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Insights into inflammation and epilepsy from the basic and clinical sciences
Journal of Clinical Neuroscience 19 (2012) 1071–1075
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Review
Insights into inflammation and epilepsy from the basic and clinical sciences Gustavo Silveira a, Antonio Carlos Pinheiro de Oliveira b, Antonio Lucio Teixeira a,⇑ a Departamento de Bioquímica e Imunologia, Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenue Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais 31270-901, Brazil b Departamento de Farmacologia, Laboratório de Neurofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil
a r t i c l e
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Article history: Received 23 August 2011 Accepted 25 October 2011
Keywords: Cytokines Epilepsy Inflammation Immunology
a b s t r a c t Inflammatory mediators are overexpressed in brain tissue after induction of seizures in animal models, and several studies demonstrate their involvement in neuronal hyperexcitability, seizure frequency and duration. In accordance with these results, the study of cerebrospinal fluid and brain specimens from patients with chronic epilepsy have shown increased levels of cytokines and areas of hippocampal sclerosis, respectively. Here we review the current findings supporting the existence of an ongoing inflammatory process in the physiopathology of epilepsy. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Epileptogenesis, which can be defined as persistent brain changes leading to spontaneous seizures, is thought to comprise complex interactions between genetic and environmental factors. Recently, the role of inflammation has attracted great attention in the physiopathology of epileptogenesis. Evidence of an ongoing inflammatory process, as demonstrated by increased cytokine concentrations in circulation and brain tissue,1 has been obtained for a series of neurological2,3 and psychiatric diseases.4–6 We present recent findings regarding the role of inflammation in seizure susceptibility and discuss its possible implication in epileptogenesis. 2. Role of cytokines in animal models of epilepsy The most consistent evidence regarding inflammation and epilepsy comes from animal models. Increased release of inflammatory mediators by glial cells following the induction of seizures in animal models has been demonstrated in many studies, as reviewed by Vezzani et al.7 Cytokine transcripts8 and their protein levels,9 such as interleukin-1 beta (IL-1b),8,10,11 interleukin-6 (IL6),8,10,12,13 IL-10 and tumor necrosis factor-alpha (TNF-a),8,10 are increased in animal brains following the induction of status epilepticus (SE) and after generalized convulsive seizures.14,15 Additionally, cytokines have been shown to contribute to excitotoxic16 ⇑ Corresponding author. Tel.: +55 31 34092651. E-mail address: [email protected] (A.L. Teixeira). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.10.011
and apoptotic neuronal death,17 besides lowering the neuronal excitability threshold18,19 and increasing the duration15 of seizures after exogenous application. IL-1b might act as proconvulsive cytokine20 and could induce neuronal damage.11,21 Pre-treatment with IL-1 receptor antagonist (IL-1ra) decreases the severity of convulsions8 and prevents induction of seizures,22,23 while selective inhibition of interleukin converting enzyme (ICE; which cleaves IL-1b to its active form) blocks seizure induction in rats and mice.24,25 Moreover, transgenic mice overexpressing IL-1ra in astrocytes are less sensitive to seizure induction.26 Although most studies demonstrate proconvulsive effects of IL-1b, this cytokine has an anti-convulsant effect in amygdala-kindled rats.27 These differential results might be dose-dependent.28 Similarly, the roles of IL-6 and TNF-a remain controversial since there are studies demonstrating either proand anti-convulsive effects or neuroprotection and neurotoxicity.13,29–32 Results regarding the expression and possible roles of cytokines and cyclooxygenase-2 (COX-2) in human and animal models of epilepsy are summarized in Table 1. Neuronal hyperexcitability may be affected by cytokines in different ways. IL-1b increases calcium influx into neurons by N-methyl-D-aspartate (NMDA) receptors, contributing to excitotoxicity,42 besides inhibiting reuptake of glutamate by astrocytes,43 which may modulate the strength of the ictal (seizure)-like event.44 In addition, application of IL-1b to hippocampal neurons results in the block of gamma-aminobutyric acid type A (GABAA) receptor function and may underlie central nervous system (CNS) hyperexcitability.45 Similarly, TNF-a has also been implicated in GABAA transmission decrease by endocytosis of its receptors and
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Table 1 Expression and possible roles of cytokines and cyclooxygenase-2 (COX-2) in human and animal models of epilepsy Mediator
Expression
Function
IL-1b
" Animal model: kainic acid10 " Animal model: electrical stimulation of the CA3 region8 " Animal model: pilocarpine11 " Human: different epileptic syndromes, TLE11,33 " Animal model: kainic acid10,13 " Animal model: electrical stimulation of the CA3 region8 – Animal model: picrotoxin12 " Human: different epileptic syndromes, TLE33,34 " Animal model: kainic acid10 " Animal model: electrical stimulation of the CA3 region8 " Human: different epileptic syndromes, TLE33,35 " Animal model: kainic acid36
Neurotoxic,11,21 proconvulsant,20 anticonvulsant27
IL-6
TNF
COX-2
Neuroprotection,13 neurotoxicity and increased sensitivity to seizure31
Neuroprotection,30 reduced number and duration of seizure (via receptor p750),29 facilitation in the development of adult seizures32
Neurotoxicity, development of spontaneous seizures37; neuroprotection and reduced seizures,38,39 reduced mortality40
" Human: TLE41 ‘‘"’’ = enhanced synthesis, ‘‘–’’ = no change. IL = interleukin, TLE = temporal lobe epilepsy.
