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PHAREP-68; No. of Pages 5 Pharmacological Reports xxx (2014) xxx–xxx

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Original research article

Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine Konrad Rejdak a,*, Dorota Nieoczym b, Mirosław Czuczwar c, Jacek Kis´ d,e, Piotr Wlaz´ b, Waldemar A. Turski f,g a

Department of Neurology, Medical University of Lublin, Lublin, Poland Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Skłodowska University, Lublin, Poland 2nd Department of Anesthesiology and Intensive Care, Medical University of Lublin, Lublin, Poland d Department of Human Anatomy, Medical University of Lublin, Lublin, Poland e Department of Urology and Urological Oncology, Medical University of Lublin, Lublin, Poland f Department of Toxicology, Institute of Agricultural Medicine, Lublin, Poland g Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Poland b c

A R T I C L E I N F O

Article history: Received 2 May 2013 Received in revised form 30 October 2013 Accepted 3 December 2013 Available online xxx Keywords: Orphenadrine Dizocilpine Refractory status epilepticus model Rats

A B S T R A C T

Background: Identification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in humans might prove essential for the breakthrough in the efforts against pharmacoresistance in epilepsy. Recently, we described a new model of generalized convulsive SE induced with orphenadrine (ORPH) in rats with unique characteristics [5]. The current study was aimed at assessing the efficacy of a new generation antiepileptic drugs (AEDs) and some of the experimental agents in suppressing ORPH-evoked seizures in rats. Methods: ORPH was administered intraperitoneally (ip) in the dose of 80 mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt SE, as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings. Results: ORPH induced seizures in 100% of animals at a dose of 80 mg/kg, associated with low mortality and good behavioural outcome. Among new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide did not affect the seizure incidence. Among the experimental drugs, only dizocilpine, the non-competitive NMDA antagonist, dose-dependently affected the occurrence of the SE (p < 0.001). However, CGP-39551 competitive NMDA antagonist, the same as scopolamine and mecamylamine (muscarinic and nictotinic receptors antagonists, respectively) showed no effect. Conclusions: Based on the above findings, one may speculate that NMDA activation is partly involved in the proconvulsant activity of orphenadrine but may not be the primary pathomechanism. ORPH-induced seizures may provide an interesting option for studying novel targets for pharmacological interventions in status epilepticus. ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Introduction Among the main challenges in modern epileptology is the discovery of new therapies effective in refractory epilepsy and modulating the natural course of the disease [1]. There is increasing awareness that currently available drugs have not fully met expectations as the proportion of patients with uncontrolled seizures reaches up to 30%, which does not differ from historical

* Corresponding author. E-mail address: [email protected] (K. Rejdak).

data [2]. In particular, refractory status epilepticus represents a clinical condition with serious consequences and the mechanisms of drug resistance in the established SE are only partly understood. Moreover, there has been little progress in pharmacotherapy of SE as only old and established therapies like benzodiazepines, phenytoin and anaesthetic drugs remain a mainstay of management. New generation drugs have not been widely used in that direction and there is no good clinical evidence supporting their efficacy [3]. It is generally agreed that identification of new molecular targets for pharmacological intervention, as well as the new models recapitulating different aspects of pathophysiology of

http://dx.doi.org/10.1016/j.pharep.2013.12.007 1734-1140/ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Please cite this article in press as: Rejdak K, et al. Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.007

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PHAREP-68; No. of Pages 5 K. Rejdak et al. / Pharmacological Reports xxx (2014) xxx–xxx

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status epilepticus in humans, might prove essential to address the above unsolved problems [4]. Recently, we described a new model of generalized convulsive status epilepticus with interesting and unique characteristics [5]. We found that among conventional AEDs only phenobarbital, valproate and diazepam, but not carbamazepine, ethosuximide and phenytoin, dose-dependently diminished the incidence of seizures in rats, which corresponds with treatment effects observed in the clinical practice of human status epilepticus. The current study was aimed at assessing the efficacy of a new generation AEDs, and some of the experimental agents in suppressing ORPH-evoked seizures in rats. Materials and methods Animals Male Wistar rats weighing 250–300 g were used. The animals were housed under strictly controlled laboratory conditions (ambient temperature 22–23 8C, relative humidity about 45– 55%, 12/12 h light/dark cycle, light on at 6:00; chow pellets and tap water continuously available). The assignment of rats to the experimental groups was random. The experimental protocol was approved by the II Committee on Animal Research and Ethics in Lublin and all the procedures were in strict compliance with the European Communities Council Directive of 24 November 1986 (86/609/EEC). Effects of antiepileptic drugs on ORPH-induced seizures The experimental procedure was used as described recently [5]. ORPH (N,N-dimethyl-2-(2-methylbenzhydryloxy)ethylamine hydrochloride; Fluka) was dissolved in saline and administered in a dose of 80 mg/kg ip ORPH, injected with respective latency after antiepileptic drugs administration. The study groups consisted of 5–20 animals as presented in Table 1. The latency to first seizure, the number of seizure episodes and the duration of overt status epilepticus, as well as the incidence of deaths were scored but the primary outcome measure for studying the drug effects was the occurrence of the fully manifested status epilepticus lasting at least 0.5 h in animals.

