Effects of Verapamil, Cinnarizine and Memantine on Maximal Electroshock, Picrotoxin, and Pilocarpine-Induced Seizure Models in Albino Mice

Central Journal of Neurological Disorders & Stroke

Research Article *Corresponding author Ahmed A Abdelsameea, Department of Pharmacology, Faculty of Medicine, Zagazig University, Effects of Verapamil, Egypt, Email: Submitted: 27 January 2015 Cinnarizine and Memantine Accepted: 23 February 2015 Published: 25 February 2015 Copyright on Maximal Electroshock, © 2015 Abdelsameea et al. Picrotoxin, and Pilocarpine- OPEN ACCESS Keywords • Memantine Induced Seizure Models in • Median current strength • Pilocarpine Albino Mice • Picrotoxin Moustafa AA, Shabaeik HA, Abdelsameea AA*, Hanafy HH Department of Pharmacology, Faculty of Medicine, Zagazig University, Egypt

Abstract Verapamil and cinnarizine block L and T-type calcium channels respectively. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Ca2+-channel blockers (CCBs) and memantine, each decrease Ca2+ entry to the neuronal cell by different mechanisms. Inhibition of the inward flow of calcium ions could depress the epileptic depolarization of neurons. The aim of the present work is to assess effects of verapamil, cinnarizine and memantine on experimentally induced convulsions in albino mice. Methods: Maximal electroshock, picrotoxin and pilocarpine-induced seizure models were utilized. Results: Verapamil decreased the mean latency period in pilocarpine model. Cinnarizine increased the mean latency period and partially protected from convulsions in picrotoxin model. The drug completely prevented the occurrence of convulsions in pilocarpine model. Memantine increased the electroconvulsive threshold in maximal electroshock model. In pilocarpine model, the mean latency period was increased while, decreased in picrotoxin model after administration of memantine. Conclusion: Verapamil potentiated seizure occurrence in pilocarpine model. Cinnarizine protected from convulsions, partially in picrotoxin and completely in pilocarpine models. Memantine had anticonvulsant effect in maximal electroshock and pilocarpine models but, potentiated the occurrence of seizures in picrotoxin model.

INTRODUCTION an increase in the intracellular calcium concentrations [2]. An important characteristic of all CCBs is their ability to inhibit Epilepsy is the commonest neurological disorder, characterized by spontaneous recurrent seizures, triggered by depolarization of neurons [3,4] has shown the presence of abnormal electrical activity in the brain cortex. The involvement the inward flow of calcium ions. CCBs depress the epileptic of hyperexcitable neurons links the pathogenesis of epilepsy brain barrier. This gives important evidence for the presence of and the generation of synchronized neuronal activity with an centralspecific effectsbinding of sites CCBs. of CCBs that enable them to cross the blood imbalance between inhibitory GABA-mediated and excitatory

(glutamate-mediated) neurotransmission [1]. anticonvulsive properties in rats and mice. Verapamil, a voltage- Overwhelming evidence indicates that calcium ions (Ca2+) gated [5],calcium reported channel thatblocker, cinnarizine has been occasionally and flunarizine reported have to play an essential role in the pathophysiology of epilepsy. During have some effect on reducing seizure frequency in drug-resistant seizures one can observe a decrease in the extracellular calcium epilepsy or status epilepticus [6]. Cinnarizine is a drug derivative concentrations prior to onset of seizure activity followed by of piperazine and is characterized as an antihistamine and a

Cite this article: Moustafa AA, Shabaeik HA, Abdelsameea AA, Hanafy HH (2015) Effects of Verapamil, Cinnarizine and Memantine on Maximal Electroshock, Picrotoxin, and Pilocarpine-Induced Seizure Models in Albino Mice. J Neurol Disord Stroke 3(1): 1096. Abdelsameea et al. (2015) Email: Central

T-type calcium channel blocker [7]. Cinnarizine is predominantly Experimental groups used to treat nausea and vomiting associated with motion Control group: mice were injected with distilled water then sickness [8]. CS50 was recorded. NMDA receptors are highly permeable to Ca2+ as well as to Na+ and K+ [9]. NMDA receptor antagonists have been shown to Verapamil group: mice were injected with verapamil at doses of (5, 10, 20 mg/kg), 30 min later CS for each dose was have antiepileptic effects in both clinical and preclinical studies. 50 There is some evidence that conventional antiepileptic drugs recorded [13]. may also affect NMDA receptor function [10]. Among the low- Cinnarizine group: Mice were injected with cinnarizine at