Other inflammatory mediators also participate in leukocyte recruitment to the brain. The chemokines CCL2 (involved with the preferential recruitment of monocytes into inflammatory sites) and its receptor CCR2 are upregulated in the rat hippocampus53 and in reactive glial cells and blood vessels after induction of SE.54 Recently, it has been shown that fractalkine and its receptor CXCR1 are transiently increased after SE. Moreover intracerebroventricular infusion of recombinant fractalkine enhanced neuronal damage induced by SE.55 There is also evidence that seizure-like activity induces expression of adhesion molecules in the cerebral endothelium.56 Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1) concentrations are markedly upregulated in the mouse brain after seizure induction, whereas suppression of SE with diazepam prevents upregulation of VCAM-1.57 The blockade of adhesion molecules decreases neuronal loss and subsequent development of recurrent seizures after SE, while neutrophil depletion before SE induction reduces spontaneous recurrent convulsions.57 Together these results suggest an important role of leukocyte recruitment and BBB disruption in epileptogenesis. Finally, peripheral inflammation responses have also been linked to brain inflammation culminating in seizure activity, even though the underlying mechanisms and the signaling pathways involved are not understood. Patients with chronic inflammatory disease have a higher incidence of seizures.58 Systemic administration of bacterial endotoxin lipopolysaccharide in rodents induces microglia activation and production of proinflammatory factors, leading to a decrease in the seizure threshold.59 Similarly, animal models of arthritis and intestinal inflammation also show increased susceptibility to seizures.60 In this latter model, microglia activation and increased levels of TNF-a in the hippocampus follow the development of colitis, while resolution of inflammation reverses seizure threshold.61
3. Role of cytokines in human epilepsy in rapid exocytosis of a-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid receptors in hippocampal pyramidal cells,46 suggesting that TNF-a may exacerbate excitotoxic damage resulting from neuronal insult. It is hypothesized that seizure-induced production of cytokines may contribute to brain structural changes such as neuronal damage and gliosis.21,47 IL-1b levels, for example, remain elevated in rat brains with spontaneous seizures induced by SE.18 IL-1 receptor (IL-1R) type I (which mediates responses to IL-1b) is expressed in hippocampal neurons and in astrocytes after SE.48 Therefore, besides being associated with seizures, IL-1b may have a role in epileptogenesis. Blood–brain barrier (BBB) dysfunction has also been implicated in epileptogenesis. BBB permeability in rat limbic brain regions increases shortly after SE and is positively correlated to seizure frequency in chronic epileptic rats.49 Interestingly, cytokines might be essential to this process, since the injection of IL-1b into the CNS parenchyma leads to local neutrophil recruitment and BBB breakdown.50 Moreover, focal disruption of the BBB in the rat cortex leads to persistent extravasation of serum albumin to the extracellular space and later development of epileptiform discharges involving both glutamatergic and GABAergic neurotransmitter systems, even in the absence of a marked inflammatory response or cell loss.51 In addition, albumin uptake by astrocytes downregulates its inward-rectifying potassium channels, which leads to extracellular potassium accumulation and facilitates NMDA-receptor-mediated neuronal hyperexcitability and, eventually, epileptiform activity. In turn, albumin uptake is mediated by transforming growth factor b (TGF-b) receptors, and its in vivo blockade reduces the likelihood of epileptogenesis.52
