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Epilepsy Research (2011) 96, 191—206
jou rn al h om epa ge: www.elsev ier .com/ locate /ep i lepsyres
REVIEW
Extracellular proteases in epilepsy
Katarzyna Lukasiuk ∗, Grzegorz M. Wilczynski ∗, Leszek Kaczmarek ∗
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St, 02-093 Warsaw, Poland
Received 19 May 2011; received in revised form 10 July 2011; accepted 3 August 2011Available online 4 September 2011
KEYWORDSBrain;Epilepsy;Extracellular matrix;Protease;Seizures
Summary During the last decade, multiple data have been obtained, pointing to an involve-ment of extracellular, including extrasynaptic, proteolysis in epilepsy pathogenesis. The mostproductive avenues of investigations have been analyses of seizure-evoked gene and proteinexpression patterns, both hypothesis-driven and unbiased (e.g., DNA microarrays), comple-mented by functional analyses in animal models, as well as expression and gene polymorphismstudies carried out on human tissue In result, serine proteases (e.g., tPA, thrombin, trypsin-likeproteases, etc.), metalloproteinases, natural protease inhibitors, as well as complement com-
ponents, and reelin have been identified as a novel molecular system, emerging as a key factorin the development of epilepsy, in addition to well known contribution of ion channels and sig-nal transduction pathways. The extracellular location of the enzymes makes them particularly attractive potential targets for future pharmacological therapeutic interventions.© 2011 Elsevier B.V. All rights reserved.Contents
Introduction: epilepsy and its experimental models ...................................................................... 192Plasminogen activator/plasminogen system .............................................................................. 193
Plasminogen......................................................................................................... 193tPA .................................................................................................................. 193
uPA........................................................Plasminogen activator inhibitors ...........................uPAR .......................................................Abbreviations: ADAM, a disintegrin and metalloproteinase; ADAMTS,
CCI, controlled cortical impact; ECM, extracellular matrix; ECS, electrdispersion; KA, kainate or kainic acid; LGI1, leucine-rich, glioma inactivMAC, membrane-attack complexes; MMP, matrix metalloproteinase; PAI,
PTZ, pentylenetetrazol; SE, status epilepticus; TBI, traumatic brain injurylobe epilepsy; tPA, tissue type plasminogen activator; uPA, urokinase typereceptor; VLDLR, very low density lipoprotein receptor.
∗ Corresponding authors. Fax: +48 22 8225342.E-mail addresses: [email protected] (K. Lukasiuk), g.wilczynsk
(L. Kaczmarek).
0920-1211/$ — see front matter © 2011 Elsevier B.V. All rights reserved.doi:10.1016/j.eplepsyres.2011.08.002
.......................................................... 195......................................................... 195......................................................... 195
a disintegrin and metalloproteinase with thrombospondin motifs;oconvulsive shock; FH, complement inhibitor; GCD, granule cellated 1; LRP1, low density lipoprotein receptor-related protein 1;plasminogen activator inhibitor; PAR, protease activated receptor;; TIMP, tissue inhibitor of matrix metalloproteinases; TLE, temporal
plasminogen activator; uPAR, urokinase type plasminogen activator
[email protected] (G.M. Wilczynski), [email protected]
192 K. Lukasiuk et al.
Thrombin and protease nexin-1 .......................................................................................... 196Trypsin and trypsin-like serine proteases ................................................................................. 196
Trypsin .............................................................................................................. 196Neuropsin ........................................................................................................... 196
Metzincins ............................................................................................................... 197TIMPs and MMPs ..................................................................................................... 197ADAMs............................................................................................................... 198
Complement ............................................................................................................. 199Reelin.................................................................................................................... 200Concluding remarks ...................................................................................................... 200Acknowledgement........................................................................................................ 201References .............................................................................................................. 201
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ntroduction: epilepsy and its experimentalodels
ccording to the World Health Organization, epilepsy is ahronic disorder characterized by recurrent seizures, whichay vary from a brief lapse of attention or muscle jerks,
o severe and prolonged convulsions. Approximately 0.8%50 million) of the world population suffers from epilepsyhttp://www.who.int/mediacentre/factsheets/fs165/en/).urrently over 40 different epilepsies and syndromes ofifferent etiology have been described (Berg et al., 2010).pilepsies are divided based on underlying etiology to:i) genetic, that are caused by genetic factors; (ii) struc-ural/metabolic, which have distinct structural or metaboliconditions, including acquired epilepsies caused by stroker brain trauma; and, (iii) of unknown cause, in which theature of underlying cause is as yet unknown (Berg et al.,010). Acquired epilepsies constitute about 30% of all casesf epilepsy and are most commonly caused by stroke, brainrauma, alcohol, neurodegenerative diseases, or infectionBanerjee and Hauser, 2008). In acquired epilepsies, brainamaging insult leads to epileptogenesis (latency periodithout seizure) lasting up to several years that culmi-ates in appearance of spontaneous seizures and epilepsyiagnosis. During epileptogenesis a number of molecularnd cellular alterations occur, including also changes inhe extracellular matrix (ECM) (Pitkanen and Lukasiuk,009, 2011; Dityatev, 2010b). Due to their localizationnd activity, extracellular proteases are in a position totrongly influence function of neurons and might constitutettractive targets for antiepileptogenic or antiepilepticherapy (Dityatev, 2010b). In this review we summarize theurrent knowledge on expression and proteolytic activity ofxtracellular proteases in epilepsy.
To understand the fundamental mechanisms of seizurenitiation and propagation, cellular and molecular eventsccompanying epileptogenic insult, epileptogenesis andpilepsy or to test treatment strategies, animal models arextensively used. Variety of experimental models, mostlyn rodents, have been designed, and different models aremployed to answer specific questions. Since we hope thathis review will attract not only epileptologists, but also
esearchers not familiar with the field, selected experi-ental models that are relevant to this review are brieflyentioned below. We believe that this will help to appre-iate complexity of studied phenomena and gaps in our
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urrent knowledge and understanding of the role of ECMemodelling in epilepsy.
Brief, acute seizures of different electrophysiological andehavioral characteristics can be induced by electrical stim-lation or treatment with chemical convulsants. Seizuresan be generated by electrconvulsive shock (ECS), appliedia e.g., corneal electrodes (Browning and Nelson, 1985;oscher and Schmidt, 1988). Seizures can be induced alsoy focal stimulation of selected brain structures such as theeocortex, hippocampus or amygdala (Mares and Kubova,006). Chemoconvulsants most frequently used for inductionf brief seizures are GABA-antagonistic substances such asentylenetetrazol (PTZ), bicuculline or picrotoxin (Velisek,006). It should be noted that models of acute seizures doot represent epilepsy or epileptogenesis.