dose of 30 mg/kg, 45 min CS50 was recorded [3]. 5-aminoadamantane) was approved for treatment of Alzheimer dementiaaffinity NMDA. Memantine receptor exhibits antagonists, anticonvulsant memantine effects (1,3-dimethyl- against Memantine group: mice were injected with memantine at doses of (5, 10, 20 mg/kg), 60 min later CS for each dose of generalized tonic–clonic seizures [11]. 50 memantine was recorded [14]. The aim of the present work is to assess the effects of verapamil, cinnarizine and memantine on maximal electroshock, Induction of convulsion by picrotoxin picrotoxin and pilocarpine-induced seizure models in albino Picrotoxin (5 mg/kg) was administrated and the animals mice. MATERIALS AND METHODS and hind limb with falling on back sometimes with spasm of neck muscleswere observed (clonic-tonic until occurrence seizures) [15].of extension-flexion Latency period of of forelimb seizure Animals and number of convulsed /all number of animals in each group were recorded. Adult male albino mice (weighing 22–26 g) were obtained from National Research Laboratory, Cairo, Egypt and kept in colony Experimental groups cages with free access to food and tap water, under standardized housing conditions (natural light-dark cycle, temperature of 22 Control group (n=9), mice were injected with distilled water ± 1°C). After 7 days of adaptation to laboratory conditions, the then picrotoxin. animals were randomly assigned to experimental groups. Each Verapamil group includes three subgroups (9 mice/each), mouse was used only once and all tests were performed between mice were injected with verapamil 5, 10 and 20mg/kg followed 08.00 and 15.00 h. All experimental protocols were approved by 30min later by picrotoxin. the Ethics Committee of Zagazig University. Cinnarizine group (n=9), mice were injected with cinnarizine Drugs (30 mg/kg) followed 45 min later by picrotoxin.

Verapamil powder {Sigma Co., Egypt}, cinnarizine powder Memantine group includes three subgroups ((9 mice/ {Adco Co., Egypt}, memantine: powder {Adwia Co., Egypt}, each)), mice were injected with memantine (5, 10 and 20mg/kg) Picrotoxin: powder {Sigma Co., Egypt}, Pilocarpine: powder followed 60 min later by picrotoxin. {Merk Co., Germany}, Lithium chloride: powder {Sigma Co., Egypt}. All drugs were dissolved in distilled water just before Pilocarpine-induced sustained epilepsy injection. All drugs were injected intraperitoneal (i.p). Lithium chloride 127.17 mg/kg; i.p, was injected 24 Maximal Electroshock Seizure Threshold test (MEST- pilocarpine (350mg/kg, i.p.) administration, animals exhibited test) hoursintense before salivation, pilocarpine. immobility, Briefly, facial within automatisms, the first 15 and min headafter Electroconvulsions were produced by means of an alternating tremors. After 15–60 min, animals show increased head tremors current (0.2 s stimulus duration, 50 Hz, maximum stimulation with vigorous mastication, forelimb clonus, and falling with voltage of 500 V) delivered via ear-clip electrodes by a Rodent convulsive tonus of the hind limbs. Once initiated, these behaviors Shocker Generator (Type 221, Hugo Sachs Elektronik, Freiburg, occurred every 2–5 min and developed into sustained epilepsy Germany). The criterion for the occurrence of seizure activity [16]. was the tonic hind limb extension. To evaluate the threshold all Number of animals used in each group were recorded. for maximal electroconvulsions, at least four groups of mice, Latency period to first seizures and number of convulsed / consisting of eight animals per group, were challenged with Experimental groups electroshocks of various intensities to yield 10–30, 30–50, 50–70, Control group (n=9), mice were injected with distilled water and 70–90% of animals with seizures. Then, a current intensity– then pilocarpine. response relationship curve was constructed, according to a log- probit method by [12], from which a median current strength Verapamil group, includes three subgroups (9 mice/each), mice were injected with verapamil (5, 10 and 20mg/kg) followed (CS50 in mA) was calculated. Each CS50 value represents the current intensity required to induce tonic hind limb extension in 30min later by pilocarpine. 50% of the mice challenged. After administration of a single dose Cinnarizine group (n=9) mice were injected with cinnarizine of each drug to 4 groups of animals, the mice were subjected to (30 mg/kg) followed 45 min later by pilocarpine. electroconvulsions (each group with a constant current intensity) and the threshold for maximal electroconvulsions was recorded. Memantine group includes three subgroups (9 mice/