Increased serum levels of pro-inflammatory cytokines, such as TNF-a, IL-1b, and IL-6, have been reported in patients with different epileptic syndromes in the post-ictal phase.33,35 Patients with treatment-resistant (or refractory) epilepsy also display a highly pro-inflammatory cytokine profile in the circulation, including high IL-6, low IL-1Ra and low IL-1Ra/IL-1b ratio.62 Liimatainen et al.34 found increased serum levels of IL-6 in patients with refractory epilepsy and higher levels in patients with temporal lobe epilepsy (TLE) when compared to patients with extra-TLE, suggesting a chronic immune mechanism in refractory epilepsy and the influence of clinical parameters in cytokine overproduction. The most likely origin for these cytokines seems to be the brain, where cytokines could, in turn, exert neuromodulatory functions. Indeed excessive neuronal activity and seizure itself directly stimulate cytokine production in the brain. For instance, IL-6 concentrations are significantly increased in the cerebrospinal fluid (CSF) and plasma within 24 hours after tonic–clonic seizures,63 suggesting that it may act as an activation signal for other cytokines in brain tissue as demonstrated in an experimental model.64 IL-6 levels increased even more after recurrent seizures,65 providing further evidence of cytokine production by seizure activity per se. Along this line, Lehtimak et al.66 found a mild increase in CSF IL1Ra levels after a single seizure, but significantly elevated levels after prolonged partial or recurrent tonic–clonic seizures. Many patients with TLE have hippocampal sclerosis, consisting of massive neuronal loss, gliosis and mossy fiber sprouting.67 Surgically resected hippocampus from these patients with epilepsy shows elevated levels of cytokines, chemokines and other inflammatory molecules. For example, IL-1a,68 VCAM-169 and chemokines
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Fig. 1. Schematic representing the mechanism by which different brain injuries are thought to participate in the onset of a brain inflammatory cascade in epileptogenesis. Cerebral infection or trauma, stroke and even peripheral inflammation may determine the production of several inflammatory mediators in the brain. Neuronal hyperexcitability and the blood–brain barrier breakdown are involved in seizure predisposition and duration, while leukocyte homing to the brain and chronic cytokine production seem to be central to cell damage and epileptogenesis. Ca2+ = calcium ion, CCL2 = chemokines, CNS = central nervous system, GABAA = gamma-aminobutyric acid type A, IL = interleukin, NMDA = N-methyl-D-aspartate, TNF-a = tumor necrosis factor-alpha.
CCL3 and CCL470 were upregulated in resected hippocampus. Also, marked activation of microglia and astrocytes, and diffuse cell death were observed in epileptogenic tissue resected from children with epilepsy in whom IL-1b, IL-8 and macrophage inflammatory protein 1b (MIP-1b) were significantly increased.71 Moreover, hippocampal tissue from patients with TLE with hippocampal sclerosis exhibits overexpression of the nuclear factor (NF)-kappa B (NF-jB) that is implicated in the transcription of cytokine genes.72 Therefore, persistent inflammatory mediators and vascular adhesion molecule expression might be involved in epileptogenesis in the human brain, in accordance with those findings from animal models. Initial data suggest that innate immune processes predominate over adaptive immune responses in this context. Granulocytes and monocytes, which are present in areas of neuronal loss in TLE with hippocampal sclerosis, may contribute to neuronal injury.11 Conversely, cells that are part of adaptive immunity (T, B or NK cells) seem to be absent in hippocampal sclerosis, distinguishing inflammation in TLE from other neuroinflammatory diseases, including Rasmussen’s encephalitis.73 4. Anti-inflammatory drugs in epilepsy There is an increasing search for anti-convulsant drugs that could be efficacious in different types of epilepsy. Considering the growing body of evidence that inflammation has a role in epilepsy, some studies have investigated whether reducing the inflammatory process with anti-inflammatory strategies would block seizures and epileptogenesis. COX inhibitors and glucocorticoids (GC) are among the most commonly used anti-inflammatory drugs. Various studies have investigated the effect of the conventional non-steroidal antiinflammatory drugs (NSAID), COX-2 inhibitors and GC in different animal models of epilepsy. However, their role in this pathological condition is still controversial.