Both, electrical stimulation and chemoconvulsants cane used for induction of status epilepticus (SE), that iseizures lasting longer than 30 min. SE results in severe dam-ge to selected brain areas and induces extensive structuralnd molecular changes that eventually lead to appearancef unprovoked seizures following latency period of days oreeks. Therefore, depending on the time point from SE
nduction and the context, SE models are used to modelonsequences of brain insult, epileptogenesis or epilepsy.ost commonly used way to induce SE electrically is pro-
onged stimulation of the hippocampus, perforant path orhe amygdala (Nissinen et al., 2000). Popular convulsantseliably evoking SE are: kainic acid (KA) that can be appliedither systemically or focally to the ventricles, hippocam-us or amygdala, and cholinergic agent pilocarpine with orithout lithium pre-treatment (Ben-Ari et al., 1979; Turskit al., 1989).
A useful model of epileptogenesis and seizure inducedlasticity as well as susceptibility to seizures is kindling.indling is defined as progressive increase in susceptibilityo evoked seizures. It is produced by repeated applicationsf initially subconvulsive electrical stimulation (to the hip-ocampus or amygdala) or subthreshold dose of convulsantuch as PTZ, which following several kindling sessions startso evoke convulsive seizures (Morimoto et al., 2004). Evenully kindled animals usually do not express spontaneouseizures.
One of major causes of acquired epilepsy is traumaticrain injury (TBI), but animal models of TBI have noteen extensively used in epilepsy research. Recent stud-es confirmed that at least two models of TBI, controlled
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Extracellular proteases in epilepsy
cortical impact (CCI) and fluid percussion injury in rodents,can be successfully used to model posttraumatic epilepsy,since experimental animals develop spontaneous seizuresor hyperexcitability following insult (Pitkanen et al., 2009,2011).
In this review we summarize the data obtained fromabove experimental models as well as from human epilepsyon the role of extracellular proteases in seizures andepilepsy. It should be stressed, that experimental mod-els differ in terms of etiology, expression of spontaneousseizures or presence and extent of neurodegeneration.Neurodegeneration, although its relevance for epilepsydevelopment is not clear, may influence activity of extra-cellular protelysis. Here we concentrate only on proteolyticsystems which are known to express their proteolytic activ-ity outside the cell and have been implied in epilepsy, that is:plasminogen activator/plasminogen system, thrombin andnexin-1, trypsin and trypsin-like serine proteases, metz-incins, complement system and reelin (Fig. 1). For clarityof presentation we describe all systems separately, start-ing from description of the components of each system,followed by presentation of data relevant for seizures andepilepsy. Interplay between the systems is indicated whenrelevant for seizures or epilepsy.
Plasminogen activator/plasminogen system
The plasminogen activator/plasminogen system was initiallydiscovered as a proteolytic cascade involved in dissolvingblood clots in circulation (Collen, 1999; Fay et al., 2007).Later on, its role in the normal brain and in brain pathol-ogy has been discovered (Gingrich and Traynelis, 2000;Yepes and Lawrence, 2004b; Melchor and Strickland, 2005;Yepes et al., 2009). The action of proteolytic cascade startswith cleavage of plasminogen to its active form plasminby one of plasminogen activators: tissue type plasmino-gen activator (tPA) or urokinase type plasminogen activator(uPa) (Collen, 1999). Plasmin, being a broad spectrumserine protease, has several substrates in the brain, includ-ing ECM proteins (Benarroch, 2007). By this, plasminogenactivator/plasminogen system is in a position to exten-sively modulate ECM. Additionally, plasminogen activatorshave been shown to have plasminogen-independent effects(Nicole et al., 2001; Melchor and Strickland, 2005). Activityof all three proteases is tightly regulated by serine proteaseinhibitors, serpins. Neuroserpin and plasminogen activatorinhibitors PAI-1 and PAI-2 inhibit with different affinities tPAand uPA, while alpha2-antiplasmin inhibits plasmin (Yepesand Lawrence, 2004a). Another regulator of plasminogenactivator/plasminogen system is urokinase-type plasmino-gen activator receptor (u-PAR), that localizes uPA and itszymogen pro-uPA to the cell membrane. This leads to localamplification of plasminogen cascade due to positive loopbetween uPA producing active plasmin which in turn cleavespro-uPA (Smith and Marshall, 2010). Upon binding uPA, uPARcan activate several signaling pathways within the cell, butthis action of uPAR is not dependent on uPA proteolytic activ-
ity (Smith and Marshall, 2010). Cleavage of plasminogen toplasmin by tPA can be substantially augmented by form-ing complex consisting of tPA, plasminogen and annexin 2(Hajjar et al., 1994; Flood and Hajjar, 2011). tPA activity ispipc
193
dditionally regulated by its scavenging receptor LRP-1 (But al., 1994).
Plasminogen activator/plasminogen system is deregu-ated in experimental models of seizures and epilepsy asell as in human disease, as described below. Different ele-ents of this system have been linked to susceptibility to
eurodegeneration, seizure threshold, or axonal plasticity.owever the mechanisms of its involvement in epilepto-enesis and epilepsy in terms of cellular compartment orownstream molecules and pathways that are affected areot deciphered.
lasminogen
lasminogen mRNA is expressed in most of the hippocam-al neurons, while protein is expressed at appreciable levelsnly in fraction of them (Tsirka et al., 1997). Intrahippocam-al injection of KA induces increase in plasminogen proteinxpression in the hippocampus (Tsirka et al., 1997).
PA
irst data linking tPA to epilepsy were provided by workf Qian et al. (1993) who have shown increased tPA mRNAxpression in the rat cortex and hippocampus at 0.5—4 hollowing PTZ induced seizures. Qian et al. (1993) havelso observed induction of tPA mRNA expression in theippocampus 1 h following the afterdischarge evoked byingle perforant path stimulation. Increase in tPA mRNAnd protein expression in the hippocampus has been alsobserved following intrahippocampal KA injection (Sallesnd Strickland, 2002). Gorter et al. (2007) have describednduction of tPA mRNA expression acutely at 1 day, anduring the latent phase at 1 week after angular bundle stim-lation induced SE in rats. Increased mRNA expression inhe CA3 persisted also in chronically epileptic animals 3—4onths after SE. In human epilepsy, increase in tPA mRNAas observed in patients with gangliogliomas, but not in
amples from temporal lobe epilepsy with hippocampal scle-osis or focal cortical dysplasia (Iyer et al., 2010).
In experimental models, in addition to increase inPA mRNA expression, also an increase in tPA enzymaticctivity has been observed. An increase in proteolytic activ-ty specific to tPA was detected at 10—60 min followingntraamygdala KA injection (Yepes et al., 2002). An increasef tPA catalytic activity was also observed in the CA3 area ofhe hippocampus 7 h after SE induced by intraventricular KAnjection in mice (Endo et al., 1999). In contrast, tPA enzy-atic activity was transiently decreased in the hippocampus
nd cortex at 1 day following the amygdala stimulationnduced SE, as well as after intrahippocampal injection of KASalles and Strickland, 2002; Lahtinen et al., 2006). Theseata indicate dynamic temporal regulation of tPA activity.
