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Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid
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Research Report
Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid$ Fridha Villalpando-Vargas1, Laura Medina-Cejan,1 Laboratory of Neurophysiology and Neurochemistry, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Jalisco, Mexico
art i cle i nfo
ab st rac t
Article history:
The long-term effects of status epilepticus (SE) include severe clinical conditions that result
Accepted 15 July 2015
in disorders of various organs and systems as well as neurological damage that could lead
Keywords:
anticonvulsive effect was evaluated in the pentylenetetrazole model of SE. However,
Kainic acid
efforts to clearly determine the anticonvulsive effect of sparteine have not been made
Pentylenetetrazole
previously. For this reason, we consider it important to study the anticonvulsant effects of
Pilocarpine
sparteine at the level of behavior and EEG activity in three different SE models. The
Seizures
animals of the control groups, which received intraperitoneal pentylenetetrazole (90 mg/
Sparteine
kg), kainic acid (9 mg/kg) or pilocarpine (370 mg/kg), exhibited convulsive behavior and
Status epilepticus
epileptiform activity. After sparteine pretreatment (13 mg/kg, administered 30 min before
to death. Sparteine is a quinolizidine alkaloid synthesized from most Lupine species, and its
the convulsive drug), the animals administered pentylenetetrazole and pilocarpine exhibited reduced mortality rates compared with the corresponding control groups, while the animals administered kainic acid exhibited a delayed onset of convulsive behavior and decreased seizure duration compared with the corresponding control group. In the three models of SE, a significant reduction in the amplitude and frequency of discharge trains was observed. These results support the anticonvulsant effect of low doses of sparteine and allow us to direct our efforts to other new anticonvulsant strategies for seizure treatment. However, it is necessary to perform more experiments to determine the precise mechanism through which sparteine produces an anticonvulsant effect at this concentration. & 2015 Published by Elsevier B.V.
☆
Grant sponsor: CONACYT. Grant number: 106179. Correspondence to: Laboratorio de Neurofisiología y Neuroquímica, Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Camino Ing. R. Padilla Sánchez 2100, Las Agujas, Nextipac, Zapopan, Jalisco CP 45110, Mexico. Fax:þ52 33 37771191. E-mail addresses: [email protected], [email protected] (L. Medina-Ceja). 1 FVV and LMC contributed equally to this work. n
http://dx.doi.org/10.1016/j.brainres.2015.07.017 0006-8993/& 2015 Published by Elsevier B.V.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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1.
Introduction
Epilepsy is a neurological disorder that affects 50 million people worldwide. Antiepileptic drugs (AEDs) are effective in 70% of patients, although in developing countries, this percentage drops drastically (Newton and Garcia, 2012). Status epilepticus (SE) (Sanchez-Fernandez et al., 2014) is defined as a prolonged seizure or recurrent seizures without full recovery between them, and in the literature, a seizure lasting longer than 30 min is classified as SE (McCandless, 2012). The long-lasting effects of SE include severe clinical conditions that result from disorders of various organs and systems as well as neurological damage that can lead to death (Jenssen et al., 2006). Models of SE provide good tools to study the cellular and molecular mechanisms of this pathological condition. Pilocarpine (Pilo, a non-selective muscarinic receptor agonist) and kainic acid (KA; an agonist of kainate-type glutamate receptors) models induce electroencephalographic (EEG) discharges in limbic structures with secondary generalization (Turski et al., 1983, 1984; Miller et al., 1990; Sampieri et al., 2011), while the pentylenetetrazole (PTZ) model induces primary generalized discharges (Erdogan et al., 2014). PTZ acts as a noncompetitive agonist of GABAA receptors by binding at the t-butylbicyclophosphorothionate site (Olsen, 1981; Ramanjaneyulu and Ticku, 1984; Hansen et al., 2004). Sparteine (Sp) is a quinolizidine alkaloid (QA) synthesized from most Lupine species (Wink, 1992, 1993a). In the nervous system, Sp inhibits ganglionic transmission (Schmitt, 1980; Yovo et al., 1984), activates acetylcholine receptors (nicotinic and muscarinic (mAChRs)) and inhibits Naþ and Kþ channels (Kinghorn and Balandrín, 1984; Piéri and Kirkiacharian, 1986; Wink, 1987, 1992, 1993a, 1993b; Schmeller et al., 1994; Körper et al., 1998). Subcutaneous administration of Sp (25 mg/kg) in neonatal rats decreases the mRNA of the m1–m3 subtypes of mAChRs and increases m7 mRNA between 7 and 14 days postadministration (Flores-Soto et al., 2006). The anticonvulsive effect of Sp was evaluated in the PTZ model of SE, and intraperitoneal (i.p.) administration of Sp (13 mg/kg) 30 min before PTZ (125 mg/kg, i.p.) delayed the onset of convulsive behavior and increased the survival period (Pothier et al., 1998). However, there have not been previous efforts to clearly determine the anticonvulsive effects of Sp. For this reason, we consider important to study the anticonvulsant effects of Sp on acute seizures at the level of behavior and EEG activity in three different SE models. To accomplish this objective, convulsive behavior and the survival period as well as the amplitude, frequency, duration and latency of discharge trains were analyzed after Sp administration. Furthermore, the protocol applied allowed us to evaluate behavior and EEG activity before and after drugs administration.
2.
Results
2.1.
