YEBEH-04344; No of Pages 4 Epilepsy & Behavior xxx (2015) xxx–xxx

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Review

Status epilepticus, blood–brain barrier disruption, inflammation, and epileptogenesis Jan A. Gorter a,⁎, Erwin A. van Vliet b, Eleonora Aronica a,b,c b c

Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands Academic Medical Center, Department of (Neuro)Pathology, University of Amsterdam, Amsterdam, The Netherlands SEIN — Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands

a r t i c l e

i n f o

Article history: Accepted 19 April 2015 Available online xxxx Keywords: Status epilepticus Blood–brain barrier Leakage Inflammation Angiogenesis Immune response Epilepsy

a b s t r a c t Over the last 15 years, attention has been focused on dysfunction of the cerebral vasculature and inflammation as important players in epileptogenic processes, with a specific emphasis on failure of the blood–brain barrier (BBB; Fig. 1) (Seiffert et al., 2004; Marchi et al., 2007; Oby and Janigro, 2006; van Vliet et al., 2014; Vezzani et al., 2011) [3–7]. Here, we discuss how the BBB is disrupted as a consequence of SE and how this BBB breakdown may be involved in epileptogenesis. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.

1. Blood–brain barrier breakdown as trigger for epileptogenesis

⁎ Corresponding author at: Science Park 904 1098XH Amsterdam, The Netherlands. E-mail address: [email protected] (J.A. Gorter).

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There is an increased risk of developing epilepsy in patients that have experienced status epilepticus (SE) (Hesdorffer et al., 1998) [1]. Excitotoxic neuronal death and reorganization of neuronal networks are considered as crucial triggers for the development of epilepsy after convulsive SE (Chen andWasterlain, 2006) [2]. Blood–brain barrier leakage is one of the earliest characteristic pathophysiological disturbances during SE and might, therefore, play an important role in the development of epilepsy [5–10]. This also has been investigated in detail in poststatus epilepticus animal models and in models of acquired epilepsy (Fig. 1) [3,4,11–13]. The BBB disruption may contribute to the development of epilepsy after SE either via a direct mechanism (neuronal depolarization via influx of potassium) or via a cascade of events triggered by leakage of serum proteins that leads to glial activation, impaired potassium buffering, inflammation, and synaptogenesis [14,15]. In patients as well as in animal models, brain hemorrhages may also occur as a consequence of SE [16–18]. These bleedings also contribute to brain inflammation, thrombin formation, iron toxicity, cell death, and subsequent destabilization of neuronal networks causing epilepsy [19,20].

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Year of publication Fig. 1. Pubmed search for the number of yearly publications related to “epilepsy and blood– brain barrier” (blue bars) and “epilepsy and inflammation” (yellow bars; keywords in “any field”). After 2000, there is a gradual increase in the number of publications in both categories triggered by publications related to multidrug transporters [21], epileptogenesis [3], and/or increased interest in cytokines and glial activation (inflammation) [22]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

2. Time course of BBB breakdown after SE in animal models Research in rodent models in which BBB leakage has been visualized with markers such as Evans Blue or the serum protein albumin,

http://dx.doi.org/10.1016/j.yebeh.2015.04.047 1525-5050/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Gorter JA, et al, Status epilepticus, blood–brain barrier disruption, inflammation, and epileptogenesis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.047

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J.A. Gorter et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