Little data are available concerning tPA expression in theuman epilepsy. Iyer et al. (2010) studied expression and dis-ribution of tPA protein in the human tissue, derived fromatients suffering from temporal lobe with the hippocam-
al sclerosis and in the focal cortical dysplasia. Significantncrease in tPA protein level has been observed in all studiedathologies. Immunohistochemical analysis revealed that inontrol tissue tPA immunoreactivity was present mostly in
194 K. Lukasiuk et al.
Figure 1 Simplified representation of the interaction network of extracellular proteases in the brain. Red — serine proteases;purple — MMPs; green — enzyme inhibitors; black — extracellular matrix constituents; blue — receptors; light pink — NMDA receptorchannel; red arrows with a scissors — proteolytic cleavage; green arrows with a dash — enzyme inhibition; black arrows — director indirect interaction other than cleavage or enzyme inhibition; gray arrows — putative or controversial interactions; red dashedarrows — transition from the inactive to active state; ADAM — a disintegrin and metalloproteinase; FX — factor X; LGI1 — leucine-rich, glioma inactivated 1; LRP1 — low density lipoprotein receptor-related protein 1; MMP — matrix metalloproteinase; N-CADN —N-cadherin; NMDA-R — N-methyl-D-aspartate receptor; PAI — plasminogen activator inhibitor; PAR — protease activated receptor;t lasmr
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PA — tissue type plasminogen activator; uPA — urokinase type peceptor; VLDLR — very low density lipoprotein receptor.
eurons. In specimens form patients, an increase in tPAxpression was detected in hippocampal CA1—CA3 neuronsnd granule cells in the dentate gyrus. Additionally, strongmmunoreactivity was present in reactive astrocytes andicroglia, and the majority of blood vessels (Iyer et al.,
010).The increased expression of tPA can have pronounced
onsequences for susceptibility to seizure activity. Involve-ent of tPA in seizure induction has been shown for therst time by Tsirka et al. (1995) who studied effect ofPA deficiency in knock-out mice on seizures induced byntraperitoneal injection of either KA or PTZ. tPA deficientice required higher doses of KA or PTZ than control mice
o enter seizures. In case of KA injections, tPA knock-outice did not develop SE even with the highest dose tested
Tsirka et al., 1995). Similar effect has been shown by Yepes
t al. (2002) who found decrease in rate of seizure pro-ression and lack of seizure generalization in tPA−/− miceollowing intra-amygdala KA injection. Additionally, Yepest al. (2002) have shown that application of tPA inhibitor,tarN
inogen activator; uPAR — urokinase type plasminogen activator
euroserpin, attenuates generalization of seizures in modelf SE induced by intra-amygdala injection of KA in micend rats. This tPA action was not dependent on plasmino-en activation, since spreading of seizures in plasminogeneficient mice did not differ from wild-type control (Yepest al., 2002).
The role of tPA has been also described in ethanol-ithdrawal seizures (Pawlak et al., 2005). tPA deficientice had less severe handling-induced seizures following
thanol-withdrawal than wild type mice. This effect wasiminished by intraventricular tPA injection indicating thatPA promotes ethanol-withdrawal seizures, and was notependent on plasminogen. tPA interacted with NR2B sub-nit of NMDA receptor modulating NMDA receptor functiony non-proteolytic mechanism (Pawlak et al., 2005).
Mechanisms of facilitation of seizure activity by tPA in
he plasminogen-independent way are not fully explained. Inddition to the mechanism involving NR2B subunit of NMDAeceptor described above, the cleavage of NR1 subunit ofMDA receptor by tPA in cortical neurons in vitro has been
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Extracellular proteases in epilepsy
shown (Nicole et al., 2001). However this mechanism is con-troversial (Matys and Strickland, 2003). Proteolysis of NR1by tPA has not been detected in the brain lysates or brainendothelial cells (Matys and Strickland, 2003; Liu et al.,2004; Pawlak, 2005). Moreover, there are evidence thatNR1 cleavage is mediated rather by plasmin, not tPA (Matysand Strickland, 2003; Pawlak et al., 2005; Samson et al.,2008). It has been also shown that tPA can indirectly regu-late NMDA receptor function engaging other proteins suchas low-density lipoprotein receptor family (Samson et al.,2008). The relevance of these mechanisms or yet uncharac-terized mechanisms of tPA influence on NMDA receptors forepilepsy are not clear.
tPA participates in execution of KA induced neurode-generation; Tsirka et al. (1995) have shown that tPAdeficiency protected against neurodegeneration induced byintracerebral injection of KA in tPA knockout mice. Suchneurodegeneration is plasminogen-dependent and involvesproteolysis of laminin (Chen and Strickland, 1997; Tsirkaet al., 1997). tPA deficiency has been shown to be neuro-protective also in TBI. tPA knock-out mice had significantlydecreased lesion volume following CCI when compared towild-type animals (Mori et al., 2001).
The role of tPA has also been implicated in mossy fibersprouting, a pathological form of axonal plasticity of gran-ule cell neurons in the dentate gyrus, that is a hallmark ofTLE. Wu et al. (2000) have observed the decreased mossyfiber outgrowth following SE induced by intra-amygdala KAinjection in tPA−/− mice. This effect was independent onplasminogen and was not observed in plasminogen-deficientmice.
uPA
uPA has been studied to lesser extent than tPA, however,recently interesting findings relevant to epilepsy have beendemonstrated. uPA mRNA has been detected in transcrip-tomic studies as one of the most upregulated genes in animalmodels of TLE, including angular bundle stimulation andamygdala stimulation models in rats (Lukasiuk et al., 2003;Lahtinen et al., 2006; Gorter et al., 2007). Increased mRNAexpression was long lasting and persisted from 1 day up to 2weeks (Lukasiuk et al., 2003). Lahtinen et al. (2006) studieduPA expression and activity in more details using amygdalastimulation model of the temporal lobe. Increased mRNAexpression was accompanied by increase in uPA enzymaticactivity in the hippocampus and extrahippocampal tempo-ral lobe that also persisted between 1 day and 2 weeks afterthe amygdala stimulation (Lahtinen et al., 2006). IncreaseduPA enzymatic activity in the hippocampus has also beenreported following KA-induced SE (Masos and Miskin, 1997).When localization of the uPA protein expression was ana-lysed by immunohistochemistry, expression in normal brainwas observed only in a small population of astrocytes andneurons, and in the blood vessels. Following the amygdalastimulation-induced SE, the number of uPA-immunopositivecells increased remarkably. Increased uPA protein expres-
sion was found in astrocytes, neurons and neuropil, as wellas blood vessels, especially at 1—4 days after SE that is dur-ing epileptogenesis, before the occurrence of spontaneousseizures (Lahtinen et al., 2006).ufrp
195
Expression of uPA mRNA and protein has also been studiedn the human epilepsy (Iyer et al., 2010). Increased mRNAnd protein expression was detected in cases of temporalobe epilepsy with hippocampal sclerosis and focal corticalysplasia. uPA immunoreactivity was low in control brain,ut an increase in uPA mmunoreactivity was observed in neu-ons, astrocytes, microglia and vessels in the diseased brainsIyer et al., 2010).
