain or influence most pathological phenomena displayed on TBI. Clinical trials in the future, focusing on elements such as thrombin or TGF-b, are expected to be useful from a multitargeting perspective. EXCITOTOXICITY Clinical and animal-model studies with microdialysis and spectroscopy (see, e.g., Mellegard et al., 2012) have shown a significant posttraumatic increase in extracellular levels of glutamate, the main excitatory endogenous neurotransmitter of the central nervous system, leading to cellular damage and death, upon activation of ionotropic receptors NMDA or AMPA type (Hansson et al., 2000; Floyd and Lyeth, 2007). Studies on primary cultures of human brain endothelial cells (Takahashi et al., 1997; Collard et al., 2002) have shown that glutamate and excitotoxicity might play a role in posttraumatic BBB permeability as well, through its metabotropic glutamate receptors (mGluRs; Krizbai et al., 1998; Yi and Hazell, 2006), susceptible to interference by antagonists (reducing BBB permeability) or agonists (increasing BBB permeability in animal models of hypoxia; Gillard et al., 2003). The role of NMDA receptor activation by glutamate, causing similar effects on BBB permeability, is still disputed (Sharp et al., 2003; Briones et al., 2011). Much attention has been given to the glutamatergic regulation system and its role and mechanisms of action in a secondary response to TBI, focusing on cortical and hippocampal neuronal loss, areas vulnerable to acute and delayed damage (Zhong et al., 2006). However, different trials have failed to show any clinical significance so far, so excitotoxicity’s relation to BBB disruption might become a promising therapeutic target as well (glutaminase inhibitors, hemichannel blockers; Takeuchi et al., 2006). As presented above, given all previously described agents and pathways of BBB/gliovascular unit upset in TBI, one can describe a self-sustained, complex, and relatively unknown mechanism of BBB permeability deregulation and promotion of posttraumatic vasogenic edema. THERAPY Corticosteroids, and dexamethasone specifically, are wellknown therapeutic agents with antiedematous properties in brain tumors, acting on the BBB. Use of cortcosteroida is based mainly on their ability to stabilize lysosomal membranes and reduce tissue vasogenic edema, also inhibiting lipid peroxidation. Experimental studies have demonstrated both benefits and drawbacks (Braughler and Hall, 1986; Graber et al., 2012), although their possible use for TBI in current clinical practice is still debated (Lei et al., 2012). This raises a crucial question: how to

address the complexity of multiple pathophysiological processes associated with TBI with one therapeutic agent, focusing on a single mediator/mechanism, eventually with an inadequate timing. Changes of paradigm toward combination therapies, focusing on diverse processes, such as expression of adhesion molecules and interference with signaling molecules (cytokines, chemokines), with an adequate and tested window of opportunity, may be the only viable solution in TBI management (Shlosberg et al., 2010; Thal et al., 2012). Other therapeutic targets, already evaluated in clinical trials with little or no success, such as excitoxicity and oxidative stress, should be tested from a different perspective, keeping in mind (in mechanisms of action and objectives) the importance of BBB disruption and the ensuing edema and signaling cascades. BBB breakdown should therefore become a major future therapeutic target (Shlosberg et al., 2010; Perez-Polo et al., 2013) or, from another perspective, become a pathway to administer drugs more effectively to an injured brain (Begley, 2003; Bressler et al., 2007). The complex pathogenesis of brain edema on a cellular level must be taken into account, considering deregulation of water homeostasis in relation to altered expression of aquaporin-1 (AQP-1; Tran et al., 2010) and AQP-4 (Lo Pizzo et al., 2012; Katada et al., 2012) stressing the need to consider multifactorial therapeutic approaches that might include, for example, selective AQP-1 blockage or HgCl2 (Tran et al., 2010). Many questions remain to be answered and should be considered in focused future research: molecular migration through the BBB, possible strategies for specific neuroinflammation control, a more accurate description of the BBB molecular mechanisms of transportation, cellular communication among different functional groups (glia, neurons, endothelial system, vascular wall), signaling mechanisms on a protein level, and modulation of tight junctions. From a patient-based approach, there is increasing evidence of prominent age-related disparities, pediatric and juvenile patients being more prone to brain edema, with higher water content; specific expression pattern of AQP-4 (Fukuda et al., 2012) in younger patients; and distinct BBB structure and response to injury, namely, gene expression of basal lamina components, occludin, MMP-9, and tight junctions (FernandezLopez et al., 2012). Other specific clinical conditions, such as tau pathology, apparently aggravated by repetitive mild TBI (Ojo et al., 2013) and influencing inflammatory responses and BBB selective permeability (Jaworsky et al., 2011), should also be considered, although it is still unknown whether age or medical background should preclude differentiated therapeutic protocols. CONCLUSIONS With regard to TBI, solid experimental data and clinical evidence support an increasing interest in BBB disruption and loss of function. Unlike the case in other neurological diseases, such as in neurodegenerative processes, BBB malfunction is solely a consequence of trauma and cannot Journal of Neuroscience Research