The following drugs were used: felbamate (Wallace Laboratories, Cranbury, NJ, USA), lamotrigine (Lamictal, GlaxoSmithKline, Duchnice, Poland), levetiracetam (Keppra, UCB, Belgium), progabide (Gabrene, Sanofi-Synthelabo, France), topiramate (Topamax, Janssen-Cilag, Belgium), dizocilpine (Sigma), CGP-39551 (R&D Systems Europe, Abingdon, UK), riluzole (Rilutek, Sanofi-Aventis, France), scopolamine (Sigma), mecamylamine (Sigma). Dizocilpine, CGP-39551, scopolamine and mecamylamine were dissolved in water. All other drugs were suspended in a 1% solution of Tween 80 (Sigma). In control experiments, rats were injected with saline at the volumes used in the respective drug sessions. Route of i.p. administration, pre-treatment times and doses before testing of the AEDs were based on information about their biological activity from the literature and our pilot studies. All experimental procedures on animals were performed at times corresponding to the peak of maximum anticonvulsant effects of tested AEDs [6– 17]. Surgery and electroencephalographic recording procedure After performing the behavioural assessment of drug effects, additional animals were subjected to EEG recording in order to verify the drug effects on ORPH induced seizures. The rats were anaesthetized with intraperitoneal (ip) administration of chloral hydrate (360 mg/kg) and bipolar electrodes were implanted in the basolateral amygdala and hippocampus at the following coordinates (in mm, respective to bregma) derived from the atlas of Paxinos and Watson [11] (the basolateral amygdala — anterior/ posterior (AP) – 2.3, lateral (L) – 4.8, and ventral (V) – 8.5; hippocampus — AP – 4.5, L – 3.3, V – 2.9. Each electrode consisted of 2 twisted Teflon-coated 0.2 mm diameter stainless steel wires separated by 0.5 mm at the tip. Surface recordings were led from jeweller screws positioned bilaterally over the cortex (AP +2.2, L 2.0). One screw, placed over the left parietal cortex, served as the indifferent reference electrode; two others were screwed into the skull to anchor the electrode assembly. Both bipolar and reference electrodes were connected to miniature female plugs, and the assembly was fixed on the skull with dental acrylic cement. After electrode implantation, the animals were treated with gentamycin for 3 days to prevent infection. The rats were given at least a 10-day

Table 1 Effects of drugs on orphenadrine-induced seizures. Treatment (pretreatment time) Saline New-generation antiepileptic drugs Felbamate (60 min) Levetiracetam (60 min) Lamotrigine (120 min) Progabide (30 min) Topiramate (45 min) Experimental drugs Dizocilpine (30 min)

CGP-39551 (30 min) Riluzole (15 min) Scopolamine (30 min) Mecamylamine (15 min)

Dose (mg/kg)

100 500 1000 20 100 200 100

0.05 0.1 0.5 1.0 10 12 10 5

Number of animals with seizures/total number of animals

ED50 (mg/kg) (95% confidence limits)

20/20

ND

5/5 5/5 5/5 5/5 6/6 6/6 6/6

ND ND

4/6 3/6** 1/6*** 0/3*** 5/5 5/6 5/5 5/5

0.10 (0.03–0.30)

ND ND ND

ND ND ND ND

ND: not determined; ED: effective dose. Orphenadrine was administered at the dose of 80 mg/kg, ip. * p < 0.05; respective drug versus saline. ** p < 0.01; respective drug versus saline. *** p < 0.001; respective drug versus saline.

