Epilepsia, 45(11):1300–1307, 2004Blackwell Publishing, Inc.C© 2004 International League Against Epilepsy

Laboratory Research

Synergism between Topiramate and Budipine in RefractoryStatus Epilepticus in the Rat

Andrew Fisher, Xiaolan Wang, Hannah R. Cock, Maria Thom, Philip N. Patsalos,and Matthew C. Walker

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

Summary: Purpose: To evaluate the antiepileptic and neuropro-tective properties of topiramate (TPM) alone and with coadmin-istration of the N-methyl-D-aspartate (NMDA)-receptor antago-nist budipine in a rat model of refractory status epilepticus.

Methods: Male Sprague–Dawley rats had electrodes im-planted into the perforant path and dentate granule cell layerof the hippocampus under halothane anesthesia. Approximately1 week after surgery, the perforant path of each animal was elec-trically stimulated for 2 h to induce self-sustaining status epilep-ticus. Successfully stimulated rats were given intraperitoneallyvehicle (n = 6), TPM (20–320 mg/kg; n = 28), budipine (10mg/kg; n = 5), or budipine (10 mg/kg) and TPM (80 mg/kg;n = 6) 10 min after the end of the stimulation and monitoredbehaviorally and electroencephalographically for a further 3 h.

The animals were killed 14 days later, and histopathology wasassessed.

Results: Neither budipine alone nor TPM at any dose termi-nated status epilepticus. Despite this, TPM resulted in variousdegrees of neuroprotection at doses between 40 and 320 mg/kg.Coadministration of budipine with TPM terminated the statusepilepticus in all rats. This combination also significantly im-proved the behavioral profile and prevented status-induced celldeath compared with control.

Conclusions: Budipine and TPM are an effective drugcombination in stopping self-sustained status epilepticus, andTPM alone was neuroprotective, despite the continuation ofseizure activity. Key Words: Topiramate—Budipine—Statusepilepticus—Perforant path—Neuroprotection.

Status epilepticus is a medical emergency with a highmorbidity and mortality. Existing pharmacotherapeuticapproaches successfully treat fewer than 70% of patientswith status epilepticus (1), and there thus remain a substan-tial proportion of individuals whose condition is refractoryto conventional treatments. Status epilepticus is associatedwith severe neuronal damage. The degree of excitotoxicneuronal damage that occurs during status epilepticus isdependent on the presence and duration of electrographicseizure activity (2). Therefore the most effective way tominimize neuronal damage is to stop seizures as soon aspossible after their onset. Furthermore, status epilepticusbecomes progressively more difficult to treat as the timebetween seizure manifestation and pharmacologic inter-vention increases (3,4). In the 40% of cases that are esti-mated to be unresponsive to first-line treatment (1), gen-eral anesthesia in an intensive care unit can often be the

Accepted June 23, 2004.Address correspondence and reprint requests to Dr. M.C. Walker at

Department of Clinical & Experimental Epilepsy, Institute of Neurol-ogy, Queen Square, London, WC1N 3BG, U.K. E-mail: m.walker@ion.ucl.ac.uk

only option available to treat refractory status epilepticus.However, this approach is associated with increased risksof hypotension and infection and with a high morbidityand mortality (5,6).

Administration of neuroprotective compounds offersan alternative approach to combat the neuronal dam-age that occurs with continual seizure activity. Activa-tion of ionotropic glutamate receptors has been thoughtto play an integral role in the pathophysiology of status-induced neuronal damage (7). Therefore glutamate antag-onists would be expected to be effective in combating theinitiation and propagation of seizure-induced excitotox-icity and its associated neuropathology. Several groupshave confirmed this hypothesis in rodents that have beentreated with glutamate-receptor antagonists either before(8–10) or after the induction of status epilepticus (11,12).Furthermore, N-methyl-D-aspartate (NMDA)-receptorantagonists enhance the effect of diazepam (DZP) in thetreatment of status epilepticus (13) and prevent the de-velopment of DZP refractoriness (14). NMDA-receptorantagonists exhibit limited clinical effectiveness on ac-count of their psychotomimetic side effects. However,

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evidence suggests that low-affinity NMDA-receptor an-tagonists such as budipine and memantine may displaybeneficial effects in the early treatment of some clini-cal conditions such as Parkinson’s disease (15,16) andepilepsy (17).