Behavior analysis
During basal analysis (30 min), normal behavior was observed in every group, and motor impairment secondary to the
surgical procedure was discarded. Normal behavior was characterized as chewing and search and grooming movements, with short and intermittent periods of sleep. After saline solution (SS) or Sp administration, normal behavior was observed for 3 h and compared with basal behavior. After PTZ administration, the animals showed progressive convulsive behavior according to Velisek's scale, while in the experimental group (pre-treated with Sp), the convulsive behavior was not progressive, and the animals came back to “minor” phases (from phase V to III or from phase III to I). In some Sp pre-treated animals, behavior was even normal during long periods or throughout almost the entire experiment (3 h) (Fig. 1A). The time to reach phase V from phase II in Sp pretreated animals increased, as did the time to reach loss of posture (po0.05) (Fig. 1A). Seizure duration with Sp pretreatment was prolonged, but not significantly different from the control group, and a tendency toward a higher survival rate was observed in animals pretreated with Sp in comparison with the PTZ control group (68.64726.16 vs. 18.3772.6 min, respectively). In addition, pretreatment with Sp reduced the mortality rate compared with the PTZ control group (75% vs. 100%, respectively; po0.05) (Fig. 1A). Animals administered Pilo had progressive convulsive behavior according to the Racine (1972), but in Sp pretreated animals, a non-significant delay in the onset of each phase (1–4) was observed, and the convulsive behavior was prolonged (Fig. 1B). However, Sp pretreatment reduced the mortality rate in comparison with the control group (17% vs. 80%), and there was also an increase in survival time (164.9715.08 vs. 115.7722.18 min, respectively; po0.05) (Fig. 1B). The convulsive behavior was progressive in the group treated with KA. Sp pretreatment in the animals significantly delayed the onset of convulsive behavior in scales 1–3 (po0.05) (Fig. 1C). In addition, Sp pretreatment decreased seizure duration in the experimental animals compared with the control group (142.776.65 vs. 169.573.14 min, respectively; po0.05). The mortality was 0% in both groups.
2.2.
EEG analysis
During basal recording (30 min) in all of the studied groups, the EEG activity showed slow activity characterized by low amplitude and frequency, without evidence of pathological activity (Table 1). Similar EEG activity was found after SS and Sp administration. No significant differences between basal EEG activity and EEG activity after SS and Sp administration were observed (Table 1). The epileptiform activity of the PTZ group was characterized by rhythmic spike waves with discharge trains of high amplitude and frequency. In the animals pretreated with Sp, this pattern was preserved but there was a significant reduction in the amplitude and frequency of the discharge trains during status compared with controls (Fig. 2). In both groups, the epileptiform activity was initiated in the fronto-parietal region (Fig. 2). Regarding the number and duration of discharge trains during status, no significant differences were found in the first segments, but at the end of the experiment, there were not discharge trains in 28% of the experimental animals. The onset of partial and widespread epileptiform
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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activity was delayed with Sp pretreatment, but the delay was not significant (Fig. 3). In Pilo treated animals as well as in animals pretreated with Sp, the epileptiform activity was characterized by the presence of rhythmic spike waves and discharge trains during status of high amplitude and frequency; in both groups, the epileptiform activity began in the fronto-parietal region (Fig. 4). The amplitude and frequency of discharge trains during status was significantly reduced in Sp pretreated animals (Fig. 4; po0.05). The onset of partial and widespread epileptiform activity was delayed in animals pretreated with Sp, but the delay was not significant. There was a trend toward a decrease in the number of discharge trains during status with Sp pretreatment, but the effect was not significant (Fig. 4). In addition, one Sp treated rat did not present epileptiform activity post-Pilo administration during the 3 h of the experiment. Animals treated with KA showed epileptiform activity characterized by poly-spike and spike-wave patterns that began in the fronto-parietal region (Fig. 5). The amplitude and frequency of the discharge trains during status were significantly decreased with Sp pretreatment (Fig. 5; po0.05). The onset of partial and widespread epileptiform activity was delayed, and there was a trend toward a decrease in the duration of the discharge trains during status, but the effect was not significant, and no significant changes in the number of discharge trains during status with Sp pretreatment were found (Fig. 5).
3.
