Epilepsia, 48(Suppl. 8):66–68, 2007doi: 10.1111/j.1528-1167.2007.01354.x

OUTCOMES OF STATUS EPILEPTICUS

Neuroprotection in epilepsyMatthew Walker

Department of Clinical & Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom

SUMMARYNeuroprotection following status epilepticusshould encompass not only the prevention ofneuronal death, but also preservation of neuronaland network function. This is critical because theseaims are not necessarily equivalent; preventionof neuronal loss, for example, does not inevitablyprevent epileptogenesis. There are endogenousneuroprotective mechanisms that can serve di-chotomous roles (e.g. ERK1/2 activation can resultin either neuroprotection or promote neuronaldeath). The roles of potential endogenous mech-anisms can depend upon the pattern and timingof their activation. The simplest exogenous neu-roprotective mechanism is to halt seizure activity.

Other approaches consist of early NMDA receptorantagonism or later inhibition of apoptotic path-ways. The problem with the latter approach is thatcalcium accumulation results in the activation of anumber of downstream pathways, the importanceof which varies from region to region and in acell-type specific manner. Neuroprotection inepilepsy is not a straightforward concept, and weneed to be clear about our eventual objectives (e.g.preventing cognitive decline). There are numerouspossible approaches to neuroprotection, and theefficacy of these depends upon their timing, thespecific aims and even the method of statusepilepticus induction.KEY WORDS: Neuroprotection, Status epilepti-cus.

Status epilepticus sets in motion a myriad of changes in-cluding modification of receptors and ion channels, alter-ations in network connectivity, and neuronal death (Walkeret al., 2002; Chen and Wasterlain, 2006). These changesoccur not only during status epilepticus but also after-wards, leading to the possibility of intervening at differentstages: during status epilepticus, immediately followingstatus epilepticus, during the latent period prior to the oc-currence of recurrent unprovoked seizures, and later whenseizures have occurred.

The concept of neuroprotection in status epilepticus wasoriginally restricted to the prevention of neuronal loss,which is the overt and easily quantifiable consequence ofstatus epilepticus. However, our primary aim is the pre-vention of the deleterious effects of status epilepticus in-cluding the development of chronic epilepsy and cognitivedecline. Therefore, a more pertinent definition of neuro-protection in status epilepticus needs to include protection

Address correspondence and reprint requests to Dr. Matthew Walker,UCL Institute of Neurology, National Hospital for Neurology and Neu-rosurgery, Box 29, Queen Square, London WC1N 3BG, U.K. E-mail:m.walker@ion.ucl.ac.uk

Blackwell Publishing, Inc.C© International League Against Epilepsy

not just against neuronal death but also against neuronaland network dysfunction (Sutula et al., 2003). These arenot equivalent, as is borne out by growing evidence of dis-sociation between neuronal death and the functional con-sequences of status epilepticus (Walker et al., 2002). In-deed, some neuroprotective mechanisms may promote thedevelopment of chronic epilepsy (see below). As a networkof neurons is necessary to sustain epileptic activity, thenextensive neuronal loss should logically prevent seizures.Certainly, there is evidence that the extensive destruction ofCA1 pyramidal neurons following ischemic injury can pro-tect rats from seizures induced by tetanus toxin (Milwardet al., 1999). This emphasizes the very obvious dichotomybetween neuronal damage and epileptogenesis.

ENDOGENOUS NEUROPROTECTION

Endogenous neuronal survival mechanisms followingan insult depends upon a number of signaling pathways,prominent among these are the phosphoinositide 3-kinase(PI3-kinase)/Akt and the extracellular signal regulated ki-nase 1/2 (ERK1/2) pathways that can be activated througha number of different routes including neurotrophins andcalcium entry through NMDA receptors. Indeed, the ac-tivation of these pathways and CREB/CRE by NMDA