COX-2 is up-regulated during SE and might be important for epileptogenesis. COX-2 immunoreactivity is increased in the hippocampus of animals treated with kainic acid and patients with treatment-resistant TLE.36,41 In a model of pilocarpine-induced SE, celecoxib, a COX-2 inhibitor, prevented neuronal loss and microglia activation in the hippocampus.37 Moreover, there was a reduction in neurogenesis and gliogenesis in this brain area in parallel with decrease of the frequency and duration of spontaneous recurrent seizures.73 Recently, it has been shown that parecoxib, another COX-2 inhibitor, reduced the damage in the hippocampus and piriform cortex induced by pilocarpine, although it did not reduce the incidence, frequency or duration of spontaneously recurrent seizures.74 Naproxen, a non-selective COX inhibitor, and nimesulide, a preferential COX-2 inhibitor, have also reversed kindling induced by a subconvulsive dose of pentylenetetrazol (PTZ) every other day for 15 days.75,76 Celecoxib, as well as anti-prostagladin (PG)E2 antibodies, reduced seizures induced by PTZ. Conversely, the association between PGE2 and a subconvulsive dose of PTZ induced seizures in the animals. Intracerebroventricular administration of PGE2 also reversed the anticonvulsant effect of celecoxib.77 It remains to be defined which PGE2 receptor is involved in the facilitation of seizures since a PGE2 receptor (EP2) agonist, as well as EP1, EP3 and EP4 antagonists, increased the latency for clonic and generalized tonic–clonic seizures induced by PTZ.78 Conventional NSAID, such as acetylsalicylic acid, ibuprofen, indomethacin, metamizole, paracetamol and piroxicam, enhances the protective activity of valproate against maximal electroshockinduced seizures.79 This might be due to a number of different mechanisms of action, since these compounds inhibit COX isoforms by distinct means. Contrary to the work presented above, COX inhibitors might have deleterious effects in epilepsy. For instance, pre-treatment with indomethacin (a non-selective COX inhibitor), nimesulide,
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celecoxib or NS-398 (COX-2 inhibitors), is reported to have aggravated seizures and enhanced neuronal cell death in the hippocampus, as well as the mortality induced by kainic acid.38,39 In a rat model of TLE, chronic administration of SC-58236, a COX-2 inhibitor, increased the number of animals that died after two weeks of SE.40 These controversial results may be partly due to different animal models used in these studies. Taking into account that COX-2 and other prostaglandin synthases are differently expressed along the process, the time of administration of the drugs could also account for the discrepancies observed. In humans, GC are used to treat some pediatric epilepsies, such as Landau–Kleffner syndrome, and seizures due to Rasmussen’s encephalitis.80 In pediatric patients affected by drug-resistant epilepsy, dexamethasone reduces the occurrence of seizures and induces interruption of SE.81 However, the role of GC in other epileptic syndromes needs to be determined. Only a few studies have investigated the effect of GC in animal models of epilepsy. In contrast to its effect in the periphery, GC seem to determine proinflammatory effects in the CNS and may have neurotoxic properties. Metyrapone, an inhibitor of GC production, reduces neuronal death induced by kainic acid.82,83 In a model of neuronal insult induced by infusion of kainic acid in the CA3 area of the hippocampus, GC increased the death rate of neurons. GC treatment was associated with higher numbers of infiltrating cells and pro-inflammatory molecule production in the CNS. Moreover, adrenalectomized animals developed smaller CNS lesions than control animals in a model of hippocampal injection of kanic acid,84 suggesting a deleterious role of GC. However, Marchi et al.81 have demonstrated that the number of animals that developed SE after pilocarpine injection was reduced. Interestingly, when SE developed, the onset of SE was delayed and the mortality was reduced. Therefore, the role of GC in epilepsy needs to be further investigated. 5. Concluding remarks Seizure initiation may be regarded as an imbalance between neuronal excitation and inhibition, and can be acutely provoked by factors influencing this equation, including metabolic abnormalities, drug intoxication and fever. Epilepsy, in turn, involves persistent changes in the brain structure or in neuronal and glial cell functioning. Many brain insults, including head trauma, infection or stroke, which are associated with an increased risk of epilepsy development, are capable of inducing inflammation in the brain. However, seizure activity itself can induce an inflammatory response by activation of microglia and release of cytokines. In this scenario, a primary brain insult could activate inflammatory pathways leading to an acute BBB dysfunction and neuronal hyperexcitability, interfering with the seizure threshold. Subsequent activation of innate immune mechanisms could be associated with epileptogenesis through persistence of an uncontrolled inflammatory state in the brain (Fig. 1). Even though many aspects of these molecular mechanisms are yet to be unveiled, we expect that full understanding of this cascade of events will lead to novel therapeutic strategies for refractory epilepsy, as well as opening new perspectives to our understanding of neurodegenerative disorders. Conflict of interest The authors have declared that no conflict of interest exists. Acknowledgments This work was funded by a FAPEMIG/FAPESP grant (Neuroscience: Epilepsy).