Blood–Brain Barrier and Brain Injury

be regarded as a potential site of origin for the disease, although it can actively promote and help perpetuate mechanisms of secondary damage. With a multidisciplinary effort and profound knowledge of all complex regulation systems involved, new specific therapies should be expected that are capable of actively modulating posttraumatic BBB dysfunction, counterbalancing proedematous pathways, and possibly enhancing drug delivery to the damaged central nervous system, effectively playing a role in diminishing morbidity and mortality from TBI. REFERENCES Abbott NJ, R€ onnb€ack L, Hansson E. 2006. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K. 2007. The fibrin-derived g377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 204:571–582. Agarwal R, Shukla GS. 1999. Potential role of cerebral glutathione in the maintenance of blood–brain barrier integrity in rat. Neurochem Res 24:1507–1514. Armstead WM, Hecker JG. 2005. Heat shock protein modulation of KATP and KCa channel cerebrovasodilation after brain injury. AJP Heart 289:1184–1190. Bajetto A, Bonavia R, Barbero S, Schettini G. 2002. Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J Neurochem 82:1311–1329. Ballabh P, Braun A, Nedergaard M. 2004. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobio Dis 16:1–13. Begley DJ. 2003. Understanding and circumventing the blood–brain barrier. Acta Paediatr 92:83–91. Bolton SJ, Anthony DC, Perry VH. 1998. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo. Neuroscience 86:1245–1257. Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gr€afe M, Fleck E. 1992. In vivo measurement of endotheliumdependent vasodilation with substance P in man. Herz 17:284–290. Braughler JM, Hall ED. 1986. High-dose methylprednisolone and CNS injury. J Neurosurg 64:985–986. Bressler, JP, Olivi L, Cheong JH, Kim Y, Maerten A, Bannon D. 2007. Metal transporters in intestine and brain: their involvement in metalassociated neurotoxicities. Hum Exp Toxicity 26:221–229. Briones TL, Rogozinska M, Woods J. 2011. Modulation of ischemia induced NMDAR1 activation by environmental enrichment decreases oxidative damage. J Neurotrauma 28:2485–2492. Brown GC, Neher JJ. 2010. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 41:242–247. Buki A, Kovesdi E, Pal J. 2009. Clinical and model research of neurotrauma. Neuroproteomics Methods Mol Biol 556:41–55. Chodobski A, Zink BJ, Szmydynger-Chodobska J. 2011. Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2: 492–516. Choi BY, Jang BG, Kim JH, Lee BE, Sohn M, Song HK, Suh SW. 2012. Prevention of traumatic brain injury-induced neuronal death by inhibition of NADPH oxidase activation. Brain Res 1481:49–58. Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, Colgan SP. 2002. Neutrophil-derived glutamate regulates vascular endothelial barrier function. J Biol Chem 277:14801–14811. Cook JL, Marcheselli V, Alam J, Deininger PL, Bazan NG. 1998. Temporal changes in gene expression following cryogenic rat brain injury. Brain Res Mol Brain Res 55:9–19. Journal of Neuroscience Research