J Neurol Disord Stroke 3(1): 1096 (2015) 2/5 Abdelsameea et al. (2015) Email: Central each), mice were injected with memantine (5, 10 and 20mg/kg) Table 2: Effects of verapamil, cinnarizine, and memantine on mean followed 60 min later by pilocarpine. latency period, number of convulsed to total number of mice tested and protection % in picrotoxin-induced convulsions in mice. Statistical analysis Mean latency No of convulsed Protec- Treatment mg/kg period(min) mice/total number The CS50 tion % calculated by computer log-probit analysis according to [12]. ±S.E.M. of mice values with their 95% confidence limits were Picrotoxin 5 14.7±1.5A 9/9 0% Verapamil 5 + picro- transformed to standard error of the means (S.E.M.s) as described 13.2±2.1A 9/9 0% previouslySubsequently, [17]. the Statistical respective analysis 95% of confidence data in all limitsmodels were was toxin 5 Verapamil 10 + picro- performed with one-way ANOVA followed by the post hoc Tukey- 12.8±1.2A 9/9 0% Kramer test for multiple comparisons. Differences among values toxin 5 Verapamil 20 + picro- 12.7±1.1A 9/9 0% toxin 5 Cinnarizine 30 mg/kg + wereRESULTS considered statistically significant if p < 0.05. 18.4±3.8* 6/9 33.3% Picrotoxin5 Verapamil (5, 10 and 20mg/kg, i.p.) and cinnarizine (30mg/ Memantine 5 + picro- 13.3±5.7A 9/9 0% toxin 5 electroconvulsive threshold (Table 1). In contrast, administration Memantine 10 + picro- kg, i.p.) administration produced non-significant increases in the 6.3±0.5# 9/9 0% of memantine (5, 10 and 20mg/kg, i.p.) increased, in a dose- toxin 5 dependent manner, the electroconvulsive threshold in MEST test. Memantine 20 + picro- 10.3±1.5# 9/9 0% toxin 5

CS50 from 8.3 to 128.2 mA. Results are presented as mean latency period (min) of convulsion. In this case, administration of 20 mg/kg significantly elevated the Statistical analysis of data was performed with one-way ANOVA Administration of verapamil (5, 10 and 20mg/kg, i.p.) • followed by the post hoc Tukey-Kramer test for multiple comparisons. • picrotoxin-induced convulsions. Cinnarizine (administered produced non-significant changes in mean latency period in controlDifferences and amongother treatment values were groups. considered statistically significant if p < 0.05. *Significantly increased while, # significantly decreased versus from 14.7 to 18.4 min and protected 33.3% of mice from S.E.M.: standard error of the mean of CS50. picrotoxin-induced30mg/kg, i.p.) significantly convulsions. increased In contrast,the mean administrationlatency period • of memantine (5, 10 and 20mg/kg, i.p.) decreased the mean 13 to 8.5 min. In contrast, cinnarizine administration (30mg/kg, i.p.) completely protected all mice from convulsions. Memantine kg, reduced from 14.7 to 6.3 and 10.3 min respectively (Table 2). (administered 5, 10 and 20mg/kg, i.p.) produced dose-dependent latency period which were significant only with 10 and 20 mg/ Verapamil administration (5, 10 and 20mg/kg, i.p.) decreased with the highest dose from 13 to 27.5 min (Table 3). the mean latency period in pilocarpine-induced sustained increase in the mean latency period which was significant only DISCUSSION Epilepsy is characterized by spontaneous recurrent seizures epilepsy which was significant only with the highest dose from Table 1: Effects of verapamil, cinnarizine, and memantine on the in which electrical activity in particular brain regions becomes threshold of maximal electroconvulsions in mice in MEST test. over-excitable. As different brain regions interact in cycle, one

Treatment mg/kg CS50 mA (confidence limits)± S.E.M. excites the next until they become locked into a self-propagating Control 8.3 (6.36-9.45) ±0.91 loop [18]. Electroconvulsive seizures are particularly sensitive to Verapamil 5 8.9 (8.4-9.5) ±0.62 drugs blocking sodium channels [19]. The results of the present study showed that, administration of verapamil in different