Topiramate [TPM;2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulphamate] is a novel anticon-vulsant that displays multiple mechanisms of actionincluding antagonism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate receptors;blockade of voltage-activated Na+ and L-type Ca2+

channels; potentiation of γ -aminobutyric acid (GABA)-mediated inhibitory neurotransmission, and the activationof K+ channels (18,19). The actions of TPM on GABAA

receptors are not mediated through the benzodiazepine(BZD) or barbiturate sites. This is an important distinc-tion, as drugs that act at these loci within the GABAA

receptor–ionophore complex experience a loss of efficacyduring status epilepticus (3).

The aim of the current study was to investigate the ef-fectiveness of TPM alone and in combination with budip-ine (1-tert-butyl-4,4-diphenylpiperidine), a low-affinityNMDA-receptor antagonist, in a rodent model of refrac-tory status epilepticus (20) and to assess its role as aputative neuroprotectant when administered once statusepilepticus has been established.

METHODS

AnimalsMale Sprague–Dawley rats (Tuck, Battlesbridge, Essex,

England) weighing 250 to 320 g were used. Rats were indi-vidually housed in a temperature-controlled environmentunder a 12-h light/dark cycle with food and water availablead libitum. All animal procedures strictly adhered to local(Institute of Neurology, London, U.K.) and Home Officeregulations under the Animal (Scientific Procedures) Act,1986.

DrugsTPM (R.W. Johnson Pharmaceutical Research Institute,

Spring House, PA, U.S.A.) was dissolved in deionized wa-ter containing 1 M NaOH (2–5% vol/vol) and protectedfrom light. Budipine (Byk Gulden, Konstanz, Germany)was dissolved in warm deionized water. Both drugs wereprepared in solution immediately before injection. Alldrugs were administered intraperitoneally in an injectionvolume of 0.1 ml/100 g body weight.

Electrode implantationThis procedure has been previously described in de-

tail (21). In brief, animals were fully anaesthetized withhalothane in oxygen (3% vol/vol induction; 1.5% vol/volmaintenance) and placed into a stereotaxic frame (DavidKopf Instruments, Tujunga, CA, U.S.A.). Before elec-trode placement, ventral measurements were recorded for

bregma and lambda to ensure that the skull was as level aspossible while in the frame. Fine adjustments of the nosebar were made until differences in ventral coordinates be-tween bregma and lambda were ≤0.1 mm. A bipolar stim-ulating electrode was then slowly lowered into the angularbundle (coordinates, 8.1 mm caudal to bregma; 4.4 mm lat-eral; 3.5–4.0 mm ventral from brain surface) to stimulatethe perforant pathway, and a unipolar recording electrodewas lowered into the ipsilateral hippocampal dentate gran-ule cell layer (coordinates, 4.0 mm caudal to bregma; 2.5mm lateral; 3.5–4.0 mm ventral from brain surface). Allstereotaxic coordinates were in reference to the stereotaxicrat brain atlas of Paxinos and Watson (22). The depths ofthe electrodes were finely adjusted to maximize the slopeof the field potential.

After 7 to 10 days’ recovery from surgery, each animalwas challenged with a single monopolar pulse (2 mA, 50µs) to ensure continual functional competency of the elec-trodes after the postoperative recovery period. Rats thatdisplayed a population spike of <2 mV were not includedfor further study.

The perforant pathway was stimulated in freely movingrats with a Neurolog stimulator (Digitimer Ltd., WelwynGarden City, U.K.) delivering 2-mA, 50-µs monopolarpulses at 20 Hz for 2 h to induce self-sustaining statusepilepticus (SSSE). EEG signals were transferred via anNB-MIO-16 interface (National Instruments, Newbury,Berkshire, U.K.) to a computer equipped with LabViewsoftware. Drugs were administered intraperitoneally (i.p.)10 min after electrical stimulation was terminated. Ani-mals that failed to display self-sustaining chronic limbicstatus 10 min after the electrical stimulation was stoppedwere excluded from further analysis. We assessed the de-gree of sedation by using a well-established scale: 0, spon-taneous movement; 1, intermittent spontaneous move-ment; 2, no spontaneous movement; 3, loss of auditoryreflex; 4, loss of corneal reflex; 5, loss of response to tailpinch (20,23). We assessed the seizure severity by usingthe classification of Racine (24). For the purposes of thesedation score, the presence of only seizure-related move-ments was scored as no spontaneous movements. We con-tinually monitored the EEG recordings for a further 3 h.Seizure severity, level of sedation, spike frequency, andmaximal spike amplitude were recorded every 10 min.