Please cite this article in press as: Rejdak K, et al. Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.007

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recovery period before the experiments started. For recording the electroencephalographic (EEG) signals, awake, freely moving animals were individually placed in a transparent box and they were allowed 15 min habituation period prior to the recording setup. QP511 amplifier (Grass Technologies, West Warwick, MI, USA) was used for amplification (about 2000 times) and initial filtration (0.1–100 Hz). The resulting signal was digitized (at 100 Hz), filtered (low-pass filter set at 10 Hz), stored and analyzed using PowerLab/8SP system (ADInstruments Ltd., Chalgrove, UK). The control EEG sample was recorded before study drug and ORPH administration, and was used as a baseline value to compare all subsequent EEG recordings. ORPH was administered in a dose of 80 mg/kg ip in the same time sequence after respective antiepileptic drugs, as described above. Data analysis and statistics The CD50 value (50% convulsive dose), ED50 (50% protective dose) and their 95% confidence limits were calculated by computer software implementing the method of Litchfield and Wilcoxon [18]. Fisher’s exact probability test was used to compare the frequencies of seizures between drug-treated groups as compared

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to vehicle. In all calculations, p < 0.05 was considered as statistically significant. Results Behavioural and EEG characteristics of the ORPH seizures Systemic administration of ORPH in a dose of 80 mg/kg ip produced seizures in 100% adult rats (Table 1). The characteristics of the seizures were consistent with a recent description [5]. Similarly, the mortality rate was very low and typically SE was associated with 15% mortality. Animals recovering from status epilepticus appeared relatively normal, returning to full motor activity within subsequent several hours. Consistent with a previous description [5] free of drug, baseline EEG recordings displayed spells of desynchronized activity interrupted by periods of theta rhythm (typically accompanied by motor activity); the amplitude was higher than that of beta waves in the cortical leads. Administration of ORPH induced a change of EEG pattern (Fig. 1) There were intermittent synchronized generalized spikes from CTX and BLA and continuous high amplitude spike discharges from HIP at 20 min. This transformed

Fig. 1. Representative EEG traces recorded from depth electrodes in hippocampus (HIP), basolateral amygdale (BLA) and cortex (CTX) at different time points from orphenadrine (ORPH)-treated (80 mg/kg ip) rat. At 20 min there were intermittent synchronized generalized spikes from CTX and BLA and continuous high amplitude spike discharges from HIP. This transformed into bursts of high voltage generalized spike and polyspike complexes from 3 regions at 45 and 60 min as the evidence of overt generalized status epilepticus. The epileptic activity subsequently resolved over several hours starting from approximately 2 h. At 24 h after ORPH, EEG recordings were indistinguishable from the pre-drug baseline activity.

Please cite this article in press as: Rejdak K, et al. Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.007

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Fig. 2. Representative traces of intracranial EEGs from orphenadrine (ORPH)-treated rat in order to demonstrate the effects of dizocilpine (1 mg/kg ip) given 30 min before ORPH (80 mg/kg ip). BLA traces were free of any discharges while CTX showed only mildly elevated amplitude of fast activity at 45, 60 min. Similarly, HIP traces displayed fast activity with also increased amplitude but without any bursts of polyspike discharges at 45 and 60 min, which subsequently normalized at 120 min. Dizocilpine induced slowing of the EEG baseline activity, as evidenced 30 min after drug administration and just before ORPH.

into bursts of high voltage generalized spike and polyspike complexes from 3 regions at 45 and 60 min as the evidence of overt generalized SE. The epileptic activity subsequently resolved over several hours starting from approximately 2 h. At 24 h after ORPH, EEG recordings were indistinguishable from the pre-drug baseline activity. Effect of antiepileptic drugs on ORPH-induced seizures The effects of new-generation and experimental antiepileptic drugs on ORPH-evoked seizures in experimental animals were studied. None of the new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide, influenced the seizure activity based on the behavioural observation, including the latency to first seizure, the number of seizure episodes and the duration of overt status epilepticus (Table 1) as well as on EEG recordings (data not shown). Among the studied experimental drugs, CGP-39551 and riluzole was not effective, the same as anticholinergic drugs: scopolamine and mecamylamine based on all behavioural and EEG variables. In contrast, dizocilpine dose-dependently affected the occurrence the epileptic seizures with calculated ED50 = 0.10 (0.03–0.30) (Table 1), which was supported by EEG recordings (Fig. 2). Dizocilpine given in a dose of 1.0 mg/kg suppressed completely the behavioural seizures and was associated with clear suppression of epileptic discharges on EEG. BLA traces were free of any discharges while CTX showed only a mildly elevated amplitude of fast activity at 45, 60 min. Similarly, HIP traces displayed fast activity with also increased amplitude but without any bursts of polyspike discharges at 45 and 60 min, which subsequently normalized at 120 min. Discussion We provide here further evaluation of a new model of generalized convulsive status epilepticus induced by administra-

