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The protection of the brain from blood-borne toxins, proteins, and cells is critical to the brain’s normal function. Accordingly, a compromise in the blood–brain barrier (BBB) function accompanies many neurologic disorders, and is tightly associated with brain inflammatory processes initiated by both infiltrating leukocytes from the blood, and activation of glial cells. Those inflammatory processes contribute to determining the severity and prognosis of numerous neurologic disorders, and can both cause, and result from BBB dysfunction. In this review we examine the role of BBB and inflammatory responses, in particular activation of transforming grown factor β (TGFβ) signaling, in epilepsy, stroke, and Parkinson’s disease.
The blood–brain barrier (BBB) is formed and maintained by endothelial cells that line cerebral capillaries, pericytes around the capillaries, and finally astrocytic end-feet that surround these two layers. The BBB regulates the microenvironment of the brain by selectively regulating transport of molecules and cells in and out of the brain (Wolburg & Lippoldt, 2002). This in turn maintains the homeostasis of the neurovascular unit, which comprises the vascular and neuronal cells (Abbott et al., 2006). Dysfunction of the BBB is strictly associated with brain pathophysiology in numerous neurologic disorders, including stroke (Lo et al., 2003), traumatic brain injury (TBI) (Shlosberg et al., 2010), epilepsy (Marchi et al., 2007; van Vliet et al., 2007; Friedman et al., 2009), and chronic neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (Farkas & Luiten, 2001; Zlokovic, 2008). Therefore, understanding the mechanisms that underlie BBB dysfunction in these different brain pathologies may lead to the identification of new therapeutic targets.
Brain inflammation prominently contributes to determining the severity and prognosis of numerous neurologic disorders, and can both cause and result from BBB dysfunction. Loss of BBB integrity can allow immune cells, inflammatory molecules, and albumin to infiltrate, leading to glial activation and alterations in the extracellular milieu around neurons in the neurovascular unit. In PD, BBB dysfunction leads to the infiltration of leukocytes and cytokines such as tumor necrosis factor α (TNFα) that are known to be associated with the progression of this disorder (Qin et al., 2007). On the other hand, the inflammatory response in brain cells such as glia and neurons can increase BBB permeability (Abbott, 2000; Huber et al., 2001). Indeed, there are numerous examples in which pathology in neurologic disorders is mediated by BBB dysfunction that is in turn a direct result of increased inflammation. For example, inflammatory processes in the brain increase neuronal excitability and are associated with alterations in BBB permeability in animal models of epilepsy (Vezzani & Friedman, 2011). A specific proinflammatory pathway such as interleukin (IL)-1 receptor/Toll-like receptor (TLR) signaling is induced in glia and neurons in human epilepsy (Ravizza et al., 2008; Maroso et al., 2010; Zurolo et al., 2011) and contributes to the onset and recurrence of experimental seizures (Vezzani et al., 2011a). Microarray analysis in a rat model of temporal lobe epilepsy (TLE) has shown altered expression of immune and inflammatory genes including complement factors and ILs, during the different stages of epileptogenesis evolving after the induction of status epilepticus in rats (Gorter et al., 2006). Immunohistochemical analysis of various proteins induced by these genes in human and experimental epilepsy tissue showed that glial cells and neurons are the principal cell sources. Following epileptogenic injuries such as TBI, microglia cells are activated and leukocytes are recruited into the brain (Holmin et al., 1998), leading to the release of proinflammatory cytokines (Aihara et al., 1995). Ischemia also initiates brain inflammation including the activation of microglia and astrocytes, and acute inflammation exacerbates ischemic lesions (Moskowitz et al., 2010). Finally, brain inflammation as indicated by increased levels of inflammatory molecules, is also one of the risk factors for ischemic stroke (Di Napoli et al., 2005).
In this article, we describe the recent findings of activation of specific inflammatory pathways in experimental models of neurologic disorders such as epilepsy, stroke, and PD. These findings suggest that brain inflammation is one key factor determining brain pathologies associated with BBB dysfunction. We also highlight the novel concept that sophisticated new therapies that regulate the phenotype and timing of inflammatory responses may be useful in treating neurologic diseases, and discuss the challenges of using current antiinflammatory drugs in the clinical setting.