Animals that displayed seizure activity 3 h after drugadministration had their seizures terminated by i.p. admin-istration of 20 mg/kg DZP.

HistologyFourteen days after stimulation, all animals were

deeply anaesthetized and transcardially perfused with 4%buffered paraformaldehyde (pH 7.2). The brains were re-moved and stored in 4% paraformaldehyde before be-ing embedded in paraffin wax. Coronal sections (5 µmfor hematoxylin and eosin staining and 20 µm for Nissl

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1302 A. FISHER ET AL.

labeling) were taken every 200 µm to assess semiquan-titively acute neuronal injury (eosinophilic and pyknoticneurons on H&E sections) and cell density, respectively.Within the hippocampus, the dentate granule (DG) celllayer, the hilus, and the CA1 and the CA3 regions wereindependently graded. The investigator was blinded to thetreatment that the rat had received. In all slides, three ran-dom areas within each hippocampal subregion were se-lected, and the number of neurons (distinguished fromother cell types on the basis of their size, the presence ofNissl granules in the cytoplasm, and a large pale-stainingnucleus with one or more nucleoli) partly or wholly con-tained within a 50-µm2 area was counted by using anOlympus CK inverted microscope with a ×20 objectivelens and a 10 × 10 eyepiece graticule (grid area, 0.5 ×0.5 mm2).

Statistical methodsSpike frequencies between drug groups were analyzed

by using a general linear model with repeated-measuresanalysis of variance (ANOVA) on SPSS for Windows withalterations in spike frequency and spike amplitude overtime as the within-subject factors. Where significance wasreached, post hoc analysis was conducted by using Tukey’sHSD test. Results for cell density and acute neuronal dam-age were determined by using a multifactorial ANOVA onSPSS for Windows, and significance was determined byusing Pillai’s trace. Variables included brain hemisphere,

FIG. 1. Topiramate (TPM, 20–320mg/kg, i.p.) has no effect on the spikefrequency (A) or amplitude (B) in ani-mals 10 min after self-sustaining sta-tus epilepticus had been established.Each point is expressed as the mean± SEM of at least four individualsper treatment group. C: Typical sam-ples of EEG after drug administration.Recordings are continually analyzedbut are represented here at time 0, 30,60, and 180 min after the onset of self-sustaining status epilepticus.

brain region, and drug treatment. Behavioral assessmentwas quantified by using the Kruskal–Wallis H test for sig-nificance between groups. Significant behavioral differ-ences from control were subsequently assessed by usingthe Mann–Whitney U test. In all statistical tests, a valueof p < 0.05 was taken as the level of significance.

RESULTS

EEG/behavioral analysisAfter the stimulation protocol, all rats that went into

status epilepticus (n = 45) had an initial spike frequencyof 1.0–2.1 Hz and exhibited marked behavioral seizures(Racine score, ≥3).

TPM at doses of 20, 40, 80, 160, and 320 mg/kg failed toabolish EEG seizure activity (Fig. 1). Differences in spikefrequency over time between treatment groups was notsignificant [F(5, 26) = 0.8; p = 0.570]. Despite the lackof effect of TPM on seizure frequency, a trend was notedtoward a reduction of spike amplitude after high-dose ad-ministration (160 and 320 mg/kg), but this effect did notreach statistical significance at any TPM dose tested [F(5,26) = 2.3; p = 0.078]. High-dose administration of TPMwas accompanied by profound ataxia and sedation in allanimals tested at these doses (Table 1). Moreover, TPMat 320 mg/kg induced severe respiratory depression in allrats tested and exhibited lethal toxicity in two rats. We thenasked whether an NMDA-receptor antagonist would en-

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TABLE 1. The effect of topiramate (TPM, 40–320 mg/kg, i.p), budipine (BDP, 10 mg/kg), or BDP and TPM treatment (10 and 80mg/kg, respectively) on sedation scores

Sedation Score DrugTime afterdrug (min) Saline TPM 40 TPM 80 TPM 160 TPM 320 BDP 10 BDP +TPM