145

Cunningham LA, Wetzel M, Rosenberg GA. 2005. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339. Dietrich WD, Alonso O, Halley M. 1994. Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J Neurotrauma 11:289–301. Dinkel K, Dhabhar FS, Sapolsky RM. 2004. Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures. Proc Natl Acad Sci U S A 101:331–336. DiStasi MR, Ley K. 2009. Opening the flood-gates: how neutrophil–endothelial interactions regulate permeability. Trends Immunol 30:547–556. Dixon CE, Kochanek PM, Yan HQ, Schiding JK, Griffith RG, Baum E. 1999. One-year study of spatial memory performance, brain morphology and cholinergic markers after moderate controlled cortical impact in rats. J Neurotrauma 16:109–122. Donkin JJ, Vink R. 2010. Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments. Curr Opin Neurol 23:293–299. Donkin JJ, Nimmo AJ, Cernak I, Blumbergs PC, Vink R. 2009. Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury. J Cereb Blood Flow Metab 29:1388–1398. Donkin JJ, Cernak I, Blumbergs PC, Vink R. 2011. A substance P antagonist reduces axonal injury and improves neurological outcome when administered up to 12 h after traumatic brain injury. J Neurotrauma 28:217–224. Donovan FM, Pike CJ, Cotman CW, Cunningham DD. 1997. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and rhoA activities. J Neurosci 17:5316–5326. Fernandez-L opez D, Faustino J, Daneman R, Zhou L, Lee SY, Derugin N, Wendland MF, Vexler ZS. 2012. Blood–brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. J Neuroci 32:9588–9600. Fischer S, Wiesnet M, Renz D, Schaper W. 2005. H2O2 induces paracellular permeability of porcine brain-derived microvascular endothelial cells by activation of the p44/42 MAP kinase pathway. Eur J Cell Biol 84:687–697. Floyd CL, Lyeth BG. 2007. Astroglia: important mediators of traumatic brain injury. Prog Brain Res 161:61–79. Fukuda AM, Pop V, Spagnoli D, Ashwal S, Obenaus A, Badaut J. 2012. Delayed increase of astrocytic aquaporin 4 after juvenile traumatic brain injury: possible role in edema resolution? Neuroscience 222:366–378. Garcia CM, Darland DC, Massingham LJ, D’Amore PA. 2004. Endothelial cell–astrocyte interactions and TGFb are required for induction of blood–neural barrier properties. Brain Res Dev Brain Res 152:25–38. Gillard SE, Tzaferis J, Tsui HC, Kingston AE. 2003. Expression of metabotropic glutamate receptors in rat meningeal and brain microvasculature and choroid plexus. J Comp Neurol 461:317–332. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. 2002. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 65:1704–1711. Graber DJ, Hickey WF, Stommel EW, Harris BT. 2012. Anti-inflammatory efficacy of dexamethasone and Nrf2 activators in the CNS using brain slices as a model of acute injury. J Neurol Pharm 7:266–278. Hansson E, Muyderman H, Leonova J, Allansson L, Sinclair J, Blomstrand F, Thorlin T, Nilsson M, R€ onnb€ack L. 2000. Astroglia and glutamate in physiology and pathology: aspects of glutamate transport, glutamate-induced cell swelling and gap-junction communication. Neurochem Int 37:317–329. Hess DC, Bhutwala T, Sheppard JC, Zhao W, Smith J. 1994. ICAM-1 expression on human brain microvascular endothelial cells. Neurosci Lett 168:201–204. Holsinger T, Steffens DC, Phillips C, Helms MJ, Havlik RJ, Breitner JC. 2002. Head injury in early adulthood and the lifetime risk of depression. Arch Gen Psychiatry 59:17–22. Hooper C, Taylor DL, Pocock JM. 2005. Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes. J Neurochem 92:1363–1376.