Recent findings support the concept that inflammation is an important factor contributing to the pathogenesis of pharmacoresistant seizures in epilepsy (Vezzani et al., 2011a). Seizures or epileptogenic injuries trigger the synthesis and release of proinflammatory molecules such as IL-1β and High Mobility Group Box 1 (HMGB1) in glial cells. These cytokines induce a decrease in seizure threshold, thereby contributing to seizure precipitation and recurrence by inducing rapid changes in glutamate and γ-aminobutyric acid (GABA) receptor phosphorylation and subunit composition, as well as channelopathies that alter intrinsic neural excitability (Viviani et al., 2007; Vezzani et al., 2011b). BBB breakdown may also occur during seizures, and artificial BBB opening induces synchronization of neuronal activity in rats (Fieschi et al., 1980), symptomatic seizures in pigs (Marchi et al., 2007), and increases seizure frequency in epileptic rats (van Vliet et al., 2007). Prominent BBB breakdown occurs 24 h after status epilepticus, and lasts for about 2 h after each spontaneous seizure occurrence (van Vliet et al., 2007), leading to albumin and immunoglobulin G (IgG) extravasation in the neuropil. Albumin in turn contributes to neuronal hyperexcitability by altering K+ buffering capacity of astrocytes (David et al., 2009).
It has been recently reported that intracerebroventricular injection in naive rats of recombinant rat albumin to attain hippocampal levels for 2–24 h similar to those reached after prominent BBB breakdown, was found to induce inflammatory molecules in astrocytes, downregulate Kir4.1 channels, and provoke transient spiking activity, without evoking frank seizures. Furthermore, these rats showed increased spike frequency following an intra-hippocampal convulsant dose of kainic acid, and an average 50% reduction in the threshold for afterdischarge induction following hippocampal electrical stimulation (Frigerio et al., 2011). These findings support the hypothesis that brain inflammation and BBB damage are reinforcing phenomena, and that brain exposure to albumin due to BBB breakdown contributes to neuronal network hyperexcitability by decreasing seizure threshold.
It was also tested whether seizures can induce brain inflammation and BBB damage, independently of leukocytes or blood-borne molecules, and whether brain-borne inflammation supports BBB impairment and seizure reoccurrence (Librizzi et al., 2012) using the guinea pig brain isolated in vitro. Seizures induced by brain arterial perfusion of bicuculline triggered the release of IL-1β from brain cells and enhanced its synthesis in astrocytes. In the same experimental setup BBB damage was observed, demonstrating that it can occur in the absence of either leukocytes or blood-borne inflammatory molecules. Moreover, anakinra, a specific IL-1β receptor blocker, terminated seizures, prevented their recurrence, and attenuated seizure-associated BBB damage and inflammation. These studies support the involvement of glia-derived brain inflammation and BBB damage in ictogenesis (Librizzi et al., 2012).
As discussed earlier, status epilepticus and recurrent seizures can cause opening of the BBB, a parenchymal brain inflammatory response and subsequent development of epileptic activity. Furthermore, epilepsy can develop following different precipitating events that all share BBB dysfunction and brain inflammation as the common denominator (Friedman et al., 2009). What are the mechanisms that lead from BBB dysfunction to epileptogenesis? We recently found that albumin signaling in astrocytes is critical in the generation of epilepsy following BBB compromise, and that activation of the transforming growth factor β (TGFβ) signaling pathway plays a key role (Ivens et al., 2007; Cacheaux et al., 2009). Accordingly, the direct activation of the TGFβ pathway by TGFβ1 results in epileptiform activity. Coimmunoprecipitation experiments revealed binding of albumin to TGFβ receptor II. As assessed by Western blot, the phosphorylation of Smad2, a main effector of the TGFβ signaling, confirmed downstream activation of this pathway. Transcriptome analysis revealed similar expression patterns following BBB break-down, and albumin and TGFβ1 exposure, which included induction of genes associated with the TGFβ signaling pathway, inflammatory pathways, astrocytic activation, and reduced levels of transcripts associated with inhibitory synaptic transmission (Cacheaux et al., 2009). Prominent changes in various astrocytic transcripts following BBB disruption and albumin treatment included downregulation of glutamate transporters, glutamine synthetase, the potassium channel Kir 4.1, and several connexins (Cacheaux et al., 2009). Because gene expression changes were detected in primary cultures enriched for astrocytes (but not in cultures enriched for neurons), we conclude that astrocytes play a major role in mediating the effect of albumin extravasation (due to BBB leakage) into the brain environment and contribute to induce pathologic events associated with epileptogenesis.