uPA−/− mice experience more severe loss of hippocam-al pyramidal and hilar neurons following intrahippocampalA injection than wild-type animals, indicating that uPAight be neuroprotective (Lahtinen et al., 2010). Similar
ffect was observed following CCI in mice. uPA−/− micead significantly larger lesion volume than wild-type ani-als (Morales et al., 2006). No effect of uPA deficiency on
ascular density following SE was observed (Lahtinen et al.,010).
lasminogen activator inhibitors
euroserpin is a member of serine proteinase inhibitoruperfamily, expressed primarily in the brain and acting as
plasminogen activator inhibitor, preferentially inhibitingPA (Miranda and Lomas, 2006; Yepes et al., 2009). It haseen proposed, that neuroserpin protein is synthesized inynapses and is released following depolarization (Sappinot al., 1993; Berger et al., 1999). Neuroserpin immunoreac-ivity increases in the hippocampus at 30—60 min followingntra-amygdala KA injection (Yepes et al., 2002). Applica-ion of neuroserpin has been shown to diminish progressionf seizures during SE induced by KA injection to the amyg-ala, suggesting its anti-epileptic function. This action ofeuroserpin was tPA-dependent, since in tPA−/− mice neu-oserpin did not influence seizures (Yepes et al., 2002).utation in neuroserpin has been associated with neurolog-
cal disorders characterized by presence of seizures (Takaot al., 2000; Filla et al., 2002; Hagen et al., 2011).
Expression of plasminogen activator inhibitor 1 (PAI-1)as been studied following SE induced by systemic admin-stration of KA (Masos and Miskin, 1997). While in controlrain PAI-1 mRNA was present in the hypothalamus and bloodessels, its expression was elevated by SE in the limbic struc-ures and cortex for up to 3 days. Expression pattern of PAI-1RNA only partially overlapped with uPA mRNA, suggesting
hat these components of plasminogen activator system canct together, as well as independently of each other (Masosnd Miskin, 1997). Increased expression of PAI-1 mRNA haslso been observed in human TLE with hippocampal sclero-is and focal cortical dysplasia (Iyer et al., 2010). Expressionf PAI-1 protein is induced following intra-hippocampal KAnjection and it has been suggested that this increase isesponsible for decrease in tPA enzymatic activity at 24 hfter the insult, despite high tPA protein level in this modelSalles and Strickland, 2002).
PAR
PAR mRNA expression is strongly upregulated at 1—2 daysollowing SE induced by amygdala stimulation and thaneturns to the control level (Lahtinen et al., 2009). Therotein level is increased during epileptogenesis induced
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p to 2 weeks after the amygdala stimulation (Lahtinent al., 2009). In normal brain uPAR immunoreactivity isow and constrained to astrocytes and parvalbumin-positiventerneurons. During epileptogenesis increased expressionas observed in astrocytes, neurons and blood vessels butot in microglia (Lahtinen et al., 2009).
Increased expression of uPAR mRNA and protein has beenetected in the human TLE with hippocampal sclerosis andocal cortical dysplasia (Iyer et al.). Increase in uPAR pro-ein expression has been observed also in patients withrontal lobe epilepsy (Liu et al.). Immunohistochemical anal-sis revealed that while in the control brain uPAR expressionas low, strong uPAR staining was present in neurons andery few astrocytes (Liu et al., 2010).
The putative role of uPAR for epilepsy development isighlighted by the fact that uPAR−/− mice express sponta-eous seizures and are more prone to PTZ induced seizures,ossibly due to the developmental loss of parvalbuminnterneurons (Powell et al., 2003). What is the function ofPAR receptor in epileptogenesis and epilepsy and whethert acts via amplification of uPA enzymatic activity or ratheria activation of intracellular signaling pathways, remainso be studied.
hrombin and protease nexin-1
hrombin is the central effector protease of the coagula-ion system, mediating cleavage of fibrinogen to fibrin, androviding both positive and negative regulation of clot for-ation by acting on other coagulation proteases (Coughlin,
005). In addition, thrombin cleaves and activates a fam-ly of transmembrane G protein-coupled protease-activatedeceptors (PAR-1, -3, -4), thereby influencing the behavior of
variety of cell types in a hormone-like manner (Coughlin,005). The inactive form of thrombin (prothrombin), syn-hesized mainly in the liver, is present at high concentrationn plasma, and gets activated therein by Factor Xa, as aesult of the release of the tissue factor upon endothelialamage (Coughlin, 2005). Interestingly, prothrombin is alsoxpressed at low levels by neurons and astrocytes in sev-ral brain regions, including the hippocampus, in both ratnd human brain (Dihanich et al., 1991; Arai et al., 2006).actor X and PARs are also present in the brain, suggest-ng a physiological role for thrombin therein (Niclou et al.,998; Shikamoto and Morita, 1999; Striggow et al., 2001).ccordingly, nanomolar concentrations of thrombin (likely toccur in normal brain) were shown both to potentiate NMDAeceptor currents, and to induce long-term enhancementf neuronal responses (saturating LTP) in the hippocampallices (Gingrich et al., 2000; Maggio et al., 2008). Theseffects were shown to be PAR-1-dependent. In addition, aroad range of actions of thrombin has been demonstratedn glial cells (reviewed by Sokolova and Reiser, 2008).
The concept of thrombin involvement in seizures andpilepsy stems from early clinical observations that bleedingnto the brain parenchyma was associated with seizures. Forxample, in spontaneous intracerebral hemorrhage there
s up to 50% of cumulative risk of seizure occurrence in aong-term follow-up (Faught et al., 1989; Cervoni et al.,994). Also in TBI, the occurrence of blood within therain tissue was identified as a leading risk factor for sub-scmi
K. Lukasiuk et al.
equent development of epilepsy (Kaplan, 1961; Annegerst al., 1980). Likewise, hemorrhagic stroke imposes sig-ificantly higher risk of seizure occurrence than ischemictroke of the similar magnitude (Lancman et al., 1993).he causative role of thrombin in seizure generation bylood entering the brain has been experimentally demon-trated by intracerebral infusion of thrombin in rats (Leet al., 1997). Importantly, Maggio et al. (2008) provided theolecular-electrophysiological explanation for the afore-entioned observations, by demonstrating that thrombinecreased the threshold for induction of epileptiform activ-ty in slices, in a PAR-1-dependent manner.