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receptors may be one mechanism underlying precondition-ing, in which exposure to sublethal insults results in protec-tion against subsequent larger insults (Soriano et al., 2006).Thus, low level and chronic activation of synaptic NMDAreceptors is neuroprotective, while sudden and excessiveactivation of extrasynaptic NMDA receptors is neurotoxic.A similar dichotomous role is also seen with peroxynitrite,which is a potent reactive oxygen species that can resultin neuronal death; at very low concentrations peroxynitritecan activate the Akt pathway and neuroprotect (Delgado-Esteban et al., 2007). Akt (protein kinase B) is a proteinkinase that is activated by PI3-kinase. Activated Akt phos-phorylates and so inactivates a number of proapoptotic pro-teins such as Bad (Datta et al., 1997), caspase-9 (Cardoneet al., 1998), and transcription factors of the forkhead fam-ily (Brunet et al., 1999).

ERK1/2 are members of the mitogen activated proteinkinase family and promote neuronal survival (Hetman andGozdz, 2004). ERK1/2 can be activated by a variety ofextracellular stimuli including neurotrophins (Hetman andGozdz, 2004). ERK1/2 activation has been proposed toplay a critical role in neuronal survival following a hypoxicinsult (Jin et al., 2002), and inhibition of ERK1/2 activa-tion increases epileptic activity and decreases animal sur-vival in the pilocarpine model of status epilepticus (Berke-ley et al., 2002). Although these studies have suggested aneuroprotective role for ERK1/2, other studies have sug-gested that ERK1/2 activation can promote neuronal death(Chu et al., 2004). An explanation for this dichotomy is thatERK1/2 activation may initially counter oxidative stress,but when cellular defences are exhausted it serves as a sig-nal to trigger cell death (Luo and DeFranco, 2006). Therole of ERK1/2 in status epilepticus is further confoundedby evidence suggesting that ERK1/2 activation is epilepto-genic (Merlo et al., 2004).

EXOGENOUS NEUROPROTECTION

Undoubtedly the most effective way of preventingseizure related damage is to halt seizure activity (Chenand Wasterlain, 2006). Indeed, the treatment of statusepilepticus in the premonitory phases before status epilep-ticus has become established may prevent many of thepathological consequences (Walker et al., 2002). There-fore, early recognition and administration of effectivetreatment are paramount. If seizures continue, then theexcitotoxic cascade is activated. NMDA receptor andmetabotropic glutamate group I receptor activation resultin both calcium influx into the neuron and also release ofcalcium from internal stores (Meldrum, 2002). Other re-ceptors and ion channel, such as voltage gated calciumchannels and calcium permeable AMPA receptors, mayalso contribute to intracellular calcium accumulation. Inaddition, seizure-induced ion shifts may lead to neuronalswelling and necrotic cell death. Inhibition of NMDA re-

ceptors prior or soon after status epilepticus leads to sub-stantial and widespread neuroprotection (Clifford et al.,1990; Fujikawa et al., 1994), but it is likely that NMDAreceptor antagonists will need to be administered early inorder to prevent calcium accumulation.

Calcium accumulation activates a number of down-stream mechanisms leading to programmed cell death(apopotosis), similar mechanisms can also be activatedduring necrosis, blurring the distinction between necroticand apoptotic processes (Fujikawa et al., 2000; Fujikawa,2005). There are, however, many distinct and intercon-nected downstream mechanisms such as the extrinsic cas-pase pathway through caspase 8,10 activation, the intrin-sic caspase pathway activated by cytochrome c releasefrom mitochondria, BCL-2 pathways, formation of reac-tive oxygen species such as peroxynitrite, disruption ofmitochondrial function through mitochondrial calcium ac-cumulation, activation of calpain 1, activation of poly(ADP-ribose) polymerase-1, etc. (Cock et al., 2002;Fujikawa, 2005; Henshall and Simon, 2005). There is con-siderable controversy about the relative roles of these dif-ferent pathways, for example, some studies demonstrateneuroprotective effects of caspase 3 inhibition (Narkilahtiet al., 2003a), whilst others finding no evidence for a roleof caspase 3 (Fujikawa et al., 2002)—this whole debate isfurther confounded by the possibility that different path-ways are activated in different seizure models (Fujikawaet al., 2007), and that the mechanism of neuronal deathmay be region/cell specific (Narkilahti et al., 2003b). Theadvantage of targeting these down stream mechanisms isthat this approach may permit later (delayed) interven-tions. An alternative approach may be to use drugs such asvalproate that activate endogenous neuroprotective mecha-nisms (Boeckeler et al., 2006).