10 9.6 (6.51-11.7) ±1.29 doses did not affect the threshold of maximal electroconvulsions 20 9.2 (6.3-10.25) ±3.04 in MEST test (Table 1). These results are in agreement with [13] Cinnarizine 30 10.2 (7.29-12.31) ±1.25 who concluded that; verapamil (up to 20 mg/kg) did not affect Memantine 5 10.9 (7.2-13.2) ±1.52 the electroconvulsive threshold in mice. 10 11.96 (8.18-14.86) ±1.7 The present study also showed that administration of 20 128.2 (124.9-132.8) ±17.27* verapamil, in different doses did not change the mean latency period in picrotoxin-induced convulsion in mice (Table 2). In Results are presented as median current strengths (CS in mA; with 50 pilocarpine induced-sustained epilepsy, verapamil (20 mg/ • hind limb extension in 50% of animals tested. The CS50 values were 95%calculated confidence using the limits log-probit in parentheses) method [12], required followed to by produce the method tonic [20]kg; i.p.) who produced concluded significant that, high decrease doses inof mean verapamil latency produced period Statistical analysis of data was performed with one-way ANOVA spontaneousto first seizure tonic-clonic (Table 3). seizures Our results and could also be with parallel [21], withwho transformingfollowed by the 95% post confidence hoc Tukey-Kramer limits into test S.E.M. for multiple[17]. comparisons found that Cromakalim ( k+ channel opener) counteracts the • epileptiform activity elicited by diltiazem and verapamil in

groups.Differences among values were considered statistically significant if S.E.M.:p < 0.05. standard *Significantly error of increased the mean versus of CS control. and other treatment changes in the activation of potassium currents [22]. This effect 50 rats. In fact, modifications of the cytosolic+2 calcium+ level lead to MEST: Maximal electroshock seizure threshold. could be attributed to the role of Ca -activated K -channel which •

J Neurol Disord Stroke 3(1): 1096 (2015) 3/5 Abdelsameea et al. (2015) Email: Central share for the resting transmembrane potential, so decrease Also, the drug decreased sodium inward current and antagonized cytosolic Ca+2 decrease the activity of these channels. [23] found bursts induced by strychnine, tetanus toxin and picrotoxin, in that verapamil failed to improve seizure control in dogs with mouse spinal cord cultures [27]. Our results demonstrated that, phenobarbital-resistant epilepsy. In contrary, [24] found that, memantine decreased the mean latency period in picrotoxin- verapamil, at doses of 20 and 40 mg/kg, decreased mortality and induced seizures (Table 2). This effect could be explained by severity of seizures on Dichlorvos-induced seizures in mice. The inhibition of NMDA-evoked GABA release [28]. A case report latter effect may be attributed to difference in model and the use described that a 72-year-old Caucasian woman, taking memantine of high doses of the drug. for Alzheimer’s disease, was admitted to the hospital with new- onset, generalized tonic–clonic seizure. After memantine was The results of our study showed that, administration discontinued, the disturbance resolved and increased D-waves of cinnarizine did not affect the threshold of maximal on the patient’s EEG were improved Memantine, at dose of 20 electroconvulsions in MEST test (Table 1). The drug increased the mean latency period in picrotoxin-induced convulsion pilocarpine-induced sustained epilepsy (Table 3). Pilocarpine and provided 33.3% protection (Table 2) and prevented the induced-statusmg/kg, increased epilepticus the mean model latency is period initiated to firstvia muscarinic seizure in occurrence of seizures in pilocarpine-induced sustained epilepsy receptors and further mediated via NMDA receptors [29] which and provided 100% protection (Table 3). These results cope were blocked with memantine. had anticonvulsant effects against Bicuculline-induced seizures. Also, CONCLUSION [3]with demonstrated the findings of that, [25] cinnarizine who concluded had anticonvulsant that cinnarizine action Although, each of verapamil, cinnarizine, and memantine in PTZ (pentylenetetrazole)-induced seizures. [26] mentioned that, the possible mechanism of the anticonvulsant action of utilized experimental models of convulsion were different. Block cinnarizine is the potent antagonism of disturbances in neuronal blocked calcium influx into neurons their effects on the three calcium conductance, through blocking of T- type Ca+2 channel, of L-type calcium channels by verapamil had no anticonvulsant which is implicated in the generation and propagation of seizure effect even had proconvulsant effect in pilocarpine model. Block of activity. T-type calcium channels by cinnarizine had anticonvulsant effect in picrotoxin and pilocarpine models. Block of NMDA receptor by The results of the present study showed that administration memantine had anticonvulsant effect in maximal electroshock of memantine at a dose of 20 mg/kg; increased the threshold of and pilocarpine models but, potentiated the occurrence of convulsion in picrotoxin model. Further experimental and coincide with the studies of Brian et al. 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Cite this article Moustafa AA, Shabaeik HA, Abdelsameea AA, Hanafy HH (2015) Effects of Verapamil, Cinnarizine and Memantine on Maximal Electroshock, Picrotoxin, and Pilocarpine-Induced Seizure Models in Albino Mice. J Neurol Disord Stroke 3(1): 1096.

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