146

Alves

Hooper C, Pinteaux-Jones F, Fry VA, Sevastou IG, Baker D, Heales SJ, Pocock JM. 2009. Differential effects of albumin on microglia and macrophages; implications for neurodegeneration following blood–brain barrier damage. J Neurochem 109:694–705. Hopkins SJ, Rothwell NJ. 1995. Cytokines and the nervous system. I: Expression and recognition. Trends Neurosci 18:83–88. Jallo J, Loftus C. 2009. Epidemiology of traumatic brain injury. In Jallo J, Loftus C, editors. Neurotrauma and critical care of the brain. New York: Thieme. p 7–10. Jaworski T, Lechat B, Demedts D, Gielis L, Devijver H, Borghgraef P, Duimel H, Verheyen F, K€ ugler S, Van Leuven F. 2011. Dendritic degeneration, neurovascular defects, and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegeneration. Am J Pathol 179:2001–2015. Katada R, Nishitani Y, Honmou O, Mizuo K, Okazaki S, Tateda K, Watanabe S, Matsumoto H. 2012. Expression of aquaporin-4 augments cytotoxic brain edema after traumatic brain injury during acute ethanol exposure. Am J Pathol 180:17–23. Kelley BJ, Lifshitz J, Povlishock JT. 2007. Neuroinflammatory responses after experimental diffuse traumatic brain injury. J Neuropathol Exp Neurol 66:989–1001. Kinoshita K, Chatzipanteli K, Vitarbo E, Truettner JS, Alonso OF, Dietrich WD. 2002. Interleukin-1b messenger ribonucleic acid and protein levels after fluid-percussion brain injury in rats: importance of injury severity and brain temperature. Neurosurgery 51:195–203. Krizbai IA, Deli MA, Pestenacz A, Sikl os L, Szab o CA, Andras I, Jo o F. 1998. Expression of glutamate receptors on cultured cerebral endothelial cells. J Neurosci Res 54:814–819. Lei J, Gao G, Jiang J. 2012. Acute traumatic brain injury: is current management evidence based? An empirical analysis of systematic reviews. J Neurotrauma [E-pub ahead of print]. Mankertz J, Tavalali S, Schmitz H, Mankertz A, Riecken EO, Fromm M, Schulzke JD. 2000. Expression from the human occludin promoter is affected by tumor necrosis factor a and interferon g. J Cell Sci 113: 2085–2090. Mark KS, Trickler WJ, Miller DW. 2001. Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J Pharmacol Exp Ther 297:1051–1058. McAllister TW, Flashman LA, Maerlender A, Greenwald RM, Beckwith JG, Tosteson TD. 2012. Cognitive effects of one season of head impacts in a cohort of collegiate contact sport athletes. Neurology 78: 1777–1784. Mellegard P, Sjogren F, Hillman J. 2012. The cerebral extracellular release of glycerol, glutamate and FGF2 is increased in older patients following severe traumatic brain injury. J Neurotrauma 29:112–118. Mertsch K, Blasig I, Grune T. 2011. 4-Hydroxynonenal impairs the permeability of an in vitro rat blood–brain barrier. Neurosci Lett 314:135–138. Middleton J, Patterson AM, Gardner L, Schmutz C, Ashton BA. 2002. Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood 100:3853–3860. Mun-Bryce S, Rosenberg GA. 1998. Gelatinase B modulates selective opening of the blood–brain barrier during inflammation. Am J Physiol 274:R1203–R1211. Neuwelt E, Abbott NJ, Abrey L, Banks WA, Blakley B, Davis T, Engelhardt B, Grammas P, Nedergaard M, Nutt J. 2008. Strategies to advance translational research into brain barriers. Lancet Neurol 7:84–96. Nicole O, Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P, Hepler JR, McKeon RJ, Traynelis SF. 2005. Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. J Neurosci 25:4319–4329. Nimer F, Lindblom R, Str€ om M, Guerreiro-Cacais AO, Parsa R, Aeinehband S, Mathiesen T, Lidman O, Piehl F. 2013. Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat. Brain Behav Immun 27:109–122.