Discussion
SE is a major clinical emergency that carries significant morbidity and mortality (Verellen and Cavazos, 2011), causes important neuronal injury, and leads to the loss and structural reorganization of interneurons and alterations in their excitatory inputs (Zhang and Buckmaster, 2009; Zhang et al., 2009). Survivors of SE have a greater risk of developing epilepsy and other neurological morbidities (i.e., depression and cognitive deficits). Over 40% of SE cases are refractory to initial treatment with two or more medications, and prolonged SE can quickly develop into refractory SE (Mayer et al., 2002; Deshpande and De Lorenzo, 2014); therefore, the development of more effective anti-SE drugs is essential to prevent the establishment of SE and to decrease the mortality related to this event. In this respect, Sp is a QA obtained from most Lupine species (Wink, 1992, 1993a). The role of Sp as an anticonvulsant drug was first observed in the PTZ model (Pothier et al., 1998), but subsequent studies have not been conducted until the present work. In this study, we found that Sp administration (13 mg/kg, i.p.) did not induce alterations in behavior and EEG activity for at least 30 min post-administration. This observation contrasts with previous reports in which Sp was found to produce neurological or systemic alterations including conQ2 vulsions (Schmitt, 1980; Tsiodras et al., 1999; Wink, 1994); however, these changes were observed after chronic administration or high doses of Sp. Moreover, some of these alterations were produced by Lupinus extracts containing a mixture of some alkaloids (synergic effects) and not pure
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compounds (Bañuelos-Pineda et al., 2005). Additionally, previous studies have found 36 mg/kg and 55–67 mg/kg i.p. doses of Sp to be lethal in 50% of animals (Yovo et al., 1984; Wink, 1994) and a lethality of 100% for doses of 100 mg/kg i.p. in mice (Pothier et al., 1998). In Wistar rats, 100% mortality was found for concentrations of 30 mg/kg s.c., administered at postnatal days 1–3 (Flores-Soto et al., 2006). The concentration of Sp used in the present work was below these reported concentrations. In the present study, the anticonvulsant effect of Sp on acute seizures was demonstrated through its ability to delay the onset of convulsive behavior and decrease its severity in the three models of SE (PTZ, Pilo and KA), although a decrease in the mortality of animals treated with PTZ and Pilo was found. These findings are consistent with the results reported by Pothier et al. (1998) for animals treated with Sp (13 mg/kg, i.p.) 30 min before PTZ (125 mg/kg, s.c.) administration, where Sp delayed the onset of convulsive behavior and prolonged the survival time. Additionally, in this work, EEG activity in the Sp treated animals was characterized by slow activity of low amplitude and frequency, as observed in the control groups; however, it was not possible to compare our EEG results during Sp administration given the absence of similar experiments in the literature, highlighting the novelty of these finding. Further, analysis of the EEG recordings showed that Sp decreased the amplitude and frequency of epileptiform activity (discharge trains during status) induced by PTZ, Pilo and KA; in the PTZ model, Sp even completely blocked epileptiform activity at 105 min post-PTZ administration. In contrast, in the Pilo model, in 16% of animals, Sp blocked this activity throughout the entire experiment. In addition, Sp prevented the establishment of SE in some animals in the three models of SE studied, which also demonstrates the anticonvulsive effect of Sp on acute seizures. Similarly, these results also cannot be compared with other in vivo studies given the absence of comparable experiments in the literature; therefore, the mechanism through which Sp exerts its anticonvulsant action is not well known. However, it has been reported that Sp produces hyperexcitability through activation of the m1 and m3 subtypes of mAChR, which increase DAG and IP3 through activation of phospholipase C (PLC). These second messengers block Kþ channels (M current activated by the Kþ channel TREK/ TASK) and increase intracellular calcium concentrations (Hamilton et al., 1997; Taylor and Brown, 2006; Bista et al., 2014). Another mechanism by which Sp causes hyperexcitability is the activation of nicotinic acetylcholine receptors, in particular the α3β2 conformation of nicotinic receptors found in the CNS, which produces an influx of Naþ and an efflux of Kþ as well as an increase in glutamate release (Daly, 2005; Taylor and Brown, 2006; Salamone et al., 2014). Additionally, it has been demonstrated that either of these two mechanisms produce persistent morphologic changes, excitotoxicity, neural damage and neurodegeneration (Yovo et al., 1984; Bañuelos-Pineda et al., 2005; FloresSoto et al., 2006; Oda and Tanaka, 2014). However, according to our better understanding, the only probable mechanism by which Sp decreases hyperexcitability is through the activation of m2 and m4 subtypes of mAChR; these receptors decrease adenylate cyclase-cAMP production, which decreases acetylcholine release and increases gamma aminobutyric acid (GABA) release (Taylor and Brown, 2006; Tzavara et al., 2003). This mechanism would
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Table 1 – EEG analysis of control groups and before convulsive drug administration. Group
SS PTZ SpþPTZ Pilo SpþPilo KA SpþKA
Basal recording (30 min)
Post-Sp recording (30 min)
Post-SS recording (3 h)
Amplitude (μV)
Frequency (Hz)
Amplitude (μV)
Frequency (Hz)
Amplitude (μV)
Frequency (Hz)
220715.3 217718.9 250720.2 210722.1 222715.3 264717.4 178.6733.2
1.4070.08 1.5570.11 1.6670.11 1.7470.07 1.3970.08 1.7370.04 1.7770.09
— — 246.2717.8 — 237.4716.2 — 212.2739.5
— — 1.9370.12 — 2.0770.14 — 1.97 70.14
212718.1 — — — — — —
1.1970.11 — — — — — —
The values represent the mean7SEM. Abbreviations: SS, saline solution (0.9%); Sp, sparteine (13 mg/kg, i.p.); PTZ, pentylenetetrazole (90 mg/ kg; i.p.; n ¼8); Pilo, pilocarpine (370 mg/kg; i.p.; n ¼ 5); KA, kainic acid (9 mg/kg; i.p.; n ¼5).