0 Mean 3.00 3.00 3.00 3.00 3.00 3.00 3.00SEM 0.00 0.00 0.00 0.00 0.00 0.00 0.00

30 Mean 3.00 2.00 3.00 3.00 3.25 2a 1.5a

SEM 0.00 0.24 0.00 0.00 0.25 0.32 0.3460 Mean 3.00 2.00 3.00 3.17 3.75 1.8a 0.5a

SEM 0.00 0.24 0.26 0.17 0.25 0.37 0.34120 Mean 3.00 1.50 3.00 3.17 3.50 1.4a 0.33a

SEM 0.00 0.21 0.26 0.17 0.29 0.24 0.21180 Mean 3.00 1.33 3.00 3.17 3.25 1.6a 0.33a

SEM 0.00 0.31 0.26 0.17 0.25 0.24 0.21

See Methods: 0, no sedation; 5, deep anesthesia. Behavioral assessment represents the means ± SEM of at least four individuals per treatment group.The nonparametric Kruskal–Wallis test was used to assess between-group significance. Significant deviations from control were subsequently quantifiedby using the Mann–Whitney U test.

ap < 0.05.

hance the antiepileptic effect of TPM. We first confirmedthat the low-affinity NMDA-receptor antagonist budipinealone at low dose (10 mg/kg; i.p.) failed to exhibit any sig-nificant effect on spike frequency [F(3.4, 30.2) = 2.4; p =0.085 vs. saline control]. However, the behavioral scoreof all budipine-treated animals tested was significantlyimproved compared with those of animals receiving ve-hicle alone (see Table 1). We next tested the combinedeffect of TPM and low-dose budipine. Status epilepti-cus was terminated in all animals that received budip-

FIG. 2. The effect of combiningbudipine (BDP, 10 mg/kg, i.p.) andtopiramate (TPM, 80 mg/kg, i.p.) onspike frequency (A) and amplitude(B) in perforant path–stimulatedrats. Spike frequency was signif-icantly reduced by 50 min, andseizure activity stopped in all ani-mals by 90 min after drug admin-istration. Significant attenuation ofspike amplitude was reached 10min after combination therapy. Thelack of effect of TPM (80 mg/kg)and BDP (10 mg/kg) given aloneand the effect of saline are includedfor comparison. Each point is ex-pressed as the mean ± SEM of atleast five individuals per treatmentgroup. ∗p < 0.05 compared withcontrol (repeated measures analy-sis of variance with post hoc TukeysHSD test). C: Representative 10-sEEG traces from rats given BDP (10mg/kg) and TPM (80 mg/kg).

ine, 10 mg/kg, as an adjunct to TPM, 80 mg/kg, therapy.In all cases, the EEG returned to baseline levels within90 min after drug administration (Fig. 2). A significantdrug effect was found between the groups [F(4.8, 90.9) =6.4; p < 0.001, with a significant reduction in spike fre-quency attained 50 min after treatment with both drugs].Behavioral seizure activity was terminated in all animalssubjected to budipine and TPM coadministration withoutcompromising the motility or alertness of the animals (seeTable 1).

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FIG. 3. Neuronal damage in the CA1 region of the hippocampus secondary to status epilepticus is ameliorated by topiramate (TPM; 80mg/kg) and by the combination of budipine (10 mg/kg) and TPM (80 mg/kg). Examples of CA1 regions from unstimulated rat (A), rat withstatus epilepticus given saline (B) demonstrating marked neuronal loss with increase in microglia and reactive astrocytes, rat with statusepilepticus given TPM (C), and rat with status epilepticus given budipine and TPM (D). Examples are from 5-µm H&E sections.

NeuroprotectionIn all saline-treated animals, histologic examination re-

vealed severe bilateral neuronal damage, as previously de-scribed (21). In all cases, almost complete neuronal losswas seen in the CA1 region on the stimulated hemisphere,with an accompanying marked increase in microglia andreactive astrocytes (Fig. 3). The CA3 and hilus regionsalso were affected, with the area of the hilus reduced insaline-treated animals compared with those rats treatedwith TPM (data not shown).