In particular, it should be noted that the activation of TGFβ signaling by albumin induced rapid and persistent up-regulation of genes related to inflammation, including nuclear factor (NF)-κB pathways and complement cascades, inflammatory cytokines and chemokines such as Il6, Ccl2, and Ccl7, and the pattern recognition receptor Cd14 (Cacheaux et al., 2009). It is notable that TGFβ pathway blockers suppressed both Smad2/3 phosphorylation and most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. These findings suggest the TGFβ pathway is a novel putative epileptogenic signaling cascade, as well as a possible therapeutic target for the prevention of injury-induced epilepsy.
The incidence of epilepsy increases dramatically with aging, and stroke is a prominent cause of epilepsy in that age group. TGFβ signaling is also induced in the brain following an ischemic injury (Buisson et al., 2003). Although most of the major brain cell types have TGFβ receptors and can release TGFβ, the activation of TGFβ signaling is intricately regulated and its role in brain pathology is context dependent. Specifically, TGFβ signaling can either promote or resolve inflammation (Buckwalter & Wyss-Coray, 2004). In autoimmune disease (rheumatoid arthritis, and experimental allergic encephalomyelitis [EAE]) TGFβ generally evokes inflammation when increased at the site of disease, but can dampen inflammation when it is globally increased. For example, the overexpression of constitutively active, TGFβ1 in the brain increases T-cell autoimmune responses, whereas increased plasma TGFβ1 ameliorates experimental autoimmune encephalitis. Therefore, understanding the role of activated TGFβ signaling is essential for unravelling injury-induced pathophysiology (Buckwalter & Wyss-Coray, 2004).
In a previous study (Doyle et al., 2010), TGFβ signaling was precisely monitored following stroke by using transgenic reporter mice that give a real-time readout of TGFβ responses after stroke via a Smad-responsive promoter (SBE-Luc RT) and an ultrasensitive camera to detect bioluminescence in living mice. TGFβ increased in the brain in young adult (5-month-old) mice that received distal middle cerebral artery occlusion (dMCAO), beginning day 1 after stroke, peaking on day 7, and then beginning to return to baseline levels. Although there were no differences in the timeline of TGFβ activation and the infarct volume between young and older (18 month old) mice, the activation of TGFβ signaling and astrogliosis was substantially exaggerated in older mice in the absence of differences in infarct volume. Furthermore, immunostaining of TGFβ and markers for reactive astrocytes, neurons, and activated microglia revealed that activated microglia and macrophages were predominant sources of TGFβ, whereas immunostaining for pSmad2, a marker of TGFβ signaling, and cell type markers uncovered that reactive astrocytes and activated microglia were the major cell types responding to the poststroke increases in TGFβ (Doyle et al., 2010).
Although TGFβ signaling plays a detrimental role in epileptogenesis as mentioned earlier, in the context of stroke TGFβ signaling may actually play a beneficial role by increasing BBB integrity. Astrocytic TGFβ release is involved in increasing plasminogen activator inhibitor-1 (PAI-1), which then inhibits tissue plasminogen activator (tPA), leading to the BBB closure (Kim et al., 2003). TGFβ release from other cell types also has the same effect on BBB integrity. Recent work by Gliem et al. (2012) demonstrated that TGFβ produced in brain by invading macrophages was required for maintaining the integrity of BBB after stroke. The ablation of macrophages using clodronate was found to result in central nervous system (CNS) hemorrhages due to BBB leakages that were alleviated by the later addition of TGFβ, confirming the importance of TGFβ from macrophages in reducing the BBB permeability. Put together, these data demonstrate that TGFβ signaling is pleiotropic, complex, and context-dependent.