explain the decrease in the severity of convulsive behavior and the reduction in the amplitude and frequency of epileptiform activity found in the present study. In addition, it has been reported that Sp has higher affinity for muscarinic than nicotinic acetylcholine receptors (IC50 21 vs. 331 μM, respectively), as measured by the displacement of radiolabeled ligands (Schmeller et al., 1994), Sp and Ach also compete for a common binding site (Voitenko et al., 1991). The distribution of mAChR subtypes, particularly in cerebral cortex and hippocampus (Levey et al., 1995; Tohyama and Takatsuji, 1998) also supports our hypothesis of the mediation of the anticonvulsive effect of Sp on acute seizures through m2/m4 receptors. Further, the study by Flores-Soto et al. (2006), provides other indirect evidence supports this hypothesis, showing a decrease in the mRNA of m1, m2, and m3 subunits as well as a decrease in the protein of the m1 and m2 subunits and an increase in the mRNA of the m4 subunit of the mAChR was observed in the cortex of animals treated with Sp (25 mg/kg, s.c. at postnatal days 1–3) at postnatal days 7 and 14; these changes in the expression of mAChR subunits represent a compensatory mechanism by which the hyperexcitability induced by the activation of m1 and m3 mAChRs is diminished and m4-dependent inhibition is facilitated, in accordance with our hypothesis. However, to support our hypothesis, it is necessary to carry out more experiments in which the administration of antagonists of m2 and m4 mAChR subtypes counteracts anticonvulsant effect of Sp. Also, the classical anticonvulsive drugs most frequently prescribed in the clinical treatment of
epilepsy are the valproate (valproic acid), carbamazepine, phenytoin, lamotrigine and levetiracetam (Harit et al., 2015; FernandezSuarez et al., 2015). The anticonvulsants carbamazepine, phenytoin and lamotrigine cause a use-dependent reduction in voltagedependent Naþ channels (Westbrook, 2000), while the mechanism of action of valproic acid has been linked to blockade of voltage-dependent Naþ channels as well as the potentiation of GABAergic transmission (Ogungbenro et al., 2014). However, Sp has another mechanism of action that allows a partial anticonvulsant effect on acute seizures as demonstrated in this study and has not previously been used in other studies of basic biomedical research, highlighting the novelty of these finding. In addition, in the present study, the effects of Sp in convulsive behavior were slightly variable in the three models of SE; this may be due to genetic variability in the animals as well as differences in the susceptibility of the animals to convulsive drugs and the mechanism of action of PTZ, Pilo and KA. Also in the present study, the anticonvulsant effect of Sp on acute seizures was observed at a concentration of 13 mg/kg (i.p.), which is below the non-lethal concentration (30 mg/kg, i.p.); thus, it would be interesting to perform a dose–response curve with different non-lethal concentrations of Sp to determine if Sp at higher concentrations has a greater anticonvulsive effect on acute seizures compared with the Sp concentration used in the present study. Similarly, intracerebral administration of specific doses of Sp could eliminate its systemic effects and address the anticonvulsant effect of Sp on acute seizures mediated by
Fig. 1 – Analysis of convulsive behavior in three status epilepticus models. The bars show the mean7SEM of all parameters analyzed. (A) The first graph shows the onset of different phases of convulsive behavior in the experimental group pretreated with sparteine (Sp; 13 mg/kg, i.p.) plus pentylenetetrazole (PTZ, 90 mg/kg, i.p.; n¼ 8) compared with the control group with only PTZ (n ¼ 7), according to Velisek's scale (1992): I, isolated myoclonic jerks; II, only some components presenting atypical minimal seizures; III, minimal seizures (characterized as isolated myoclonic jerks and clonic seizures accompanied by facial and front extremity muscle clonus); IV, major seizures without a tonic phase; and V, complete major seizures (characterized by head, neck and tail extension with loss of the tonic flexor reflex and tonic flexion-extension following the protracted clonus). The time of the loss of posture, convulsive behavior time, survival time and % of survival are also shown. (B) The graphs show similar parameters as in (A) but in animals pretreated with Sp plus pilocarpine (Pilo; 370 mg/kg i.p.; n ¼ 6) compared with the Pilo control group (n ¼ 5). The convulsive behavior was analyzed with the Racine scale (1972): 0, no behavioral changes; 1, facial movements and ear and facial twitching; 2, myoclonic convulsions without rearing; 3, myoclonic convulsions with rearing; 4, clonic convulsions with loss of posture; and 5, generalized tonic-clonic seizures. (C) The graphs show similar parameters as in (B), in experimental animals pretreated with Sp plus kainic acid (KA; 9 mg/kg, i.p.; n ¼6) compared with the KA control group (n¼ 3), *po0.05. Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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nicotinic or muscarinic receptors, in accordance with its affinity for these particular receptors. In addition, analysis of the expression of mAChR subtypes during the acute anticonvulsant effect of Sp (1–3 h after its administration) could support the
principal role of these receptors in mediating the anticonvulsive effect of Sp on acute seizures. In conclusion, this is the first study in which the anticonvulsant effect of Sp on acute seizures pretreatment
Fig. 2 – Amplitude (lV) and frequency (Hz) of EEG activity in animals treated with pentylenetetrazole (PTZ) and pretreated with sparteine (Sp). The X-axes of the graphs show the time in minutes: -30 to 0 min, time of Sp pretreatment administration; 0 min, time of saline solution (SS, 0.9%) or PTZ (90 mg/kg i.p.) administration. The Y-axes of the graphs show the amplitude and frequency of the EEG activity of each animal of the three groups treated with SS, PTZ and Sp (13 mg/kg, i.p.) plus PTZ; *po0.05. The composition of the EEG traces shows the EEG activity for 30 s after SS, Sp and PTZ administration; the epileptiform activity (PTZ and SpþPTZ) was characterized by rhythmic spike waves, with a decrease in their amplitude and frequency in experimental animals pretreated with Sp. Abbreviations: F, frontal; P, parietal; T, temporal; and O, occipital. Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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(13 mg/kg, i.p.), applied 30 min before PTZ, Pilo and KA, was observed on convulsive behavior (decrease of severity) and epileptiform activity (decrease in amplitude and frequency). However, it is necessary to perform more experiments to determine the precise mechanism through which Sp produces an anticonvulsant effect at this concentration.