TABLE 2. The effect of topiramate (TPM, 40–320 mg/kg, i.p), budipine (BDP, 10 mg/kg), or BDP and TPM treatment (10 and 80mg/kg, respectively) as a neuroprotectant against status-induced neuronal loss compared with animals given saline

Right DG Left DG Right hilus Left hilus Right CA3 Left CA3 Right CA1 Left CA1

Saline 10.9 ± 1.5 11.8 ± 0.8 1.0 ± 0.6 2.3 ± 0.1 1.5 ± 0.7 2.6 ± 0.2 0.8 ± 0.6 1.4 ± 0.3TPM 40 10.0 ± 0.6 9.7 ± 0.5 2.4 ± 0.2 2.5 ± 0.2 2.9 ± 0.2a 2.8 ± 0.1 3.6 ± 0.5a 3.4 ± 0.4TPM 80 15.8 ± 0.6a 16.0 ± 0.7a 4.5 ± 0.4a 4.7 ± 0.3a 5.9 ± 0.3a 6.7 ± 0.8a 8.5 ± 0.5a 8.1 ± 0.7a

TPM 160 11.5 ± 1.0 9.6 ± 0.6 1.7 ± 0.5 2.6 ± 0.1 2.8 ± 0.3 2.4 ± 0.3 1.1 ± 0.4 4.8 ± 0.5a

TPM 320 10.3 ± 0.6 9.3 ± 0.8 2.9 ± 0.2a 3.0 ± 0.3 3.3 ± 0.3a 4.8 ± 0.6 5.2 ± 0.3a 5.0 ± 0.7a

BDP 10 11.0 ± 0.5 11.1 ± 0.5 3.4 ± 0.2a 3.3 ± 0.2 4.3 ± 0.4a 4.4 ± 0.5 5.4 ± 0.5a 5.8 ± 0.6a

BDP+TPM 11.1 ± 0.4 10.6 ± 0.3 2.9 ± 0.2a 2.8 ± 0.2 3.4 ± 0.2 3.1 ± 0.1 5.3 ± 0.2a 5.3 ± 0.2a

Cell densities were quantified from three random areas (each 50 µm2) within each hippocampal subregion. Values are expressed as mean ± SEM,n = 6, for all groups except TPM, 320 mg/kg (n = 4, as two animals died during status epilepticus) and budipine (n = 5).

ap < 0.05 for difference from saline (Tukey’s HSD test; see Methods)

Significant variability was seen in the cell density ofrats treated with TPM at doses of 40–320 mg/kg [F(40,175) = 3.23; p < 0.01; Pillai’s trace, 2.12]. Further anal-ysis revealed that TPM at 80 mg/kg was the minimal dosethat prevented the marked reduction in hilar, CA1, andCA3 cell densities after saline administration (Table 2,Fig. 3). Administration of budipine at 10 mg/kg eitheralone or concurrent with TPM at 80 mg/kg significantlyprotected against neuronal loss compared with controls[F(32, 152) = 3.13; p < 0.01; Pillai’s trace = 1.59] in

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the hilus, CA1, and CA3 brain regions (Table 2, Fig. 3).The level of neuroprotection offered by TPM alone versuscombined budipine and TPM was found to be not signifi-cantly different in any brain region studied (Table 2).

DISCUSSION

The purpose of this study was to evaluate the anticon-vulsant and neuroprotective actions of TPM in an estab-lished experimental model of refractory status epilepticus(21). The TPM doses selected in our study were basedon preclinical data (19,25) that allowed us to examinedoses that are above and below the reported median ef-fective dose (ED50) of the drug. Our experimental pro-tocol ensured that the duration and intensity of electricalstimulation was identical for all animals included in thestudy. This methodologic approach allowed direct com-parisons to be made between all experimental groups withregard to the effectiveness of the drug(s) and their abilityto afford neuroprotection or a cessation of seizure activ-ity or both. The results suggest that although TPM is aneffective AED in the clinic (26–29), and despite clinicalreports of its use in status epilepticus (30), monoadmin-istration of the drug (20–320 mg/kg, i.p.) does not stopcontinual seizure activity in perforant path –stimulatedrats. However, a single dose of TPM (80 mg/kg, i.p.)did provide a significant reduction in acute neuronal in-jury in the CA1 region of the hippocampus comparedwith control, an effect that supports previous findings inboth status epilepticus (31,32), and ischemia (33,34). Thisalso demonstrates a dissociation between the neuropro-tective and antiepileptic effects of TPM, as neuroprotec-tion was maximal at a dose (80 mg/kg, i.p.) that had nosignificant effect on spike frequency or amplitude. Thisdissociation is similar to that seen with other neuropro-tective compounds (35) and with budipine in this study.The mechanisms underlying this neuroprotective effectare unknown. The loss of the neuroprotective effect athigher TPM doses (160 and 320 mg/kg) can be partlyexplained by the respiratory depression and increasedsedation at these doses (two animals died at the high-est TPM dose). Undoubtedly such physiologic compro-mise during status epilepticus can contribute to neuronaldamage (36).