respectively, has shown that BBB leakage can be detected within minutes after induction of bicuculline-induced long-lasting seizures [23]. Initial studies in various SE animal models indicated that BBB leakage can be easily detected during the first few days after pharmacologically induced SE [24–26]. However, more recently, several studies demonstrated that BBB leakage was more persistent and may also play a role in the development of epilepsy later on, when chronic seizures have developed [12,13,27]. For instance, after electrically induced SE, parenchymal albumin staining can easily be detected during the first few days after SE, after which it declines progressively during the next few weeks when spontaneous seizures start to appear. During the chronic epileptic phase (N3 months), BBB leakage is difficult to detect, but careful examination using confocal microscopy shows intracellular (glial and neuronal) albumin uptake and subtle leakage into the limbic brain regions after intravenous injection of Evans Blue or fluorescein [13]. A comparable time course of BBB leakage has also been reported in the pilocarpine model using IgG staining [12]. Blood–brain barrier leakage can also be assessed using T1-weighted magnetic resonance imaging (MRI) with gadolinium as contrast agent. In previous MRI studies, BBB leakage has been detected during the acute phase after pharmacologically induced SE [26] but not at later phases. Using a step-down infusion protocol that led to steady state blood levels of the contrast agent during infusion in kainate-treated rats [28], we were able to show that BBB leakage can also be detected during the chronic epileptic phase. The extent of the gadolinium enhanced signal is correlated with seizure frequency which can be confirmed using fluorescein staining in brain sections. It remains to be investigated whether the BBB leakage during this chronic phase is causing the seizures or just a consequence of seizure activity [29]. Interestingly, BBB leakage is extensive during the latent period, when seizures (but not epileptiform activity) are absent, indicating that BBB leakage by itself is less likely to cause spontaneous seizures and more likely to contribute to the epileptogenic process. This has been investigated in more detail by Friedman and Heinemann in different models of BBB disruption (reviewed in [30]). They showed the onset of a complex inflammatory cascade and a gradual development of epileptiform activity initiated by leakage of serum proteins. They demonstrated that albumin, which has leaked into the brain, binds to TGFβ receptors present in glial cells. This, then, leads to glial activation, compromised potassium buffering, proictogenic inflammation, synaptogenesis, and gradual development of epilepsy [15,31, 32]. Transforming growth factor beta receptor blockade by losartan has been shown to be a promising strategy to prevent epilepsy in an animal model [33]. Since this drug also affects neurovascular coupling and blood flow via angiotensin receptor blockade, other BBB related mechanisms could also play a role.

3. What is triggering BBB disruption and how does it contribute to epileptogenesis? There are several mechanisms and processes that cause BBB disruption soon after SE has started; each process is important at its own specific point in time during and after SE.

3.1. Glutamate receptor activation of endothelial cells In vitro studies have shown that cerebral endothelial cells contain a number of glutamate receptor subtypes [34,35]. Since SE is associated with a dramatic and rapid rise of brain glutamate levels [36,37], SEinduced overactivation of endothelial glutamate receptors might be one of the earliest triggers that lead to BBB disruption in vivo. Excessive stimulation of endothelial glutamate receptors can lead to oxidative stress and subsequent BBB disruption [38].

3.2. Blood pressure rise and oxidative stress One of the first pathophysiological characteristics of SE is the quick rise of systemic blood pressure (within minutes after the start of seizures). A rise in blood pressure has been observed in different animal models during the so-called early “hyperdynamic” phase (~first hour) of convulsive SE and is caused by the increased metabolic demand in the affected brain regions leading to dilatation of brain capillaries and increased cerebral blood flow. This is followed by the “exhaustion phase” that is characterized by a drop in blood pressure and decreased cerebral blood flow, causing a mismatch between metabolic demand and supply [39,40]. This will lead to more oxidative stress, ischemic cell death, inflammation, and further BBB disruption. Interestingly, studies in rats showed that BBB leakage could be prevented if the hypertension during seizures was abolished [41] or was of short duration (~5 min) [42]. Hypertension can alter neurovascular coupling and BBB leakage by vascular oxidative stress [43]. However, although systemic blood pressure rises occur in several seizure models, BBB leakage does not occur throughout the entire brain, and the pattern varies among seizure models [44–46]. Interestingly, regions with increased BBB leakage correspond with regions of EEG spiking [47]. This indicates that BBB disruption is not simply a consequence of increased blood flow but is also linked to local seizure activity and local properties of the neurovascular units. Local seizure activity causes the release of a multitude of vasoactive substances which may alter neurovascular coupling and increase oxidative stress, which further compromises brain homeostasis [48,49]. 3.3. Brain inflammation Brain inflammation is rapidly (hours) activated in different seizure models: upregulation of different cytokines/chemokines has been observed within 60 min after bicuculline-induced seizures in the in vitro isolated guinea pig brain [50]. Proinflammatory mediators can induce and sustain BBB disruption by affecting the endothelial tight junctions and the basal membrane [48]. Moreover, they can play a role in seizure activity by modifying excitability and seizure threshold [7,51]. Therefore, different anti-inflammatory strategies have been tried to counteract these actions in the expectation that epilepsy could be modified or prevented. Several studies in seizure and post-SE models have shown some beneficial effects on seizure activity and epilepsy prevention via targeting inflammation. A successful strategy is based on targeting TGFβ receptors which are activated by albumin (see above). Another target that has been intensively investigated is related to IL1β/Toll like receptor signaling [52]. Antagonists that interfere with the IL1β pathway resolve BBB breakdown and show anticonvulsant effects with significant effects on acute seizure activity after SE in mice [53] or bicuculline-induced seizures in the in vitro guinea pig brain preparation [50]. 3.4. The immune response Other strategies that have shown promising antiepileptogenic effects related to epilepsy involve the suppression of the immune response [54,55]. The immunosuppressant rapamycin, a serine/threonine protein kinase that inhibits the mTOR pathway and that has been approved for clinical use, initially showed antiepileptogenic effects in rats and genetically modified mice [54,56]. Studies in post-SE rats have shown reduced epileptogenesis possibly via inhibitory effects on proepileptogenic processes such as mossy fiber sprouting and cell death that follow the SE [54,57]. In our hands, rapamycin reduced seizure frequency in chronic epileptic rats, suggesting that part of the antiepileptogenic effect might be caused by seizure suppression (unpublished observations) see also [58]. Considering that BBB leakage can contribute to epileptogenesis, we investigated whether the effect of rapamycin could be due to a restoration of the BBB. During the chronic epileptic phase, BBB leakage was significantly lower in rapamycin-