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Brain Res 2002;952:159–69. 73. Pardo CA, Vining EP, Guo L, et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 2004;45:516–26. 74. Polascheck N, Bankstahl M, Loscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010;224:219–33. 75. Dhir A, Naidu PS, Kulkarni SK. Effect of naproxen, a non-selective cyclooxygenase inhibitor, on pentylenetetrazol-induced kindling in mice. Clin Exp Pharmacol Physiol 2005;32:574–84. 76. Dhir A, Naidu PS, Kulkarni SK. Neuroprotective effect of nimesulide, a preferential COX-2 inhibitor, against pentylenetetrazol (PTZ)-induced chemical kindling and associated biochemical parameters in mice. Seizure 2007;16:691–7. 77. Oliveira MS, Furian AF, Rambo LM, et al. Modulation of pentylenetetrazolinduced seizures by prostaglandin E2 receptors. Neuroscience 2008;152:1110–8. 78. Oliveira MS, Furian AF, Royes LF, et al. Cyclooxygenase-2/PGE2 pathway facilitates pentylenetetrazol-induced seizures. Epilepsy Res 2008;79:14–21. 79. Kaminski R, Kozicka M, Parada-turska J, et al. Effect of non-steroidal antiinflammatory drugs on the anticonvulsive activity of valproate and diphenylhydantoin against maximal electroshock-induced seizures in mice. Pharmacol Res 1998;37:375–81. 80. Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol 2011;7:31–40. 81. Marchi N, Granata T, Freri E, et al. Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE 2011;6:e18200. 82. Smith-Swintosky VL, Pettigrew LC, Sapolsky RM, et al. Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures. J Cereb Blood Flow Metab 1996;16:585–98. 83. Stein BA, Sapolsky RM. Chemical adrenalectomy reduces hippocampal damage induced by kainic acid. Brain Res 1988;473:175–80. 84. Dinkel K, MacPherson A, Sapolsky RM. Novel glucocorticoid effects on acute inflammation in the CNS. J Neurochem 2003;84:705–16.
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Insights into inflammation and epilepsy from the basic and clinical sciences Gustavo Silveira a, Antonio Carlos Pinheiro de Oliveira b, Antonio Lucio Teixeira a,⇑ a Departamento de Bioquímica e Imunologia, Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenue Antonio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais 31270-901, Brazil b Departamento de Farmacologia, Laboratório de Neurofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil
a r t i c l e
i n f o
Article history: Received 23 August 2011 Accepted 25 October 2011
Keywords: Cytokines Epilepsy Inflammation Immunology
a b s t r a c t Inflammatory mediators are overexpressed in brain tissue after induction of seizures in animal models, and several studies demonstrate their involvement in neuronal hyperexcitability, seizure frequency and duration. In accordance with these results, the study of cerebrospinal fluid and brain specimens from patients with chronic epilepsy have shown increased levels of cytokines and areas of hippocampal sclerosis, respectively. Here we review the current findings supporting the existence of an ongoing inflammatory process in the physiopathology of epilepsy. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Epileptogenesis, which can be defined as persistent brain changes leading to spontaneous seizures, is thought to comprise complex interactions between genetic and environmental factors. Recently, the role of inflammation has attracted great attention in the physiopathology of epileptogenesis. Evidence of an ongoing inflammatory process, as demonstrated by increased cytokine concentrations in circulation and brain tissue,1 has been obtained for a series of neurological2,3 and psychiatric diseases.4–6 We present recent findings regarding the role of inflammation in seizure susceptibility and discuss its possible implication in epileptogenesis. 2. Role of cytokines in animal models of epilepsy The most consistent evidence regarding inflammation and epilepsy comes from animal models. Increased release of inflammatory mediators by glial cells following the induction of seizures in animal models has been demonstrated in many studies, as reviewed by Vezzani et al.7 Cytokine transcripts8 and their protein levels,9 such as interleukin-1 beta (IL-1b),8,10,11 interleukin-6 (IL6),8,10,12,13 IL-10 and tumor necrosis factor-alpha (TNF-a),8,10 are increased in animal brains following the induction of status epilepticus (SE) and after generalized convulsive seizures.14,15 Additionally, cytokines have been shown to contribute to excitotoxic16 ⇑ Corresponding author. Tel.: +55 31 34092651. E-mail address: [email protected] (A.L. Teixeira). 0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.10.011