Nimmerjahn A, Kirchhoff F, Helmchen F. 2005. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. Ojo JO, Mouzon B, Greenberg MB, Bachmeier C, Mullan M, Crawford F. 2013. Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice. J Neuropathol Exp Neurol 72: 137–151. Paul R, Lorenzl S, Koedel U, Sporer B, Vogel U, Frosch M. 1998. Matrix metalloproteinases contribute to the blood–brain barrier disruption during bacterial meningitis. Ann Neurol 44:592–600. Perez-Asensio FJ, Hurtado O, Burguete MC, Moro MA, Salom JB, Lizasoain I. 2005. Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia. Neurobiol Dis 18:375–384. Perez-Polo JR, Rea HC, Unabia GC, Xu G, Parsley MO, Infante SK, Dewitt D, Grill RJ Jr, Hulsebosch C. 2013. Inflammatory consequences mild traumatic brain injury. J Neurotrauma [E-pub ahead of print]. Piontek J, Winkler L, Wolburg H, Muller SL, Zuleger N, Piehl C. 2008. Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22:146–158. Pircher R, Jullien P, Lawrence DA. 1986. b-Transforming growth factor is stored in human blood platelets as a latent high molecular weight complex. Biochem Biophys Res Commun 136:30–37. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D. 2000. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology 55:1158–1166. Poncet L, Denoroy L, Dalmaz Y, Pequignot JM, Jouvet M. 1996. Alteration in central and peripheral substance P- and neuropeptide Y-like immunoreactivity after chronic hypoxia in the rat. Brain Res 733:64–72. Psen AP, Gulati A. 2010. Use of magnesium in traumatic brain injury. Neurotherapeutics 91–99. Ralay Ranaivo H, Wainwright MS. 2010. Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways. Brain Res 1313:222–231. Richardson JD, Vasko M. 2002. Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302:839–845. Rosenberg GA. 2009. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 8:205–216. Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M, Razhagi A, Miller K, Gearing A. 2001. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 893:104–112. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T. 2003. NF-jB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22:3898–3909. Schoettle RJ, Kochanek PM, Magargee MJ, Uhl MW, Nemoto EM. 1990. Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma 7:207–217. Schr€ oder ML, Muizelaar JP, Fatouros PP, Kuta AJ, Choi SC. 1998. Regional cerebral blood volume after severe head injury in patients with regional cerebral ischemia. Neurosurgery 42:1276–1280. Schwarzmaier SM, Kim SW, Trabold R, Plesnila N. 2010. Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice. J Neurotrauma 27:121–130. Sharp CD, Hines I, Houghton J, Warren A, Jackson TH, Jawahar A, Nanda A, Elrod JW, Long A, Chi A. 2003. Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol 285:6(H2592-8). Shen W, Li S, Chung SH, Zhu L, Stayt J, Su T, Couraud PO, Romero IA, Weksler B, Gillies MC. 2011. Tyrosine phosphorylation of VEcadherin and claudin-5 is associated with TGF-b1-induced permeability of centrally derived vascular endothelium. Eur J Cell Biol 90:323–332. Journal of Neuroscience Research