PD is the second most prevalent neurodegenerative disease and the most prevalent neuromuscular disorder (Nussbaum & Ellis, 2003). Loss of dopaminergic neurons defines PD as a dopaminergic syndrome, and the great majority of patients are designated “sporadic,” with no single gene responsible for the disease. Several observations suggest causal and interrelated involvement in PD of BBB promiscuity, inflammation, and impaired cholinergic signaling. The PD-affected neurons in the substantia nigra are particularly susceptible to stress reactions, and this region includes a high density of microglia compared to other brain regions. Several causes of the nonfamilial form of PD have been proposed, including mitochondrial dysfunction, abnormal protein handling, oxidative stress, and exposure to environmental toxins, suggesting that BBB promiscuity may be involved. In addition, healthy cell-to-cell interactions and immune regulation is critical for homeostasis and survival of dopaminergic neurons, which die prematurely in PD (Orr et al., 2002). Acknowledging the promiscuity of the BBB implies that inflammatory mediators released by activated glial cells or penetrating the brain from blood may have detrimental acute effects in PD. Correspondingly, various evidence suggests that the complex interplay between inflammatory mediators, aging, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration (Lucas et al., 2006). Furthermore, antiinflammatory treatments exert a neuroprotective effect, together suggesting that immune/inflammatory challenges can exacerbate the symptoms in the disease (Ferrari & Tarelli, 2011). Supporting this notion, both patients and animal models of PD were found to present brain inflammation, including phagocyte (microglia and macrophages) activation and elevated brain levels of proinflammatory cytokines. This may lead to a feed-forward hyperactivation of microglia, hyperproduction of cytokines and other proinflammatory mediators, and release of reactive oxygen species (Whitton, 2007) due to yet incompletely understood mechanisms. Specifically, environmental exposure to insecticidal acetylcholinesterase (AChE) inhibitors aggravates the risk of PD, especially in carriers of debilitating AChE polymorphisms (Benmoyal-Segal et al., 2005), suggesting added risk under intensified cholinergic signaling.
Exposure to the dopaminergic neurotoxin and AChE inhibitor 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced massive changes in brain transcripts. Compared to wild-type mice, engineered mice overexpressing the “synaptic” AChE-S splice variant showed hypersensitivity to MPTP, impaired BBB functioning (Meshorer et al., 2005), and chronic stress symptoms (Shaltiel et al., 2012). Exposure to MPTP caused greater changes in many more prefrontal cortex (PFC) transcripts in these engineered mice. In contrast, mice expressing the stress-responsive soluble, monomeric human AChE-R splice variant are relatively MPTP-protected (BenMoyal-Segal et al., 2012). Furthermore, intravenous injection of polyethylene glycol-coated recombinant human (rh)AChE-R, which protected mice from exposure to otherwise lethal doses of administered anti-AChEs (Evron et al., 2007) induced massive changes in striatal transcripts. Specifically, rhAChE-R injection raised plasma AChE activity by 1,000-fold. Nevertheless, and indicating that the injected rhAChE-R did not cross the BBB, rhAChE-R-injected mice showed unchanged AChE activity in the parietal cortex and hippocampus. C57B6J mice injected with saline maintained unchanged AChE activity throughout this period, excluding stress effects, which in wild-type FVBN-naive mice impair BBB integrity (Friedman et al., 1996) and induce brain AChE-R overproduction (Kaufer et al., 1998). Nevertheless, the peripherally administered rhAChE-R modified striatal gene expression as compared to saline-injected mice. Among other transcripts, by 8 and 16 h postinjection, massive changes were observed in the dopamine receptor D3 (DRD3) dopamine receptor, the antioxidant superoxide dismutase 2 (SOD2), and the E3 ubiquitin ligase Parkin—all shown to be aberrant in PD (BenMoyal-Segal et al., 2012). Taken together, these findings support the working hypothesis that inherited or acquired changes in the integrity of the BBB may accelerate environmentally induced Parkinsonism; that the protective features of peripherally administered rhAChE-R involve physiologically relevant changes in peripheral-brain communication and striatal gene expression; and that injection of recombinant AChE-R may attenuate the progression of PD. As shown in Figure 1, the suppressed production of proinflammatory cytokines that can penetrate the brain and affect neuronal reactions (Raison & Miller, 2012) is likely to be the mechanism by which the peripherally administered rhAChE-R exerts its protective effects.