Protease nexin-1 (PN-1) is a serpin-type thrombinnhibitor, expressed in the brain by both neurons and astro-ytes (reviewed by Gingrich and Traynelis, 2000). In additiono thrombin, PN-1 is able to inhibit plasmin, tPA, uPA andrypsin, therefore it is believed to represent a key fac-or regulating proteolytic activity in the brain tissue (Luthit al., 1997 and references therein). Interestingly, both PN-1nockout and its neuronal-specific overexpression aggra-ates KA-induced seizures in mice (Luthi et al., 1997). Ateast in part, these effects could be explained by PN-1 actiont the level of synaptic NMDA receptors (Luthi et al., 1997;vajo et al., 2004).
rypsin and trypsin-like serine proteases
everal trypsin-like proteases have been detected in brain,ncluding trypsin (trypsin IV), p22, neurosin, neurotrypsinnd neuropsin (reviewed by Wang et al., 2008b). Thenzymes are able to degrade some of the ECM compo-ents, and to activate PARs, especially PAR-2 (trypsin, p22,eurosin) (Wang et al., 2008b). During the last decade,aramount evidence has been collected, indicating impor-ant roles of trypsin-like proteases in neural development,egeneration, synaptic plasticity and neurodegenerative dis-rders (Wang et al., 2008b). In regard to seizures/epilepsy,he majority of evidence points to trypsin and neuropsinnvolvement.
rypsin
rain trypsin is expressed by both neurons and glial cells.arly electrophysiological study demonstrated that trypsins able to induce epileptiform activity in the hippocampallices in an NMDA receptor-dependent manner (Yamada andilkey, 1993). Many years later, Lohman et al. (2008) showedhat electrical amygdala kindling upregulates trypsin-likemmunoreactivity in the rat hippocampus. Interestingly, thisffect was dependent on PAR-2, since the receptor selectiventagonist blocked both trypsin overexpression, as well aseizures and epileptogenesis (Lohman et al., 2008).
europsin
europsin, known also as kallikrein 8, a member of kallikrein
erine protease family is expressed in the brain, where itan cleave components of ECM, fibronectin and adhesionolecules (Yousef et al., 2003; Wang et al., 2008b). Interest-ngly, neuropsin can also enhance NMDA receptor currents by
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Extracellular proteases in epilepsy
cleavage of EphB2 that results in modulation of its interac-tion with NR1 subunit (Attwood et al., 2011). In the normalbrain, neuropsin in expressed in the limbic structures andis particularly high in the hippocampal CA1—CA3 subfields(Chen et al., 1995; Davies et al., 1998). Increased neu-ropisn mRNA level following KA application was observedat 1—10 days after SE in oligodendrocytes (Tomizawa et al.,1999; He et al., 2001). Neuropsin mRNA was also elevatedin the CA1—CA3 hippocampal areas, amygdala and cortex(including somatosensory, perirhinal, entorhinal and piri-form cortices) 6 h following seizures in the amygdala kindlingmodel (Chen et al., 1995; Okabe et al., 1996). The neu-ropsin protein content increases following kindling seizures,especially in the hippocampus, and occipital, temporal andfrontal cortices (Momota et al., 1998). Interestingly, Momotaet al. (1998) have shown that ablation of neuropsin by asingle intraventricular injection of anti-neuropsin antibod-ies to partially kindled mice shortened significantly durationof afterdischarges and this effect persisted for 2 days afterthe injection, although no effect was observed when anti-bodies were injected to fully kindled mice. These datawould indicate that neuropsin participates in seizure gener-ation or epileptogensis, possibly by degrading yet undefinedsubstrate. However Davies et al. (2001) have shown thatneuropsin knock-out mice display hyperexcitability in thehippocampus following afferent stimulation. Additionallyneuropsin knockout mice developed more severe SE fol-lowing systemic KA application (Davies et al., 2001). Itcould be hypothesized that the precise balance of neuropsinthat mediates proteolysis is crucial for maintaining properexcitability.
Metzincins
The metzincin metalloproteinases are characterized by theconserved methionine residue at the active site and the useof a zinc ion in the enzymatic reaction (Rivera et al., 2010).This group of enzymes includes matrix metalloproteinases(MMPs), a disintegrin and metalloproteinases (ADAMs), andADAM proteases with thrombospondin motifs (ADAMTSs).These enzymes should be considered jointly with theirendogenous inhibitors, TIMPs (tissue inhibitors of matrixmetalloptoteinases).
MMPs are either secreted or membrane-bound, extra-cellularly operating, proteases. Their activation is a verycomplex and poorly elucidated process in neurons. Theenzymes are apparently released in a latent form, with apropeptide covering the enzymatic active site. Hence, theremoval of the propeptide that occurs outside the cells,is an important step in revealing the enzymatic activity. Anumber of proteases seem to be involved in cleaving offthe propeptide, including MMPs themselves and, in par-ticular components of the plasminogen-plasmin system. Itshould be emphasized that the MMPs are active very locally,at the sites of release, as well as very transiently, beingrapidly inhibited by, probably co-released, TIMPs. Little isknown about the brain, especially physiological targets of
the MMPs, especially as they are rather promiscuous in vitro,whereas in vivo the hic and nunc rule has to be obeyed. Anexample of identification of an MMP-9 target is provided byMichaluk et al. (2007) study, showing that beta-dystroglycaniatt
197
s cleaved by this enzyme in response to stimuli enhancingeuronal activity, including seizures in vivo.
ADAMs are mostly transmembrane proteins whose pro-omain is generally removed intracellularly. Their activityeleases extracellularly active peptides (e.g., TNF-alpha)nd/or intracellular protein domains that translocate tohe nucleus to regulate gene expression (e.g., Notch).otably, many ADAMs miss the proteolytic activity, sug-esting that other domains contribute to ADAM biologicalunctions. ADAMTS proteins are also activated intracellu-arly and secreted in active form. However, unlike ADAMs,DAMTSs lack a transmembrane domain. Instead, ADAMTSsossess a conserved thrombospondin type 1-like repeat thats believed to function as a binding domain for sulfated gly-osaminoglycans present on proteoglycans (see Rivera et al.,010, for review).
IMPs and MMPs
otential involvement of Metzincins and TIMPs in the epilep-ogenesis has been suggested first by their gene responseso the seizure-evoking stimuli. Nedivi et al. (1993) reportedhat KA treatment evokes TIMP-1 mRNA accumulation in theat dentate gyrus. This finding was then reproduced andxtended to both neurons and glia by Rivera et al. (1997) andaworski et al. (1999), who also demonstrated that TIMP-1ene expression in response to KA as well as PTZ seizuresas controlled by AP-1 transcription factor. Up-regulationf TIMP-1 expression in the context of epileptogenesis haslso been observed by Becker et al. (2003), Lukasiuk et al.2003) and Gorter et al. (2007). Next, Jourquin et al. (2005)eported on a lack of differences in seizure behavior fol-owing KA application, between the wild-type (WT) andhe TIMP-1 knock-out (KO) mice. However, the TIMP-1 KOice were resistant to KA-induced excitotoxicity and did
ot undergo the typical mossy fiber sprouting observed inT mice. Benekareddy et al. (2008) observed that ECS
pregulates the TIMP-1, -2 and -4 transcripts in the hip-ocampus. Increased TIMP-1 following single ECS was notedy Girgenti et al. (2011) who carefully followed electro-onvulsive seizure driven TIMP-1 accumulation also in theasculature.