NEUROPROTECTION,EPILEPTOGENESIS, AND COGNITIVE

DECLINE

Does preventing neuronal death prevent other conse-quences? There is a clear distinction between preventingneuronal death and preventing the later development ofepilepsy; indeed some endogenous neuroprotective path-ways may be proepileptogenic by encouraging axonal reor-ganization and potentiating synaptic transmission (Sweatt,2004). Preventing calcium accumulation by inhibitingNMDA receptor should prevent the downstream conse-quences and indeed NMDA receptor antagonists seem toprevent not only neuronal death, but also subsequent cog-nitive effects and epileptogenesis (Rice et al., 1998; Prasadet al., 2002). However, NMDA receptor antagonism is notalways sufficient to prevent the development of epilepsy,even when it has prevented neuronal damage (Brandt et al.,2003).

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CONCLUSION

Preventing the development of status epilepticus is per-haps the most effective way to neuroprotect. Early on dur-ing status epilepticus, inhibition of upstream targets such asNMDA receptors may neuroprotect, but later interventionsprobably need to target downstream pathways; an approachthat is complicated by the realization that there are a num-ber of pathways that may be differentially activated, per-haps depending on the aetiology and severity of the statusepilepticus. Preventing neuronal death does not necessarilyprevent other consequences of status epilepticus, and in-deed, some neuroprotective mechanisms may be proepilep-togenic.

REFERENCES

Berkeley JL, Decker MJ, Levey AI. (2002) The role of muscarinic acetyl-choline receptor-mediated activation of extracellular signal-regulatedkinase 1/2 in pilocarpine-induced seizures. J Neurochem 82:192–201.

Boeckeler K, Adley K, Xu X, Jenkins A, Jin T, Williams RSB. (2006) Theneuroprotective agent, valproic acid, regulates the mitogen-activatedprotein kinase pathway through modulation of protein kinase A sig-nalling in Dictyostelium discoideum. Eur J Cell Biol 85:1047.

Brandt C, Potschka H, Loscher W, Ebert U. (2003) N-methyl–aspartatereceptor blockade after status epilepticus protects against limbic braindamage but not against epilepsy in the kainate model of temporal lobeepilepsy. Neuroscience 118:727.

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ,Arden KC, Blenis J, Greenberg ME. (1999) Akt promotes cell survivalby phosphorylating and inhibiting a forkhead transcription factor. Cell96:857–868.

Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stan-bridge E, Frisch S, Reed JC. (1998) Regulation of cell death proteasecaspase-9 by phosphorylation. Science 282:1318–1321.

Chen JWY, Wasterlain CG. (2006) Status epilepticus: pathophysiologyand management in adults. Lancet Neurol 5:246.

Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB. (2004)Oxidative neuronal injury: the dark side of ERK1/2. Eur J Biochem271:2060–2066.

Clifford DB, Olney JW, Benz AM, Fuller TA, Zorumski CF. (1990)Ketamine, phencyclidine, and MK-801 protect against kainic acid-induced seizure-related brain damage. Epilepsia 31:382–390.

Cock HR, Tong X, Hargreaves IP, Heales SJR, Clark JB, Patsalos PN,Thom M, Groves M, Schapira AHV, Shorvon SD, Walker MC. (2002)Mitochondrial dysfunction associated with neuronal death followingstatus epilepticus in rat. Epilepsy Res 48:157.

Datta SR, Dudek H, Tao X, Masters S, Fu HA, Gotoh Y, Greenberg ME.(1997) Akt phosphorylation of BAD couples survival signals to thecell-intrinsic death machinery. Cell 91:231–241.

Delgado-Esteban M, Martin-Zanca D, Andres-Martin L, Almeida A,Bolanos JP. (2007) Inhibition of PTEN by peroxynitrite activates the

phosphoinositide-3-kinase/Akt neuroprotective signaling pathway. JNeurochem 102:194–205.