The brain immune/inflammatory response likely contributes to brain pathology in neurologic disorders, in particular those that are associated with BBB dysfunction (Fig. 2). Hence, there is a growing enthusiasm for new therapeutic agents that can target specific aspects of the inflammatory response and may prevent the onset or progression of these disorders. Numerous studies in epilepsy models explored the possible use of antiinflammatory drugs to control or prevent seizure activity, and investigated whether antiinflammatory mechanisms are part of the anticonvulsant mode of action of existing drugs (Matoth et al., 2000; Bhat et al., 2010; Gibbons et al., 2011). For example, the intracerebral administration of the endogenously occurring IL-1 receptor antagonist, that is, anakinra, has been shown to reduce seizures in various experimental models (Vezzani et al., 2000, 2002). Subsequently, the intravenous administration of anakinra was reported to significantly reduce the onset of status epilepticus and the associated BBB damage in pilocarpine-treated rats (Marchi et al., 2009). Blockade of IL-1β biosynthesis with a specific interleukin converting enzyme (ICE) inhibitor, VX-765, drastically reduced acute seizures and chronic drug-resistant epileptic activity in rodents (Ravizza et al., 2006; Maroso et al., 2011). In accordance with this pharmacologic evidence, astrocytic overexpression of anakinra or ICE gene deletion in mice greatly reduced their intrinsic seizure susceptibility (Vezzani et al., 2000; Ravizza et al., 2006). Antiepileptogenic effects have also been reported using ICE inhibitor or anakinra in kindling models (Ravizza et al., 2006; Auvin et al., 2010). Notably, the anticonvulsant drug levetiracetam displays antiinflammatory properties mediated by astrocyte membrane currents and TGFβ signaling in vitro (Stienen et al., 2011). Steroid hormones such as glucocorticoids with antiinflammatory properties, also delay the onset of pilocarpine-induced seizures in rats and their mortality, and these effects were associated with the restoration of BBB integrity. Large spectrum antiinflammatory treatments have been shown to control seizures in pediatric drug-resistant epilepsy syndromes (Marchi et al., 2011). However, it is likely that attaining global inhibition of inflammation has a limited potential of success, whereas a narrower focused approach of inhibiting specific detrimental inflammatory pathways is more likely to be clinically useful.
Indeed, pharmacologic intervention with statins that have demonstrated antiinflammatory properties showed differing results. Statins have neuroprotective effects in animal models of traumatic brain injury (Lu et al., 2004) and in cultured neurons by reducing excitotoxicity (Zacco et al., 2003), and simvastatin has an anticonvulsant effect in the kainate model of seizures (Ramirez et al., 2011). On the other hand, atorvastatin exacerbated kainate-induced seizures (Ramirez et al., 2011) or had no effect in rats with seizures induced by electrical stimulation of the angular bundle (van Vliet et al., 2011). Contrasting results have also been reported in seizure models when using anti-COX-1 or anti-COX-2 drugs (Vezzani et al., 2012). These results highlight the importance of choosing the appropriate antiinflammatory treatment for inhibiting seizures, thus targeting crucial mechanisms of inflammation underlying hyperexcitability. Although some inflammatory targets appear to commonly contribute to seizures independently of their etiology (i.e., IL-1R/TLR signaling, TGF-β), others may be more disease specific and their involvement may be determined by the specific pathologic context.
Antiinflammatory treatments that are tailored to specific aspects of the inflammatory response are attractive therapeutic strategies because brain inflammation itself can play either neurotoxic or neuroprotective roles following brain damage, depending on the stages of the pathology. Inflammatory signaling is involved at all stages of brain damage generated by ischemia, from the early neurodegenerative phase through the neuroregenerative, until the later repair phase. In particular, postischemic inflammation takes an active part in the preparation process for the reorganization in the injured brain. For instance, although T cells in the acute phase of ischemia contribute to brain damage, they can play a protective role in a delayed phase as a part of the adaptive immune response (Iadecola & Anrather, 2011). Moreover, TGFβ, generally known as an antiinflammatory cytokine, can be antiinflammatory during poststroke periods but pro-inflammatory in some experimental autoimmune encephalitis models (Buckwalter & Wyss-Coray, 2004; Taylor et al., 2006).
Hence, the targeting of inflammatory pathways in neurologic disorders needs to take into account the intricate characteristics of immune/inflammatory responses in the brain, how they vary with pathologic stages, and their context-dependent features.