and apoptotic neuronal death,17 besides lowering the neuronal excitability threshold18,19 and increasing the duration15 of seizures after exogenous application. IL-1b might act as proconvulsive cytokine20 and could induce neuronal damage.11,21 Pre-treatment with IL-1 receptor antagonist (IL-1ra) decreases the severity of convulsions8 and prevents induction of seizures,22,23 while selective inhibition of interleukin converting enzyme (ICE; which cleaves IL-1b to its active form) blocks seizure induction in rats and mice.24,25 Moreover, transgenic mice overexpressing IL-1ra in astrocytes are less sensitive to seizure induction.26 Although most studies demonstrate proconvulsive effects of IL-1b, this cytokine has an anti-convulsant effect in amygdala-kindled rats.27 These differential results might be dose-dependent.28 Similarly, the roles of IL-6 and TNF-a remain controversial since there are studies demonstrating either proand anti-convulsive effects or neuroprotection and neurotoxicity.13,29–32 Results regarding the expression and possible roles of cytokines and cyclooxygenase-2 (COX-2) in human and animal models of epilepsy are summarized in Table 1. Neuronal hyperexcitability may be affected by cytokines in different ways. IL-1b increases calcium influx into neurons by N-methyl-D-aspartate (NMDA) receptors, contributing to excitotoxicity,42 besides inhibiting reuptake of glutamate by astrocytes,43 which may modulate the strength of the ictal (seizure)-like event.44 In addition, application of IL-1b to hippocampal neurons results in the block of gamma-aminobutyric acid type A (GABAA) receptor function and may underlie central nervous system (CNS) hyperexcitability.45 Similarly, TNF-a has also been implicated in GABAA transmission decrease by endocytosis of its receptors and
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Table 1 Expression and possible roles of cytokines and cyclooxygenase-2 (COX-2) in human and animal models of epilepsy Mediator
Expression
Function
IL-1b
" Animal model: kainic acid10 " Animal model: electrical stimulation of the CA3 region8 " Animal model: pilocarpine11 " Human: different epileptic syndromes, TLE11,33 " Animal model: kainic acid10,13 " Animal model: electrical stimulation of the CA3 region8 – Animal model: picrotoxin12 " Human: different epileptic syndromes, TLE33,34 " Animal model: kainic acid10 " Animal model: electrical stimulation of the CA3 region8 " Human: different epileptic syndromes, TLE33,35 " Animal model: kainic acid36
Neurotoxic,11,21 proconvulsant,20 anticonvulsant27
IL-6
TNF
COX-2
Neuroprotection,13 neurotoxicity and increased sensitivity to seizure31
Neuroprotection,30 reduced number and duration of seizure (via receptor p750),29 facilitation in the development of adult seizures32
Neurotoxicity, development of spontaneous seizures37; neuroprotection and reduced seizures,38,39 reduced mortality40
" Human: TLE41 ‘‘"’’ = enhanced synthesis, ‘‘–’’ = no change. IL = interleukin, TLE = temporal lobe epilepsy.
Other inflammatory mediators also participate in leukocyte recruitment to the brain. The chemokines CCL2 (involved with the preferential recruitment of monocytes into inflammatory sites) and its receptor CCR2 are upregulated in the rat hippocampus53 and in reactive glial cells and blood vessels after induction of SE.54 Recently, it has been shown that fractalkine and its receptor CXCR1 are transiently increased after SE. Moreover intracerebroventricular infusion of recombinant fractalkine enhanced neuronal damage induced by SE.55 There is also evidence that seizure-like activity induces expression of adhesion molecules in the cerebral endothelium.56 Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1) concentrations are markedly upregulated in the mouse brain after seizure induction, whereas suppression of SE with diazepam prevents upregulation of VCAM-1.57 The blockade of adhesion molecules decreases neuronal loss and subsequent development of recurrent seizures after SE, while neutrophil depletion before SE induction reduces spontaneous recurrent convulsions.57 Together these results suggest an important role of leukocyte recruitment and BBB disruption in epileptogenesis. Finally, peripheral inflammation responses have also been linked to brain inflammation culminating in seizure activity, even though the underlying mechanisms and the signaling pathways involved are not understood. Patients with chronic inflammatory disease have a higher incidence of seizures.58 Systemic administration of bacterial endotoxin lipopolysaccharide in rodents induces microglia activation and production of proinflammatory factors, leading to a decrease in the seizure threshold.59 Similarly, animal models of arthritis and intestinal inflammation also show increased susceptibility to seizures.60 In this latter model, microglia activation and increased levels of TNF-a in the hippocampus follow the development of colitis, while resolution of inflammation reverses seizure threshold.61
3. Role of cytokines in human epilepsy in rapid exocytosis of a-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid receptors in hippocampal pyramidal cells,46 suggesting that TNF-a may exacerbate excitotoxic damage resulting from neuronal insult. It is hypothesized that seizure-induced production of cytokines may contribute to brain structural changes such as neuronal damage and gliosis.21,47 IL-1b levels, for example, remain elevated in rat brains with spontaneous seizures induced by SE.18 IL-1 receptor (IL-1R) type I (which mediates responses to IL-1b) is expressed in hippocampal neurons and in astrocytes after SE.48 Therefore, besides being associated with seizures, IL-1b may have a role in epileptogenesis. Blood–brain barrier (BBB) dysfunction has also been implicated in epileptogenesis. BBB permeability in rat limbic brain regions increases shortly after SE and is positively correlated to seizure frequency in chronic epileptic rats.49 Interestingly, cytokines might be essential to this process, since the injection of IL-1b into the CNS parenchyma leads to local neutrophil recruitment and BBB breakdown.50 Moreover, focal disruption of the BBB in the rat cortex leads to persistent extravasation of serum albumin to the extracellular space and later development of epileptiform discharges involving both glutamatergic and GABAergic neurotransmitter systems, even in the absence of a marked inflammatory response or cell loss.51 In addition, albumin uptake by astrocytes downregulates its inward-rectifying potassium channels, which leads to extracellular potassium accumulation and facilitates NMDA-receptor-mediated neuronal hyperexcitability and, eventually, epileptiform activity. In turn, albumin uptake is mediated by transforming growth factor b (TGF-b) receptors, and its in vivo blockade reduces the likelihood of epileptogenesis.52