Fujikawa DG, Daniels AH, Kim JS. (1994) The competitive NMDAreceptor antagonist CGP 40116 protects against status epilepticus-induced neuronal damage. Epilepsy Res 17:207–219.

Fujikawa DG, Shinmei SS, Cai B. (2000) Seizure-induced neuronalnecrosis: implications for programmed cell death mechanisms.Epilepsia 41(Suppl. 6):S9–S13.

Fujikawa DG, Ke X, Trinidad RB, Shinmei SS, Wu A. (2002) Caspase-3is not activated in seizure-induced neuronal necrosis with internucle-osomal DNA cleavage. J Neurochem 83:229–240.

Fujikawa DG. (2005) Prolonged seizures and cellular injury: understand-ing the connection. Epilepsy Behav 7:3.

Fujikawa DG, Shinmei SS, Zhao S, Aviles JER. (2007) Caspase-dependent programmed cell death pathways are not activated in gen-eralized seizure-induced neuronal death. Brain Res 1135:206.

Henshall DC, Simon RP. (2005) Epilepsy and apoptosis pathways. JCereb Blood Flow Metab 25:1557.

Hetman M, Gozdz A. (2004) Role of extracellular signal regulated kinases1 and 2 in neuronal survival. Eur J Biochem 271:2050–2055.

Jin K, Mao XO, Zhu Y, Greenberg DA. (2002) MEK and ERK protecthypoxic cortical neurons via phosphorylation of Bad. J Neurochem80:119–125.

Luo Y, DeFranco DB. (2006) Opposing roles for ERK1/2 in neuronal ox-idative toxicity: distinct mechanisms of ERK1/2 action at early versuslate phases of oxidative stress. J Biol Chem 281:16436–16442.

Meldrum BS. (2002) Implications for neuroprotective treatments. ProgBrain Res 135:487–495.

Merlo D, Cifelli P, Cicconi S, Tancredi V, Avoli M. (2004) 4-Aminopyridine-induced epileptogenesis depends on activation ofmitogen-activated protein kinase ERK. J Neurochem 89:654–659.

Milward AJ, Meldrum BS, Mellanby JH. (1999) Forebrain ischaemiawith CA1 cell loss impairs epileptogenesis in the tetanus toxin lim-bic seizure model. Brain 122:1009–1016.

Narkilahti S, Nissinen J, Pitkanen A. (2003a) Administration of caspase 3inhibitor during and after status epilepticus in rat: effect on neuronaldamage and epileptogenesis. Neuropharmacology 44:1068.

Narkilahti S, Pirttila TJ, Lukasiuk K, Tuunanen J, Pitkanen A. (2003b)Expression and activation of caspase 3 following status epilepticus inthe rat. Eur J Neurosci 18:1486–1496.

Prasad A, Williamson JM, Bertram EH. (2002) Phenobarbital and MK-801, but not phenytoin, improve the long-term outcome of statusepilepticus. Ann Neurol 51:175–181.

Rice AC, Floyd CL, Lyeth BG, Hamm RJ, DeLorenzo RJ. (1998)Status epilepticus causes long-term NMDA receptor-dependentbehavioral changes and cognitive deficits. Epilepsia 39:1148–1157.

Soriano FX, Papadia S, Hofmann F, Hardingham NR, Bading H, Hard-ingham GE. (2006) Preconditioning Doses of NMDA Promote Neuro-protection by Enhancing Neuronal Excitability. J Neurosci 26:4509–4518.

Sutula TP, Hagen J, Pitkanen A. (2003) Do epileptic seizures damage thebrain? Curr Opin Neurol 16:189–195.

Sweatt JD. (2004) Mitogen-activated protein kinases in synaptic plasticityand memory. Curr Opin Neurobiol 14:311.

Walker MC, White HS, Sander JW. (2002) Disease modification in partialepilepsy. Brain 125:1937–1950.

Epilepsia, 48(Suppl. 8):66–68, 2007doi: 10.1111/j.1528-1167.2007.01354.x