The results on elevated TIMP-1 gene expression followingeizure prompted Szklarczyk et al. (2002) to investigate ando demonstrate that also MMP-9 expression — at the levelsf mRNA, protein and enzymatic activity — was markedlypregulated by KA. Of particular interest was finding thathose responses were especially strongly pronounced in theentate gyrus, i.e., the hippocampal region undergoing theost extensive post-KA plasticity. This in turn encouragedilczynski et al. (2008) to directly interrogate the role ofMP-9 in two animal models of epileptogenesis, namely,A-evoked epilepsy and PTZ kindling. They showed that theensitivity to PTZ kindling was decreased in MMP-9 knockoutice but was increased in transgenic rats overexpress-
ng MMP-9 solely in the neurons. Furthermore, Wilczynskit al. (2008) demonstrated that MMP-9 deficiency dimin-
shed KA-evoked pruning of dendritic spines and decreasedberrant synaptogenesis after mossy fiber sprouting. Finally,hey also reported that MMP-9 was associated with exci-atory synapses, where both the MMP-9 protein levels and
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nzymatic activity become strongly increased upon seizures. role of MMP-9 in the development of epilepsy has been alsoupported by studies with such animal models of epilepsys treatment with either pilocarpine or 4-aminopyridine asell as Wistar Glaxo Rijswijk (WAG/Rij) rats (Kim et al.,009; Takacs et al., 2010). Kim et al. (2009) reportedhat inhibition of MMP-9 activity had no acute effect onilocarpine-evoked SE, however, it attenuated caspase-3ctivation and, moreover, the number of surviving cells inMP-9 inhibitor treated mice was at almost the same levels in the controls in both CA1 and CA3 after the pilocarpinereatment. Notably, integrin beta 1 was found to be involvedn the effects of MMP-9. The role of integrins, and beta1n particular, in mediating MMP-9 activity in neurons haseen supported by number of studies (see, e.g., Nagy et al.,006; Wang et al., 2008a; Michaluk et al., 2009). MMP-9as also found to be increased in traumatized brain afterontrolled cortical impact in mice, and MMP-9 KO displayedignificantly smaller than WT traumatic brain lesion volumesWang et al., 2000).
Several other reports showed increased neuronal MMP- levels, including dendritic/synaptic accumulation of itsRNA, following seizures (Kaczmarek et al., 2002; Jourquin
t al., 2003; Konopacki et al., 2007; Michaluk et al., 2007;enekareddy et al., 2008; Gawlak et al., 2009; Rylski et al.,008, 2009; Zhang et al., 1998, 2000). It can be concludedhat seizure activity drives rapid, within minutes, activationf neuronal MMP-9, including proteolysis of its substrate,eta-dystroglycan (Michaluk et al., 2007), followed by thencreased MMP-9 gene expression and mRNA accumulationn neurons within a few hours after the insult. This responseay signify a replenishment process aiming at recuperation
f an ability to supply MMP-9 when needed again. However,hose increases result in a markedly elevated protein andnzymatic activity, possibly exceeding physiological require-ents. It might be hypothesized that those sustained MMP-9
ncreases contribute to the aberrant plasticity underlyingpileptogenesis. Pivotal role of MMP-9 in the synaptic plas-icity has been well documented (see Rivera et al., 2010).he increase in MMP-9 expression and activity in neuronsre soon joined by enhanced MMP-9 expression levels inther cells, such as astroglia, microglia and components ofhe vasculature. Again, it remains as an attractive optionhat also these non-neuronal enhancements of MMP-9 mightontribute to the epileptogenesis.
Elevated expression of hippocampal MMP-3 mRNA androtein after traumatic brain injury as well as SE was alsoeported (Kim et al., 2005; Falo et al., 2006; Gorter et al.,007). Gorter et al. (Gorter et al., 2007) also demonstratednhancement in the expression of MMP-2 and -14 induced byE evoked by electrical stimulation of the hippocampus.
The prominent role of MMP-9 in epileptogenesis led Yint al. (2011) to propose that MMP-9 might comprise aherapeutic target for epilepsy and its inhibitors might beotential antiepileptogenic drugs. However, pharmacologi-al data proving antiepileptogenic action of MMP-9 inhibitionre still lacking. It is also very little is known about possibleole of MMP-9 in human epilepsy. It has been demonstrated
hat prolonged seizures are related to high serum MMP-9 lev-ls (and increased MMP-9/TIMP-1 ratio) in humans (Suenagat al., 2008). On the other hand, Heuser et al. (2010) haveecently reported lack of statistically significant associationseeeA
K. Lukasiuk et al.
etween the MMP-9 gene and TLE, as far as unbiased analysisf single nucleotide polymorphisms was concerned. How-ver, the authors have not considered the well-establishedunctional MMP-9 gene promoter polymorphisms that wereound before to associate with human neuropsychiatric dis-rders (Rybakowski et al., 2009a,b; Samochowiec et al.,010).
DAMs
DAM22 and ADAM23 are neuronal membrane proteins thathare homology to other transmembrane ADAM metallo-roteases, but are catalytically inactive. ADAM22-deficientice show cerebellar ataxia and die around 2—3 weeks
fter birth, because of multiple seizures (Sagane et al.,005). Fukata et al. (2006) demonstrated that this proteinnteracted with LGI1 (that has also been genetically linkedo human and animal epilepsy, see: Fukata et al., 2010)nd both ADAM22 and LGI1 were involved in controllingynaptic strength at excitatory synapses. Similarly. ADAM23O mice exhibit spontaneous seizures, while ADAM23 het-rozygotes mice have decreased seizure thresholds. ADAM23lso binds LGI1 (Owuor et al., 2009; Fukata et al., 2010).ukata et al. (2010) have recently demonstrated that LGI1O causes specific lethal epilepsy and that heterozygousice for LGI1 mutation show increased susceptibility to PTZ
nduced seizures. Furthermore, ADAM22 and ADAM23 wereound to be the major LGI1 receptors in the brain. Extra-ellulary secreted LGI1 might link these two receptors andrganize a transsynaptic protein complex, including bothre- and postsynaptic proteins. Importantly, loss of LGI1electively reduced AMPAR-mediated synaptic transmission.n conclusion, Fukata et al. (2010) proposed that LGI1 is
unique antiepileptogenic secreted protein that connectsre- and postsynaptic protein complexes via its ability tonteract with the aforementioned ADAM proteins. Notably,he attempts to identify ADAM22 mutations linked to theuman epilepsy have so far failed (Chabrol et al., 2007; Dianit al., 2008).
Other ADAMs implicated in the epilepsy are ADAM9 andDAM10, whose expression was reported to be induced inentate gyrus of hippocampus following KA induced sta-us epilepticus (in contrast, ADAM15 expression remainednchanged) (Ortiz et al., 2005). It has been found thatDAM10 cleaves several important cell adhesion moleculest the synapses, such as N-cadherin and nectin-1 (Uemurat al., 2006; Kim et al., 2010; Malinverno et al., 2010),nd thus it is well positioned to play a key role in theendritic spine maturation, as well as structure and func-ion of glutamatergic synapses. Functional role of ADAM10n epileptogenesis has been supported by the findings thatDAM10 dominant negative mice were seizing for a shorterime and showed less neuronal cell death as well as neu-oinflammation than wild-type mice after KA treatment. Inontrast, mice with a high ADAM10 overexpression showedore seizures and stronger neuronal damage as well as
nflammation than either wild-type mice or mice with mod-
rate ADAM10 overexpression (Clement et al., 2008). Gortert al. (2007) also demonstrated SE-evoked increases in thexpression of ADAMTS1. Finally, it should be noted thatDAMTS4 was found as a partner of Sushi-Repeat Protein,
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Extracellular proteases in epilepsy
X-linked 2 (SRPX2), whose mutations cause rolandic epilepsywith speech impairment (RESDX syndrome) (Royer-Zemmouret al., 2008).