Blood–Brain Barrier and Brain Injury Shlosberg D, Benifla M, Kaufer D, Friedman A. 2010. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6:393–403. Smith DH, Lowenstein DH, Gennarelli TA, McIntosh TK. 1994. Persistent memory disfunction is associated with bilateral hippocampal damage following experimental brain injury. Neurosci Lett 168:151–154. Song Y, Bi L, Zhang Z, Huang Z, Hou W, Lu X, Sun P, Han Y. 2012. Increased levels of calcitonin gene-related peptide in serum accelerate fracture healing following traumatic brain injury. Mol Med Rep 5:432–438. Stein SC, Chen XH, Sinson GP, Smith DH. 2002. Intravascular coagulation: a major secondary insult in nonfatal traumatic brain injury. J Neurosurg 97:1373–1377. Szmydynger-Chodobska J, Strazielle N, Zink BJ, Ghersi-Egea JF, Chodobski A. 2009. The role of the choroid plexus in neutrophil invasion after traumatic brain injury. J Cereb Blood Flow Metab 29:1503–1516. Szmydynger-Chodobska J, Fox LM, Lynch KM, Zink BJ, Chodobski A. 2010. Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury. J Neurotrauma 27:1449–1461. Takahashi M, Billups B, Rossi D, Sarantis M, Hamann M, Attwell D. 1997. The role of glutamate transporters in glutamate homeostasis in the brain. J Exp Biol 200:401–409. Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe Y, Mizuno T, Suzumura A. 2006. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281:21362–21368. Thal SC, Luh C, Schaible EV, Timaru-Kast R, Hedrich J, Luhmann HJ, Engelhard K, Zehendner CM. 2012. Volatile anesthetics influence blood–brain barrier integrity by modulation of tight junction protein expression in traumatic brain injury. Plos One 7. Tran ND, Kim S, Vincent HK, Rodriguez A, Hinton DR, Bullock MR, Young HF. 2010. Aquaporin-1-mediated cerebral edema following traumatic brain injury: effects of acidosis and corticosteroid administration. J Neurosurg 112:1095–1104. Truettner JS, Alonso OF, Dalton Dietrich W. 2005. Influence of therapeutic hypothermia on matrix metalloproteinase activity after traumatic brain injury in rats. J Cereb Blood Flow Metab 25:1505–1516. Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. 2008. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. J Intensive Care Med 34: 1384–1392. Vink R, van den Heuvel C. 2010. Substance P antagonists as a therapeutic approach to improving outcome following traumatic brain injury. Neurotherapeutics 7:74–80.

Journal of Neuroscience Research

147

Vink R, Donkin JJ, Cruz MI, Nimmo AJ, Cernak I. 2004. A substance P antagonist increases brain intracellular free magnesium concentration after diffuse traumatic brain injury in rats. J Am Coll Nutr 23: 538–540. von Oettingen G, Bergholt B, Gyldensted C, Astrup J. 2002. Blood flow and ischemia within traumatic cerebral contusions. Neurosurgery 50: 781–788. Walker K, Perkins M, Dray A. 1995. Kinins and kinin receptors in the nervous system. Neurochem Int 26:1–16. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P. 2009. Brain endothelial cells and the gliovascular complex. Cell Tissue Res 335:75–96. Wong D, Dorovini-Zis K. 1995. Expression of vascular cell adhesion molecule-1 (VCAM-1) by human brain microvessel endothelial cells in primary culture. Microvasc Res 49:325–339. Xi G, Reiser G, Keep RF. 2003. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J Neurochem 84:3–9. Xiong Y, Zhang Y, Mahmood A, Meng Y, Zhang ZG, Morris DC. 2012. Neuroprotective and neurorestorative effects of thymosin b4 treatment initiated 6 hours after traumatic brain injury in rats. Laboratory investigation. J Neurosurgery 116:1081–1092. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. 2007. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27: 697–709. Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, Qian G, Zheng JC. 2013. IL-1b and TNF-a induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem doi: 10.1111/jnc.12263 [E-pub ahead of print]. Yi JH, Hazell AS. 2006. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int 48:394–403. Zacest AC, Vink R, Manavis J, Sarvestani GT, Blumbergs PC. 2010. Substance P immunoreactivity increases following human traumatic brain injury. Brain edema. Acta Neurochirurg 106:211–220. Zhong C, Zhao X, Van KC, Bzdega T, Smyth A, Zhou J, Kozikowski AP, Jiang J, O’Connor WT, Berman RF, Neale JH, Lyeth BG. 2006. NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat. J Neurochem 97:1015–1025.