Following BBB breakdown, albumin infiltrates into the brain and initiates TGFβ signaling in astrocytes, leading the altered milieus in the brain to evoke epileptogenesis mediated by increased inflammation, neuronal hyperexcitability, and changes in neuron-glia interactions (Cacheaux et al., 2009; David et al., 2009; Friedman et al., 2009; Vezzani et al., 2011a). This indicates that astrocytic TGFβ signaling plays a prominent role in developing pathologic conditions of posttraumatic epileptogenesis. As mentioned earlier, however, the poststroke activation of TGFβ signaling has antiinflammatory effects (Taylor et al., 2006) and increases the integrity of the BBB (Gliem et al., 2012), demonstrating the protective role of TGFβ signaling following stroke. These conflicting consequences of activation of TGFβ signaling in different disorder models are likely to reflect the complexity of this signaling, as a double-edged sword in brain pathology. Given that astrocytic TGFβ release can promote BBB stability via the induction of PAI-1 gene expression (Kim et al., 2003), the activation of astrocytic TGFβ signaling by albumin extravasation following BBB breakdown may be evoked in part as a compensatory mechanism to restore the integrity of the BBB. Nevertheless, such an activation of TGFβ signaling as a “recuperative” mechanism affects aspects in the neurovascular unit other than BBB, which include astrocytic dysfunction in interactions with neurons (e.g., reduced capacity of glutamate and K+ uptake by astrocytes) and exaggerated inflammation, to the onset of epileptiform activity (Cacheaux et al., 2009; David et al., 2009). Further investigation on differences in pathophysiologic development between epilepsy and ischemic stroke is necessary to understand how the activated TGFβ signaling can be either beneficial or detrimental.
Various cell types in the brain can respond to and be the source of TGFβ, and its effect can vary with cell types. In the model of posttraumatic epilepsy, astrocytes are the main player that takes up albumin extravasated through the permeable BBB, and mediates its effect on the generation of hyperexcitability via TGFβ signaling (Cacheaux et al., 2009). In models of ischemic stroke, however, the level of TGFβ in the brain increases 1 day after stroke, and activated microglia and macrophages are the major source of increased TGFβ. Moreover, microglia and astrocytes are the main cell types to respond to the increased TGFβ following stroke (Doyle et al., 2010). According to the recent study from Monsonego’s research group (see de Vries et al., 2012, in this issue), TGFβ signaling through Smad2/3 induces the quiescent phenotype of microglia. Therefore, the effect of TGFβ signaling on inflammation and brain pathology may vary depending on which major cell type responds to TGFβ.
In the model of posttraumatic epilepsy, the uptake of albumin by astrocytes is crucial for initiating the process that generates epileptiform activity (Ivens et al., 2007). Two questions still remain open: (1) Is albumin the sole mediator of comprised BBB effects? When the BBB is compromised, the brain parenchyma is exposed to many blood constituents, and not only to albumin. It is clear that other players are participating (i.e., IgG, thrombins); however, exposure to albumin, or even to the downstream effect of TGFβ1 activation, is sufficient to induce the gene expression changes and the resultant epileptiform activity. (2) Is albumin taken up by astrocytes only? Data presented by different groups in this meeting session provided different answers to this question. In the animal model of BBB opening by deoxycholate or albumin perfusion over the cortex (Ivens et al., 2007), albumin is taken up predominantly by astrocytes and pericytes. Similar observations have been reported in human resected epileptic tissue in cases of vascular malformations (Raabe et al., 2012). However, in tissue samples from human brain after status epilepticus and in a rat model of status epilepticus albumin is prominently observed in astrocytes, microglia and neurons (van Vliet et al., 2007). When injected as a single bolus intracerebroventricularly to attain pathologic tissue concentrations in the naive rat hippocampus (as after status epilepticus), albumin has been reported to taken up primarily by neurons and by scattered astrocytic NG2-positive cells (Frigerio et al., 2011). These findings suggest that the cellular uptake of albumin is determined by the pathologic context. Therefore, the former study focused on the effect of BBB breakdown on the generation of epilepsy, in that astrocytic uptake of albumin was found to occur prior to the generation of epilepsy. In the latter studies, albumin uptake was examined in rats at the acute and chronic seizure periods, or in a naive rat brain. Therefore, it is possible that the uptake of albumin may vary with the stage of pathology.
The proof-of-principle evidence, obtained in experimental disease models, demonstrates the anticonvulsant activity of specific antiinflammatory drugs and the potential rescue of neuropathology by restoring the BBB properties compromised by the CNS diseases, thereby encouraging the development of new treatment strategies targeting brain inflammation and the BBB. Drugs that block specific inflammatory pathways have entered clinical trials as potential therapeutics for autoimmune and autoinflammatory pathologies, and may also have a therapeutic potential in disorders associated with inflammatory processes in the brain.
The authors have no conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.