Complement
Complement system is a set of more than 30 soluble pro-teins present in the blood plasma and tissue extracellularspace, considered to be the main humoral effector of theinnate immune response (Morley and Walport, 2000; Gasque,2004). Activation of the complement involves a cascade ofproteolytic events, occurring at the cell surface and cul-minating in the formation of pore-like membrane-attackcomplexes (MAC) causing the cell lysis. Several comple-ment factors have serine protease activities and belong tothe chymotrypsin family (i.e., C1r, C1s, C2, factor B, etc.);however, their only known substrates are other comple-ment components (Morley and Walport, 2000). The bulk ofthe complement components present in the body fluids issecreted by the liver and leukocytes, however, local comple-ment synthesis in various tissues, including brain, can alsooccur under certain circumstances (see below). Comple-ment system is activated as a result of binding of factor C1qto immune complexes or to cellular debris generated upontissue damage (so called classic pathway), or by mannose-binding lectin (so called lectin-dependent pathway) (Morleyand Walport, 2000; Gasque, 2004; Griffiths et al., 2010).In addition, there is also continuous wide-spread low-levelautoactivation of the complement at phospholipid mem-branes (so called alternative pathway), damaging to all cellsthat do not have protective mechanisms (such as bacte-ria) (Morley and Walport, 2000; Gasque, 2004). The threepathways differ in their initial steps, however they ulti-mately converge onto the common central step involvingproteolytic activation of C3 component (Botto, 2000), fol-lowed by stepwise assembly of MAC (C5b-9) (Morley andWalport, 2000; Gasque, 2004). Certain proteolytic frag-ments that are released upon complement activation havepotent pro-inflammatory activities, stimulating migration,phagocytosis and cytotoxic properties of leukocytes (e.g.,C3a, C5a). Others, such as C3b are potent opsonins (Morleyand Walport, 2000; Gasque, 2004). Mammalian cells areprotected from complement-mediated damage by severalmembrane-bound- (e.g., CD46, CD55, CD59) or soluble com-plement inhibitory proteins (e.g., factors H, I, S) (Liszewskiet al., 1996).
In the brain, complement activation occurs in vari-ous inflammatory conditions (infection, multiple sclerosis),stroke, traumatic brain injury and neurodegenerativedisorders (e.g., Alzheimer disease) (van Beek et al.,2003; Bonifati and Kishore, 2007; Ramaglia and Baas,2009; Griffiths et al., 2010). Interestingly, several recentreports showed that complement expression and activa-tion can occur in epilepsy. Using DNA microarray technique,increased expression of complement components C1, C3,C4, C8 as well as complement inhibitors FH and Crry wasinitially found in the rat electrically induced status epilep-
ticus models (Lukasiuk et al., 2003; Gorter et al., 2006;Aronica et al., 2007). In human TLE, prominent upregula-tion of C3 expression at both mRNA and protein level wasshowed in entorhinal cortex (Jamali et al., 2006), and in thetbhd
199
ippocampus (Aronica et al., 2007), as compared to con-rol autopsy cases. There is a discrepancy between thesewo studies in regard to the identity of cells expressing C3,s found by immunohistochemistry. Whereas Jamali et al.2006) reported the expression of C3 only in perivasculareukocyte infiltrates, the detailed morphological study byronica et al. (2007) demonstrated the presence of C3 ineactive astrocytes, in microglial cells and in the neurons ofhe Ammon horn. The latter group noticed also the upreg-lation of the C1q component at the same sites (Aronicat al., 2007). Both studies report the expression/depositionf the terminal lytic C5b-9 component in neurons in 40—80%f patients. Another piece of evidence for complement asso-iation with epilepsy pathogenesis comes from the study byasaran et al. (1994), who found C3 complement compo-ent concentration to be significantly higher in the serum ofntreated epileptic patients than in healthy controls. Mostnterestingly, however, Jamali et al. (2010) have recentlyeported a newly discovered dinucleotide repeat polymor-hism [CA(8) to CA (15)] in the promoter region of C3 gene,hich is significantly associated with a genetic risk of devel-ping TLE in patients having history of febrile seizures; theaplotypes containing the shortest repeat [CA(8)] appearedo be protective. Importantly the polymorphism was showno affect the promoter function, in such a way that theigher was the number of repeats the lower was the tran-criptional activity (Jamali et al., 2010). This might suggesthat high expression of C3 is protective against TLE.
Although the aforementioned findings are novel andotentially very important, too little is known, at present,o draw firm functional conclusions about the role of theomplement system in epileptogenesis. For example, it isot entirely clear how the complement components reachhe brain parenchyma. Normal human brain contains veryow, if any, amount of complement mRNAs and proteinsWalker and McGeer, 1992; Aronica et al., 2007). How-ver, upon epileptogenesis/epilepsy, certain complementroteins, namely those playing roles at the early steps ofomplement activation (e.g., C1—C4), appear to be synthe-ized in the brain tissue, as demonstrated by mRNA analysesGorter et al., 2006; Jamali et al., 2006; Aronica et al.,007). Unfortunately, the antibodies used by Jamali et al.2006) and by Aronica et al. (2007) to detect these proteinsn immunohistochemical assays do not distinguish betweenewly synthesized components, and the complexes assem-led and deposited upon complement activation. Therefore,t is not possible to judge whether a given cell type express-ng, for example, C3d immunoreactivity, is the source orhe target of the complement. Cell culture studies indicatehat under appropriate stimulation (e.g., with cytokines),icroglia, astrocytes, oligodendrocytes, and even neurons,
an produce the full range of complement proteins (Gasquet al., 1995; Thomas et al., 2000). In contrast to C1—C4,he level of mRNAs of the components of the terminalathway (C5—C9) have not been found to increase, except8 in the study by Lukasiuk et al. (2003). This might
ndicate that immunohistochemically demonstrated C5b-9eposited on neurons (the antibody detecting a neoepi-
ope formed upon complement activation) migrates to therain tissue through the disrupted blood—brain barrier, per-aps upon acute SE. This would exacerbate both neuronalamage and seizures, as shown experimentally by Xiong et
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l. (2003), who sequentially infused activated C5—C9 intohe rat brain cortex. Neurons are particularly vulnerableo complement-mediated damage because they are essen-ially devoid of complement inhibitors expression, exceptecreted FH (Gasque, 2004). Thus, the increased FH mRNA,s found by Gorter et al. (2006) may represent a neuronalefense mechanism.