4.
Experimental procedures
4.1.
Animal surgery
Thirty-eight adult male Wistar rats (250–350 g in weight) were used in the present study. All rats were maintained in individual cages in a temperature-controlled room on a 12-h light/dark cycle with ad libitum access to food and water. All experimental procedures were designed to minimize animal suffering and the
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total number of animals used. This protocol conformed to the Rules for Research in Health Matters (Mexican Official Norms NOM-062-ZOO-1999, NOM-033-ZOO-1995), and it was approved by the local Animal Care Committee. Rats were first anesthetized with isoflurane in 100% O2 and then secured in a Stoelting stereotaxic frame with the incisor bar positioned at 3.3 mm. Two stainless steel screws were attached to the skull, first above bregma and second below lambda, which served as the ground and reference electrodes, respectively. Eight surface electrodes with the same characteristics as the electrodes described above were implanted into the skull: in the right and left frontal cortex (rFC, lFC), the right and left parietal cortex (rPC, lPC), the right and left occipital cortex (rOC, lOC), and the right and left temporal cortex (rTC, lTC). The surface electrode wires were attached to a socket connector and fixed to the skull with acrylic dental cement. This procedure was applied in animals from the control and experimental groups to evaluate the EEG recordings.
Fig. 3 – Analysis of EEG activity in animals treated with pentylenetetrazole (PTZ) and pretreated with sparteine (Sp). The Xaxes in the graphs show the time in minutes: 0 min, time of PTZ administration (90 mg/kg, i.p.). The Y-axis in the first graph shows the duration of discharge trains in periods of 15 min (data shown for each rat). In the period of 120–180 min, no discharge trains were found in Sp pretreated animals (n¼ 2, *po0.05). In the graph of the number of discharge trains, there was a tendency for the number to decrease. No significant difference in the time to reach partial and widespread epileptiform activity was observed. The bars show the mean7SEM. Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Fig. 4 – Analysis of EEG activity in animals treated with pilocarpine (Pilo) and pretreated with sparteine (Sp). The bars in the graphs show the mean7SEM, *po0.01. Amplitude (μV) and frequency (Hz) decreased significantly in animals treated with Pilo (370 mg/kg, i.p., n ¼5) and pretreated with Sp (13 mg/kg, i.p.). No significant differences were found in the onset of epileptiform activity (partial and widespread seizures) or in the duration and number of discharge trains. The composition of the EEG traces shows the EEG activity for 30 s after the administration of saline solution (SS; 0.9%), Sp and Pilo; the epileptiform activity (Pilo and SpþPilo) was characterized by rhythmic spike waves, with a decrease in their amplitude and frequency in experimental animals pretreated with Sp. In addition, one of the Sp pretreated animals did not present epileptiform activity. Abbreviations: F, frontal; P, parietal; T, temporal; and O, occipital.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Fig. 5 – Analysis of EEG activity in animals treated with kainic acid (KA) and pretreated with sparteine (Sp). The bars in the graphs show the mean7SEM, *po0.01. Amplitude (μV) and frequency (Hz) decreased significantly in animals treated with KA (9 mg/kg, i.p.; n¼ 6) and pretreated with Sp (13 mg/kg, i.p.). No significant differences were found in the onset of epileptiform activity (partial and widespread seizures) or in the duration and number of discharge trains. The composition of the EEG traces shows the EEG activity for 30 s after the administration of saline solution (SS; 0.9%), Sp and KA; the epileptiform activity (KA and SpþKA) was characterized by rhythmic poly-spikes and spike waves, with a decrease in their amplitude and frequency in experimental animals pretreated with Sp. Abbreviations: F, frontal; P, parietal; T, temporal; and O, occipital.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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4.2.
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EEG recordings and drug administration
All drugs were obtained from Sigma (St. Louis, MO, USA), dissolved in SS (0.9%) and administered i.p. The rats were place in a container 24–72 h after surgery and connected to a cable fixed on a balance arm. EEG activity was recorded using a Grass polygraph model 6 with a low-frequency filter at 1 Hz and a high-frequency filter at 300 Hz, and it was sampled at 100 Hz/ channel (eight channels). The data were stored on a computer hard disk and analyzed with AcqKnowledge software from Biopac Systems MP150 (Biopac Systems, Inc., CA, USA). After 30 min (basal recording), the animals of the first control group received SS (2 ml, n¼ 3) and were observed continuously; EEG signals were also captured for 180 min. The animals of the other control groups received PTZ (90 mg/kg, 2 ml, n¼ 8; Erdogan et al., 2014; Moezi et al., 2012; Homayoun et al., 2015), KA (9 mg/kg, 2 ml, n¼ 6; Kotaria et al., 2013) or Pilo (370 mg/kg, 2 ml, n¼6; Turski et al., 1983); they were observed continuously, and EEG recordings were performed for 180 min or until the time of survival. The animals of the experimental groups were injected with Sp (13 mg/kg, 2 ml; according Sp effects and mortality Q3 studies previously reported; Pothier et al., 1998; Flores-Soto et al., 2006; Bañuelos-Pineda et al., 2008) 30 min before the convulsive drugs at the same doses as the control groups (three experimental groups were used, with n¼ 6 in each group). The convulsive behavior and the EEG recordings were analyzed as well. In particular, the animals treated with Pilo also received scopolamine (1 mg/kg) at the same time they received Sp.
4.3.