Combining TPM with the low-affinity NMDA-receptorantagonist budipine (1-tert-butyl-4, 4-diphenylpiperidine)provided no additional neuroprotection (no significant dif-ference was found between the neuroprotection with TPMalone and that when given in combination), but stoppedseizure activity in all animals tested. Moreover, all an-imals undergoing this polypharmacy regimen exhibiteda marked improvement in their behavioral profile 30 minafter drug administration (compared with sole administra-tion of either drug) that appeared to be directly correlatedwith their EEG recordings.

We used budipine in this study, as it offers advantagesover other NMDA-receptor antagonists. Noncompetitive,dissociative anesthetic agents (MK-801, ketamine) havelimited clinical use on account of their sympathomimeticand behavioral side effects (37–39). The binding sites forketamine and MK-801 are located within the ion channelof the NMDA receptor. Because these sites are availableto these ligands only when the NMDA receptor is acti-vated, and the ion channel is in its open conformation,these drugs should be effective in targeting NMDA re-ceptors that are activated, while having little or no ef-fect on NMDA receptors that remain quiescent. How-ever, high-affinity NMDA-receptor antagonists such asMK-801 [Ki = 3 nM; (39)] are associated with slow disso-ciation rates from their binding sites and low voltage de-pendency (40). Consequently, drugs such as MK-801 failto distinguish between NMDA receptors that are patholog-ically activated and those undergoing phasic physiologicstimulation.

In contrast, low-affinity NMDA-receptor antagonistssuch as budipine [Ki = 12 µM (41)] are clinically toleratedand are not typically associated with psychotomimeticside effects (42) on account of their fast dissociation ki-netics [offset rate of budipine, 0.63 s−1 (43)] that are ≥2orders of magnitude faster than that of MK-801 (44). Dur-ing strong depolarization, low-affinity NMDA-receptorion channel antagonists are thought to mimic Mg2+ byrapidly leaving the ion channel after its physiologic acti-vation, but differ from Mg2+in that it does not exit the ionchannel after moderate prolonged synaptic depolarization,as seen with chronic excitotoxicity (40). These propertiesof budipine may afford protection against pathologic ac-tivation of NMDA receptors while sparing any significantinfluence by transient physiologic stimulation.

Typically, low-affinity NMDA-receptor antagonists areadministered in concentrations that do not limit their activ-ity to NMDA receptors but also are likely to interact withbinding sites other than the NMDA receptor. This is notnecessarily a limitation of these drugs, especially when itis considered that the usefulness of TPM as an anticonvul-sant possibly stems from its broad pharmacologic mecha-nisms of action. The pharmacologic profile of budipine hasbeen well characterized (16,45). It has been shown to in-teract with the dopaminergic (46,47), cholinergic (17,48),serotonergic (49), and GABAergic systems (50). Any orall of these interactions with other neurotransmitter sys-tems could contribute to the drug’s synergistic effects withTPM seen in the current study. However, the observed syn-ergistic effects of TPM with MK-801 on seizure activity(n = 3, data not shown) suggest that budipine’s effective-ness may stem from its ability to inhibit NMDA recep-tors. The mechanism underlying the synergistic effect ofNMDA-receptor antagonists in status epilepticus remainslargely unexplained but could be partly due to the role ofNMDA receptors in regulating refractoriness (14).

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These results show that the use of low-affinity NMDA-receptor antagonists as adjuncts to AEDs could offer clin-ical benefits in patients who have persistent seizure activ-ity that proves to be intractable to first-line AED therapy.TPM also could have an important role as an adjunctivetreatment, especially because it seems to afford significantneuroprotection, even if it does not terminate the statusepilepticus.

Acknowledgment: We thank Johnson & Johnson for sup-porting this work. We also thank Dr. Peter Whitton for the giftof budipine, Derek Marson for assistance with the preparationof the brain slices for histologic assessment, and Hannah Slevenfor assistance with in vivo work.

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