An interesting question arises whether the complementould play any role in epileptogenesis other than being
mediator of neuronal damage? Indeed, complement by-roducts C3b and iC3b can serve as very efficient opsonins,timulating the phagocytosis of potentially neurotoxic cel-ular debris by macrophages/microglia (Mevorach et al.,998). Microglial activation and chemotaxis could be stimu-ated by other by-products, the soluble anaphylatoxins C3and C5a (Davoust et al., 1999). Interestingly, C3a and C5aere shown also to act directly on astrocytes, to induce
he expression of NGF (Jauneau et al., 2006). Finally, C1q,3a and C5a were found to have direct neuroprotectiveffects on cultured neurons (van Beek et al., 2001; Benardt al., 2004; Benoit and Tenner, 2011), and C3a was showno stimulate migration and differentiation of neural progen-tor cells in vitro (Shinjyo et al., 2009). The aforementionedacts raise the possibility of the beneficial complementontribution to the processes of brain healing after statuspilepticus.
Another explanation of complement involvement inpileptogenesis may come from the unexpected findingshat neuronal expression of C1q and C3 components aremportant for synapse elimination in the developing visualystem (Stevens et al., 2007). Both proteins were found tossociate with synapses, possibly marking them for furtherlimination by microglia (in the absence of MAC activation).he findings are in line with other studies demonstratinghe involved of ‘‘immune’’ proteins in synaptic plasticityBoulanger, 2009). Since synapse elimination followed byberrant synaptogenesis is an important feature of TLE (Ben-ri, 2001), it makes sense to have increased expression ofomplement components under such conditions.
eelin
eelin is a large ECM protein with a serine protease activ-ty (Quattrocchi et al., 2002). In the hippocampus, reelins synthesized and secreted into the ECM by Cajal—Retziusells and interneurons (Fatemi, 2005; Frotscher, 2010).fter secretion, the 400-kDa full-length reelin is cleavedroteolytically into smaller isoforms, an important pre-equisite for activation of target cells expressing theipoprotein receptors, very-low-density lipoprotein receptornd apolipoprotein E receptor 2 (Fatemi, 2005; Frotscher,010). Notably, MMPs play a major role in the cleavageLambert de Rouvroit et al., 1999; Tinnes et al., 2011).eeler mutant mice with the protein deficiency displayevelopmental deficit of proper location of the hippocampalarnule cells. Similar granule cell dispersion (GCD) result-ng in a loss of compact lamination of those cells is also
bserved in TLE. This connection has prompted investigationn a possible role of reelin in the TLE (Haas and Frotscher,010). Indeed, a strong link of reelin function to the TLE haseen provided by both functional and expression studies.vs
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n particular, infusion of reelin-blocking antibodies into theippocampus of adult mice resulted in GCD (Heinrich et al.,006), and in the KA model infusion of recombinant reelinrevented GCD formation (Muller et al., 2009). Decreasedeelin levels were observed in the hippocampus followingA and pilocaprine induced SE (Heinrich et al., 2006; Gongt al., 2007; Antonucci et al., 2008). Moreover, in tissue sam-les from human epileptic patients, the extent of GCD wasound to correlate with a loss of reelin-expressing neuronsHaas et al., 2002).
Recent genetic studies also link reelin to the humanpilepsy. Zaki et al. (2007) described a reelin gene muta-ion in the case of the cortical lissencephaly with cerebellarypoplasia, severe epilepsy, and mental retardation. Fur-hermore, Dutta et al. (2011) reported on an associationf the reelin gene polymorphisms with human childhoodpilepsy. Moreover, Kobow et al. (2009) described increasedeelin promoter methylation being associated with granuleell dispersion in human TLE.
oncluding remarks
ver the recent years a broad spectrum of data have beenccumulated pointing to a possible involvement of extra-ellular, including extrasynaptic, proteolysis in epilepsy.he most productive avenues of investigations have beennalyses of seizure-evoked gene and protein expressionatterns, both hypothesis-driven and unbiased (e.g., DNAicroarrays). One has to be, however, warned that such
response to seizure-provoking stimuli does not necessar-ly signify a role in epileptogenesis. It might often be aimple effect of enhanced neuronal activity that in exag-erated manner models neuronal stimulation, which mayr may not result in either physiological or pathologicallasticity. On the other hand, careful follow-up of the afore-entioned experimental leads may prove functional link
f the gene and protein to development of epilepsy, ashown e.g., by Wilczynski et al. (2008) for MMP-9. It isoteworthy that recent advancements in our knowledge onxtracellular proteolysis in epilepsy is paralleled by similarevelopments in our understanding of an involvement of thishenomenon in other forms of plasticity, including learningnd memory (see, e.g., Dityatev et al., 2010a; Rivera et al.,010).
Another attractive direction of research was to studyhe human tissues. One way was to look at the gene and/orrotein expression levels in the epileptic brain samples.owever, again it is difficult to decipher the meaning ofhe observed changes, as there is a lot sample-to-sampleariability and it is very difficult to extract the changeselated to the epileptogenic process from a number of otherlterations, e.g., neurodegeneration, neuroinflammation,ffects of treatment, etc., whose roles in the epilepsy aretill poorly understood. An interesting way to proceed in
quest for the epilepsy-linked genes is to investigate theene polymorphisms, specially the functional ones, such ashose observed in either the gene regulatory sequences or
ital protein domains. This approach has indeed, provenuccessful.A major obstacle in deciphering roles played by extra-ellular proteases in the brain function and dysfunction,
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including epilepsy, is apparent cellular and molecular com-plexity of the system. The enzymes are often partnered bytheir specific inhibitors and, furthermore, they act in veryintricate cascades of enzymatic activities. A good examplemight be provided by a well-known role of plasminogen sys-tem (complicated by itself) in unleashing activities of MMPsthat are released in a latent form with a propeptide to becleaved off outside the cells. On the hand, MMPs process,e.g., reelin. Another facet contributing to the complexity ofthe systems described herein is that their components areproduced and released into the ECM, with diverse dynam-ics, by various cell types, i.e., neurons (of various kinds),astrocytes, microglia, cells of the blood vessels and of theimmune system. It should be underlined that local injury,with a marked brain penetration by the peripheral immunecells, resulting in neurodegeneration and neuroinflamma-tion, is frequently a trigger of epileptogenesis. In fact, itis noticeable that many proteases implicated in a cell deathwere found to be associated with epilepsy.
Taking into account extracellular and enzymatic natureof the proteins commented on in this review, it is conspic-uous how little has apparently been done with applicationof their chemical inhibitors in epileptogenesis and epilepsy.One would expect that extracellular enzymes comprise par-ticularly attractive targets, first for the investigations, andnext for the therapy. Probably, relative immaturity of thefield and aforementioned intricacy of the proteolytic sys-tems along with a lack of good, specific inhibitors are tobe blamed for the present situation. This hopefully shouldchange soon, considering a plethora of information gatheredso far and presented herein.
Acknowledgement
This work was supported by the Polish-Norwegian Grant(GMW and LK).
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