Increased serum levels of pro-inflammatory cytokines, such as TNF-a, IL-1b, and IL-6, have been reported in patients with different epileptic syndromes in the post-ictal phase.33,35 Patients with treatment-resistant (or refractory) epilepsy also display a highly pro-inflammatory cytokine profile in the circulation, including high IL-6, low IL-1Ra and low IL-1Ra/IL-1b ratio.62 Liimatainen et al.34 found increased serum levels of IL-6 in patients with refractory epilepsy and higher levels in patients with temporal lobe epilepsy (TLE) when compared to patients with extra-TLE, suggesting a chronic immune mechanism in refractory epilepsy and the influence of clinical parameters in cytokine overproduction. The most likely origin for these cytokines seems to be the brain, where cytokines could, in turn, exert neuromodulatory functions. Indeed excessive neuronal activity and seizure itself directly stimulate cytokine production in the brain. For instance, IL-6 concentrations are significantly increased in the cerebrospinal fluid (CSF) and plasma within 24 hours after tonic–clonic seizures,63 suggesting that it may act as an activation signal for other cytokines in brain tissue as demonstrated in an experimental model.64 IL-6 levels increased even more after recurrent seizures,65 providing further evidence of cytokine production by seizure activity per se. Along this line, Lehtimak et al.66 found a mild increase in CSF IL1Ra levels after a single seizure, but significantly elevated levels after prolonged partial or recurrent tonic–clonic seizures. Many patients with TLE have hippocampal sclerosis, consisting of massive neuronal loss, gliosis and mossy fiber sprouting.67 Surgically resected hippocampus from these patients with epilepsy shows elevated levels of cytokines, chemokines and other inflammatory molecules. For example, IL-1a,68 VCAM-169 and chemokines
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Fig. 1. Schematic representing the mechanism by which different brain injuries are thought to participate in the onset of a brain inflammatory cascade in epileptogenesis. Cerebral infection or trauma, stroke and even peripheral inflammation may determine the production of several inflammatory mediators in the brain. Neuronal hyperexcitability and the blood–brain barrier breakdown are involved in seizure predisposition and duration, while leukocyte homing to the brain and chronic cytokine production seem to be central to cell damage and epileptogenesis. Ca2+ = calcium ion, CCL2 = chemokines, CNS = central nervous system, GABAA = gamma-aminobutyric acid type A, IL = interleukin, NMDA = N-methyl-D-aspartate, TNF-a = tumor necrosis factor-alpha.
CCL3 and CCL470 were upregulated in resected hippocampus. Also, marked activation of microglia and astrocytes, and diffuse cell death were observed in epileptogenic tissue resected from children with epilepsy in whom IL-1b, IL-8 and macrophage inflammatory protein 1b (MIP-1b) were significantly increased.71 Moreover, hippocampal tissue from patients with TLE with hippocampal sclerosis exhibits overexpression of the nuclear factor (NF)-kappa B (NF-jB) that is implicated in the transcription of cytokine genes.72 Therefore, persistent inflammatory mediators and vascular adhesion molecule expression might be involved in epileptogenesis in the human brain, in accordance with those findings from animal models. Initial data suggest that innate immune processes predominate over adaptive immune responses in this context. Granulocytes and monocytes, which are present in areas of neuronal loss in TLE with hippocampal sclerosis, may contribute to neuronal injury.11 Conversely, cells that are part of adaptive immunity (T, B or NK cells) seem to be absent in hippocampal sclerosis, distinguishing inflammation in TLE from other neuroinflammatory diseases, including Rasmussen’s encephalitis.73 4. Anti-inflammatory drugs in epilepsy There is an increasing search for anti-convulsant drugs that could be efficacious in different types of epilepsy. Considering the growing body of evidence that inflammation has a role in epilepsy, some studies have investigated whether reducing the inflammatory process with anti-inflammatory strategies would block seizures and epileptogenesis. COX inhibitors and glucocorticoids (GC) are among the most commonly used anti-inflammatory drugs. Various studies have investigated the effect of the conventional non-steroidal antiinflammatory drugs (NSAID), COX-2 inhibitors and GC in different animal models of epilepsy. However, their role in this pathological condition is still controversial.