Please cite this article as: Gorter JA, et al, Status epilepticus, blood–brain barrier disruption, inflammation, and epileptogenesis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.047

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treated rats than in vehicle-treated rats [57]. Whether this is simply a consequence of reduction of seizures at that later phase or is caused by a physical restoration of the BBB or via an antiangiogenic effect remains to be determined and is further investigated using MRI and molecular studies of inflammation- and growth-associated mRNAs and miRNAs in rapamycin-treated post-SE rats. The initial enthusiasm concerning rapamycin's favorable effect on epileptogenesis has been tempered recently by contrasting results in other animal models or species: in post-SE mice, mossy fiber sprouting is decreased after rapamycin treatment, but epilepsy is still developing or might even intensify instead of decrease [59,60]. Thus, the outcome of studies that investigated rapamycin's effects on epileptogenesis, seizures, and pathology are confusing and might depend on the dosage applied and the species in which rapamycin is administered. 3.5. Cell adhesion and leukocyte entry Status epilepticus also induces an upregulation of integrins and cell adhesion molecules [61]. These proteins may cause BBB disruption via extravasation of leukocytes which are attracted by an increase in expression of adhesion molecules and chemokines. For instance, increased VCAM expression has been observed within 24 h after chemically induced SE [62–64]. A strategy that targets cell adhesion has been shown to be successful in preventing epilepsy after pilocarpine-induced post-SE in the mouse model [63]. However, until now, this has not been replicated in other post-SE models and, therefore, may depend on the seizure model used. In the intrahippocampal kainate mouse model, infiltration of leukocytes, including lymphocytes, appears to play a neuroprotective role [65]. Brain entry of lymphocytes is suggested to play a minor role in the tissue of human patients with TLE [66], although this has been disputed by others [63,65]. 3.6. Angiogenesis Angiogenesis is another prominent process that occurs after the initial vascular injury that occurs after following SE [12,27]. It is well known that angiogenesis is associated with increased BBB permeability through vascular endothelial growth factor-induced inflammation [27, 67] and, thus, might further contribute to epileptogenesis via BBB leakage from newly formed vessels. Antiangiogenesis strategies have been suggested [68], but inhibition of epileptogenesis has not been reported until now. 4. Conclusion There is ample evidence that SE-induced BBB disruption and inflammation play an important role in the development of epilepsy and progression of seizure activity. Blood–brain barrier leakage is promoted by SE-associated increases of glutamate release, blood pressure rises, derailed autoregulation of cerebral blood flow, and oxidative stress and is accelerated by different pathological processes that include inflammation and angiogenesis. Early detection of these changes (e.g. by contrast enhanced MRI) might help to guide and apply a suitable therapeutic strategy to prevent or modify the development of epilepsy, possibly by protection or restoration of the BBB. Acknowledgments This paper is supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602102 (EPITARGET). Disclosure The authors declare no conflicts of interest.

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Please cite this article as: Gorter JA, et al, Status epilepticus, blood–brain barrier disruption, inflammation, and epileptogenesis, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.047

Status epilepticus, blood-brain barrier disruption, inflammation, and epileptogenesis.

Over the last 15 years, attention has been focused on dysfunction of the cerebral vasculature and inflammation as important players in epileptogenic p...
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