EEG analysis
The basal electrical activity of each group was analyzed, and the amplitude and frequency were averaged over a 5 min recording period. After Sp administration (30 min), the amplitude and frequency were averaged over a 5 min recording period. After administration of the convulsive drugs, epileptiform activity was examined in the complete EEG recording period until the animal death or at the end of the experiment (3 h), during which the amplitude, frequency and duration of every discharge trains were analyzed. Additionally, the onset of partial and widespread epileptiform activity and the number of discharge trains were analyzed. In the PTZ model, the same parameters were analyzed as previously described.
4.4.
Behavioral analysis
Normal and convulsive behaviors were continuously observed before and after drug administration throughout the entire protocol (210 min in each group). To measure the convulsive behavior of the animals during and after PTZ administration, Velisek's scale was used as follows: 0, no changes in behavior; I, isolated myoclonic jerks; II, only some components presenting atypical minimal seizures; III, minimal seizures; IV, major seizures without a tonic phase; and V, complete major seizures. Minor attacks were characterized as isolated myoclonic jerks and clonic seizures accompanied by facial and front extremity muscle clonus, and major attacks were characterized by head, neck and tail extension with loss of the tonic flexor reflex and tonic flexion–extension following the protracted clonus (Mares et al., 1990; Velisek et al.,
1211 1212 1213 1214 1215 1216 1217 1218 4.5. Data analysis 1219 1220 The data are shown as the mean7SEM. The comparisons 1221 between the control and experimental groups were per1222 formed with unpaired Student's t test or with one-way 1223 ANOVA, followed by Tukey's post-hoc test. Comparisons 1224 were considered significant at p r0.05. 1225 1226 1227 Disclosure statement 1228 1229 The authors have no actual or potential conflicts of interest. 1230 1231 1232 Acknowledgments 1233 1234 This study was supported by CONACYT Grant CONACYT-SEP- Q4 1235 CB 106179 to LMC. 1236 1237 r e f e r e n c e s 1238 1239 1240 Ban˜uelos-Pineda, J., Nolasco-Rodrı´guez, G., Monteon, J.A., Garcı´a1241 Lo´pez, P.M., Ruiz-Lo´pez, M.A., Garcı´a-Estrada, J., 2005. 1242 Histological evaluation of brain damage caused by crude 1243 quinolizidine alkaloid extracts from lupines. Histol. Histopathol. 20, 1147–1153. 1244 Bista, P., Pawlowski, M., Cerina, M., Ehling, P., Leist, M., Meuth, P., 1245 Aissaoui, A., Borsotto, M., 2014. Differential phospholipase C1246 dependent modulation of TASK and TREK two-pore domain Q5 1247 Kþ channels in rat thalamocortical relay neurons. J. Physiol., 1248 127–144 593.1. 1249 Daly, J.W., 2005. Nicotinic agonist, antagonist, and modulation 1250 from natural sources. Cell. Mol. Neurobiol. 25, 513–552. Deshpande, L.S., De Lorenzo, R.J., 2014. Mechanisms of 1251 levetiracetam in the control of status epilepticus and epilepsy. 1252 Front. Neurol. 31, 11. 1253 Erdogan, H., Ekici, F., Katar, M., Kesici, H., Aslan, H., 2014. The 1254 protective effect of endothelin-A receptor antagonist BQ-123 1255 in pentylenetetrazole-induced seizures in rats. Hum. Exp. 1256 Toxicol. 33, 1–9. Fernandez-Suarez, E., Villa-Estebanez, R., Garcia-Martinez, A., 1257 Fidalgo-Gonzalez, J.A., Zanabili Al-Sibbai, A.A., Salas-Puig, J., 1258 2015. Prevalence, type of epilepsy and use of antiepileptic 1259 drugs in primary care. Rev. Neurol. 60, 535–542. 1260 Flores-Soto, M.E., Ban˜uelos-Pineda, J., Orozco-Sua´rez, S., Schliebs, 1261 R., Beas-Zarate, C., 2006. Neuronal damage and changes in the 1262 expression of muscarinic acetylcholine receptor subtypes in 1263 the neonatal rat cerebral cortical upon exposure to sparteine, a quinolizidine alkaloid. Int. J. Dev. Neurosci. 24, 401–410. 1264 Hamilton, S.E., Loose, M.D., Qi, M., Levey, A.I., Hille, B., Mcknight, 1265 G.S., Idzerda, R.L., Nathanson, N.M., 1997. Disruption of the 1266 m1 receptor gene ablates muscarinic receptor-dependent M 1267 current regulation and seizure activity in mice. Proc. Natl. 1268 Acad. Sci. USA 94, 13311–13316. 