tion of ORPH in adult rats [5]. In the current project, we focused on the effects of different pharmacological agents on seizure activity as this might shed more light on the mechanisms underlying the orphenadrine induced convulsions. Interestingly, none of the studied new generation drugs: levetiracetam, topiramate, lamotrigine, progabide, and felbamate with well known antiseizure activity in different types of seizures, influenced the incidence of status epilepticus in our experiments. Among the experimental agents, which are not being used in clinical practice, dizocilpine, a non-competitive antagonist of NMDA receptors was effective in suppressing ORPH-induced seizures. However, it was surprising to find that other antiglutamatergic agents, e.g. CGP-39551, felbamate and riluzole, were ineffective. Similarly, scopolamine and mecamylamine did not affect seizure frequency and intensity in ORPH treated rats. Based on the above findings, the mechanism how ORPH induces seizures in rats remains elusive and seems complex. The drug in therapeutic, relatively low doses exert antagonistic activity against muscarinic and histaminic receptors, which was the basis for its clinical usage in Parkinson’s disease, pain and as a myorelaxant in neuromuscular disorders [12,19–21]. In addition, ORPH acts also as a ‘mild’, non-competitive antagonist of NMDA receptors by binding to the phencyclidine site [8] and prevented the neurotoxicity induced by kainic acid [14] and 3-nitropropionic acid [22] in rats, but when used in low, 10–30 mg/kg dose range. One of the newer studies demonstrated another important mechanism consisting of concentration, voltage, and frequency-dependent blockade of voltage gated skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels [23]. All the above mechanisms are typically anticonvulsant and the activity of ORPH in our model seems paradoxical. Indeed, the dose of 80 mg/kg used in the presented study is high and may exert different, most likely, opposite effects. Exaggerated inhibition of sodium currents by high ORPH doses would induce proconvulsive and proarrhythmic effects by the block of Nav1.1 and Nav1.5, especially because the drug displays a relatively high

Please cite this article in press as: Rejdak K, et al. Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.007

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affinity to resting channels [23]. However, lamotrigine, as a drug with predominant activity on sodium channels was completely ineffective, which corresponds with previous observations regarding carbamazepine and phenytoin [5], making the sodium channel activation by ORPH rather unlikely. Similarly, there is a possibility that high doses of ORPH display paradoxical cholinomimetic activity with increased release of acetylcholine in the CNS with secondary activation of receptors, as happens in the pilocarpine model [15]. However, scopolamine was demonstrated not to affect the seizure susceptibility acting through the anti-muscarinic mechanism. Similarly, mecamylamine, as a voltage dependent non-competitive antagonist at nicotinic receptors, did not affect seizure response after ORPH. The above observations make cholinergic effect less likely as a mechanism responsible for seizure induction by ORPH. It is interesting that modulation of the neural transmission through binding to the synaptic vesicle protein 2A by levetiracetam also did not prevent the seizure onset in our model. The demonstrated efficacy of dizocilpine might point to the important anti-glutamatergic activity against ORPH-induced seizures. Dizocilpine binds inside the ion channel of the receptor at the phencyclidine binding site and thus prevents the flow of ions, including an influx of calcium (Ca2+), through the channel. However, other drugs, like felbamate, riluzole and CGP 39551, did not display any activity. This is consistent with previous observations where dizocilpine was more effective in seizure suppression in other models of refractory seizures, compared to competitive antagonists [24,25]. One might speculate that this could result from subtle differences in the mechanisms of the above drugs on the glutamatergic system, in comparison to dizocilpine [26]. Interestingly, topiramate, which blocks a-amino3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, also did not work. Based on the above finding one may speculate that NMDA activation is at least partly involved in the proconvulsant activity of ORPH, but may not be a primary pathomechanism. Bearing in mind that seizure triggers and protection mechanisms are 2 mechanistically independent sets of events, other potential mechanisms for consideration include the increase of dopaminergic or adrenergic transmission but there is much less data to support it [27]. Summing up, ORPH-induced convulsive status epilepticus in rats may provide an interesting option for studying novel targets for pharmacological interventions as a strategy of revealing the mechanisms of refractory seizures and SE. The new model displays some unique characteristics compared to those currently in used. It is associated with low mortality and easiness to repeat SE episodes for further behavioural follow-up, does not induce drug related toxicity with no apparent histopathological changes by which it differs from pilocarpine and kainate SE models. It also facilitates the study of long-term consequences of seizures, which differs from known acute seizure models, such as MES, MEST, PTZ, picrotoxin and bicuculline models. Based on the drug effect study it seems that ORPH engages complex pathogenic mechanism that might resemble the pathophysiology of human refractory epilepsy of ‘‘unknown etiology’’, which is still an unresolved clinical problem in modern epileptology. Conflict of interest The authors declare they have no conflict of interest.

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Please cite this article in press as: Rejdak K, et al. Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2013.12.007

Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine.

Identification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in hu...
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