COX-2 is up-regulated during SE and might be important for epileptogenesis. COX-2 immunoreactivity is increased in the hippocampus of animals treated with kainic acid and patients with treatment-resistant TLE.36,41 In a model of pilocarpine-induced SE, celecoxib, a COX-2 inhibitor, prevented neuronal loss and microglia activation in the hippocampus.37 Moreover, there was a reduction in neurogenesis and gliogenesis in this brain area in parallel with decrease of the frequency and duration of spontaneous recurrent seizures.73 Recently, it has been shown that parecoxib, another COX-2 inhibitor, reduced the damage in the hippocampus and piriform cortex induced by pilocarpine, although it did not reduce the incidence, frequency or duration of spontaneously recurrent seizures.74 Naproxen, a non-selective COX inhibitor, and nimesulide, a preferential COX-2 inhibitor, have also reversed kindling induced by a subconvulsive dose of pentylenetetrazol (PTZ) every other day for 15 days.75,76 Celecoxib, as well as anti-prostagladin (PG)E2 antibodies, reduced seizures induced by PTZ. Conversely, the association between PGE2 and a subconvulsive dose of PTZ induced seizures in the animals. Intracerebroventricular administration of PGE2 also reversed the anticonvulsant effect of celecoxib.77 It remains to be defined which PGE2 receptor is involved in the facilitation of seizures since a PGE2 receptor (EP2) agonist, as well as EP1, EP3 and EP4 antagonists, increased the latency for clonic and generalized tonic–clonic seizures induced by PTZ.78 Conventional NSAID, such as acetylsalicylic acid, ibuprofen, indomethacin, metamizole, paracetamol and piroxicam, enhances the protective activity of valproate against maximal electroshockinduced seizures.79 This might be due to a number of different mechanisms of action, since these compounds inhibit COX isoforms by distinct means. Contrary to the work presented above, COX inhibitors might have deleterious effects in epilepsy. For instance, pre-treatment with indomethacin (a non-selective COX inhibitor), nimesulide,
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celecoxib or NS-398 (COX-2 inhibitors), is reported to have aggravated seizures and enhanced neuronal cell death in the hippocampus, as well as the mortality induced by kainic acid.38,39 In a rat model of TLE, chronic administration of SC-58236, a COX-2 inhibitor, increased the number of animals that died after two weeks of SE.40 These controversial results may be partly due to different animal models used in these studies. Taking into account that COX-2 and other prostaglandin synthases are differently expressed along the process, the time of administration of the drugs could also account for the discrepancies observed. In humans, GC are used to treat some pediatric epilepsies, such as Landau–Kleffner syndrome, and seizures due to Rasmussen’s encephalitis.80 In pediatric patients affected by drug-resistant epilepsy, dexamethasone reduces the occurrence of seizures and induces interruption of SE.81 However, the role of GC in other epileptic syndromes needs to be determined. Only a few studies have investigated the effect of GC in animal models of epilepsy. In contrast to its effect in the periphery, GC seem to determine proinflammatory effects in the CNS and may have neurotoxic properties. Metyrapone, an inhibitor of GC production, reduces neuronal death induced by kainic acid.82,83 In a model of neuronal insult induced by infusion of kainic acid in the CA3 area of the hippocampus, GC increased the death rate of neurons. GC treatment was associated with higher numbers of infiltrating cells and pro-inflammatory molecule production in the CNS. Moreover, adrenalectomized animals developed smaller CNS lesions than control animals in a model of hippocampal injection of kanic acid,84 suggesting a deleterious role of GC. However, Marchi et al.81 have demonstrated that the number of animals that developed SE after pilocarpine injection was reduced. Interestingly, when SE developed, the onset of SE was delayed and the mortality was reduced. Therefore, the role of GC in epilepsy needs to be further investigated. 5. Concluding remarks Seizure initiation may be regarded as an imbalance between neuronal excitation and inhibition, and can be acutely provoked by factors influencing this equation, including metabolic abnormalities, drug intoxication and fever. Epilepsy, in turn, involves persistent changes in the brain structure or in neuronal and glial cell functioning. Many brain insults, including head trauma, infection or stroke, which are associated with an increased risk of epilepsy development, are capable of inducing inflammation in the brain. However, seizure activity itself can induce an inflammatory response by activation of microglia and release of cytokines. In this scenario, a primary brain insult could activate inflammatory pathways leading to an acute BBB dysfunction and neuronal hyperexcitability, interfering with the seizure threshold. Subsequent activation of innate immune mechanisms could be associated with epileptogenesis through persistence of an uncontrolled inflammatory state in the brain (Fig. 1). Even though many aspects of these molecular mechanisms are yet to be unveiled, we expect that full understanding of this cascade of events will lead to novel therapeutic strategies for refractory epilepsy, as well as opening new perspectives to our understanding of neurodegenerative disorders. Conflict of interest The authors have declared that no conflict of interest exists. Acknowledgments This work was funded by a FAPEMIG/FAPESP grant (Neuroscience: Epilepsy).
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