1269 Hansen, S.L., Sperling, B.B., Sa´nchez, C., 2004. Anticonvulsivants and antiepileptogenic effects of GABAA receptor ligands in 1270 1992). To evaluate the convulsive behavior after Pilo and KA administration, the Racine (1972) was used: 0, no behavioral changes; 1, facial movements and ear and facial twitching; 2, myoclonic convulsions without rearing; 3, myoclonic convulsions with rearing; 4, clonic convulsions with loss of posture; and 5, generalized tonic–clonic seizures.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Ramanjaneyulu, R., Ticku, M.K., 1984. Interactions of pentamethylenetetrazole and tetrazole analogues with picrotoxin site of benzodiazepine-GABA receptor-inophore complex. Eur. J. Pharmacol. 98, 337–345. Sanchez-Fernandez, I., Klehm, J., Jillella, S., Kapur, D., Zelener, K., Rotenberg, J., Loddenkemper, T., A., 2014. Comparison of risk factors for pediatric convulsive status epilepticus when defined as seizures Z 5 min versus seizures Z 30 min. Seizure 23, 692–698. Salamone, A., Mura, E., Zappettini, S., Grilli, M., Olivero, G., Preda, S., Govoni, S., Marchi, M., 2014. Inhibitory effects of betaamyloid on the nicotinic receptors wich stimulate glutamate release in rat hippocampus: the glia contribution. Eur. J. Pharmacol. 723, 314–321. Sampieri, A., Rivera-Espinosa, L., Zavala-Tecuapetle, C., Carmona-Aparicio, L., 2011. Modelos experimentales de la Q6 epilepsia del lo´bulo temporal. Acta Pediatr. Mex. 32 (5), 311–312. Schmeller, T., Sauerwein, M., Sporer, F., Wink, M., Mu¨ller, W.E., 1994. Binding of quinolizidine alkaloids to nicotinic and muscarinic acetylcholine receptors. J. Nat. Prod. 57, 1316–1319. Schmitt, H., 1980. In: Ele´ments de pharmacologie 7th ed. Flammarion, Paris356. Taylor, P., Brown, J.H., 2006. Acetylcholine. In: Siegel, G.I., Albers, R.W., Brady, S.T., Price, D.L. (Eds.), Basic Neurochemistry: Molecular, Celular, and Medical Aspects. Elsevier Academic Press, Burlington, MA, pp. 185–209. Tohyama, M., Takatsuji, K., 1998. In: Atlas of neuroactive substance and their receptors in rat. Oxford University Press, New York. Tsiodras, S., Shin, R.K., Christian, M., Shaw, L.M., Sass, D.A., 1999. Anticholinergic toxicity associated with lupine seeds as a home remedy for diabetes. Ann. Emerg. Med. 33, 715–717. Turski, W.A., Cavalheiro, E.A., Schwarz, M., Czuczwar, S.J., Kleinrok, Z., Turski, L., 1983. Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neurophatological study. Behav. Brain Res. 9, 315–335. Turski, W.A., Cavalheiro, E.A., Bortolotto, Z.A., Mello, L.M., Schwarz, M., Turski, L., 1984. Seizures produced by pilocarpine in mice: a behavioral, electroencephalographic and morphological analysis. Brain Res. 321, 237–253. Tzavara, E.T., Bymaster, F.P., Felder, C.C., Wade, M., Gomeza, J., Wess, J., McKinzie, D.L., Nomikos, G.G., 2003. Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice. Mol. Psychiatry 8, 673–679. Velisek, L., Kubova, H., Pohl, M., Stankova, L., Mares, P., Schickerova, R., 1992. Pentylenetetrazol-induced seizures in rats: an ontogenetic study. Naunyn-Schmiedeberg’s Arch. Pharmacol. 346, 588–591. Verellen, R.M., Cavazos, J.E., 2011. Pathophysiological considerations of seizures, epilepsy, and status epilepticus in the eldery. Aging Dis. 4, 278–285. Voitenko, S.V., Purnyn, S., Omeltchenko, I., Dyadyusha, G.G., Zhorov, B., Brovtsina, N., Skok, V., 1991. Effect of (þ)-sparteine on nicotinic acetylcholine receptors in the neurons of rat superior cervical ganglion. Mol. Pharmacol. 40, 180–185. Westbrook, G.L., 2000. In: Kandel, E.R., Schwartz, J.H., Jessell, T.M. (Eds.), Seizures and Epilepsy. Principles of Neural Science, MacGraw Hill, New York, pp. 910–935. Wink, M., 1987. Role in agriculture and foresty. In: Waller G.R. (Eds.), Allelochemicals. ACS Symposium Series. Washington, D.C., pp. 524–533. Wink, M., 1992. Role of quinolizidine alkaloids in plant-insect interactions. In: Bernays, E.A. (Ed.), Focus and Insect Plant Interactions. CRC Press, Boca Rato´n, Florida, pp. 131–166. Wink, M., 1993a. Methods of plant biochemistry. 8. Academic Press, Boca Ratos, USA197–239.
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its ketonic derivate lupanine from sedes of Lupinus albus. Planta Med. 50, 420–424. Zhang, W., Buckmaster, P.S., 2009. Dysfuntion of dentate basket cell circuit in a rat model of temporal lobe epilepsy. J. Neurosci. 17, 7846–7856. Zhang, W., Yamawaki, R., Wen, X., Uhl, J., Diaz, J., Prince, D.A., Buckmaster, P.S., 2009. Surviving hilar somatostatin interneurons enlarge, sprout axons, and form new synpases with granule cells in a mouse model of temporal lobe epilepsy. J. Neurosci. 29, 14247–14256.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Research Report
Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid$ Fridha Villalpando-Vargas1, Laura Medina-Cejan,1 Laboratory of Neurophysiology and Neurochemistry, Department of Cellular and Molecular Biology, CUCBA, University of Guadalajara, Jalisco, Mexico
art i cle i nfo
ab st rac t
Article history:
The long-term effects of status epilepticus (SE) include severe clinical conditions that result
Accepted 15 July 2015
in disorders of various organs and systems as well as neurological damage that could lead
Keywords:
anticonvulsive effect was evaluated in the pentylenetetrazole model of SE. However,
Kainic acid
efforts to clearly determine the anticonvulsive effect of sparteine have not been made
Pentylenetetrazole
previously. For this reason, we consider it important to study the anticonvulsant effects of
Pilocarpine
sparteine at the level of behavior and EEG activity in three different SE models. The
Seizures
animals of the control groups, which received intraperitoneal pentylenetetrazole (90 mg/
Sparteine
kg), kainic acid (9 mg/kg) or pilocarpine (370 mg/kg), exhibited convulsive behavior and
Status epilepticus
epileptiform activity. After sparteine pretreatment (13 mg/kg, administered 30 min before
to death. Sparteine is a quinolizidine alkaloid synthesized from most Lupine species, and its
the convulsive drug), the animals administered pentylenetetrazole and pilocarpine exhibited reduced mortality rates compared with the corresponding control groups, while the animals administered kainic acid exhibited a delayed onset of convulsive behavior and decreased seizure duration compared with the corresponding control group. In the three models of SE, a significant reduction in the amplitude and frequency of discharge trains was observed. These results support the anticonvulsant effect of low doses of sparteine and allow us to direct our efforts to other new anticonvulsant strategies for seizure treatment. However, it is necessary to perform more experiments to determine the precise mechanism through which sparteine produces an anticonvulsant effect at this concentration. & 2015 Published by Elsevier B.V.
☆
Grant sponsor: CONACYT. Grant number: 106179. Correspondence to: Laboratorio de Neurofisiología y Neuroquímica, Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Camino Ing. R. Padilla Sánchez 2100, Las Agujas, Nextipac, Zapopan, Jalisco CP 45110, Mexico. Fax:þ52 33 37771191. E-mail addresses: [email protected], [email protected] (L. Medina-Ceja). 1 FVV and LMC contributed equally to this work. n
http://dx.doi.org/10.1016/j.brainres.2015.07.017 0006-8993/& 2015 Published by Elsevier B.V.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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1.
Introduction
Epilepsy is a neurological disorder that affects 50 million people worldwide. Antiepileptic drugs (AEDs) are effective in 70% of patients, although in developing countries, this percentage drops drastically (Newton and Garcia, 2012). Status epilepticus (SE) (Sanchez-Fernandez et al., 2014) is defined as a prolonged seizure or recurrent seizures without full recovery between them, and in the literature, a seizure lasting longer than 30 min is classified as SE (McCandless, 2012). The long-lasting effects of SE include severe clinical conditions that result from disorders of various organs and systems as well as neurological damage that can lead to death (Jenssen et al., 2006). Models of SE provide good tools to study the cellular and molecular mechanisms of this pathological condition. Pilocarpine (Pilo, a non-selective muscarinic receptor agonist) and kainic acid (KA; an agonist of kainate-type glutamate receptors) models induce electroencephalographic (EEG) discharges in limbic structures with secondary generalization (Turski et al., 1983, 1984; Miller et al., 1990; Sampieri et al., 2011), while the pentylenetetrazole (PTZ) model induces primary generalized discharges (Erdogan et al., 2014). PTZ acts as a noncompetitive agonist of GABAA receptors by binding at the t-butylbicyclophosphorothionate site (Olsen, 1981; Ramanjaneyulu and Ticku, 1984; Hansen et al., 2004). Sparteine (Sp) is a quinolizidine alkaloid (QA) synthesized from most Lupine species (Wink, 1992, 1993a). In the nervous system, Sp inhibits ganglionic transmission (Schmitt, 1980; Yovo et al., 1984), activates acetylcholine receptors (nicotinic and muscarinic (mAChRs)) and inhibits Naþ and Kþ channels (Kinghorn and Balandrín, 1984; Piéri and Kirkiacharian, 1986; Wink, 1987, 1992, 1993a, 1993b; Schmeller et al., 1994; Körper et al., 1998). Subcutaneous administration of Sp (25 mg/kg) in neonatal rats decreases the mRNA of the m1–m3 subtypes of mAChRs and increases m7 mRNA between 7 and 14 days postadministration (Flores-Soto et al., 2006). The anticonvulsive effect of Sp was evaluated in the PTZ model of SE, and intraperitoneal (i.p.) administration of Sp (13 mg/kg) 30 min before PTZ (125 mg/kg, i.p.) delayed the onset of convulsive behavior and increased the survival period (Pothier et al., 1998). However, there have not been previous efforts to clearly determine the anticonvulsive effects of Sp. For this reason, we consider important to study the anticonvulsant effects of Sp on acute seizures at the level of behavior and EEG activity in three different SE models. To accomplish this objective, convulsive behavior and the survival period as well as the amplitude, frequency, duration and latency of discharge trains were analyzed after Sp administration. Furthermore, the protocol applied allowed us to evaluate behavior and EEG activity before and after drugs administration.
2.
Results
2.1.
Behavior analysis
During basal analysis (30 min), normal behavior was observed in every group, and motor impairment secondary to the
surgical procedure was discarded. Normal behavior was characterized as chewing and search and grooming movements, with short and intermittent periods of sleep. After saline solution (SS) or Sp administration, normal behavior was observed for 3 h and compared with basal behavior. After PTZ administration, the animals showed progressive convulsive behavior according to Velisek's scale, while in the experimental group (pre-treated with Sp), the convulsive behavior was not progressive, and the animals came back to “minor” phases (from phase V to III or from phase III to I). In some Sp pre-treated animals, behavior was even normal during long periods or throughout almost the entire experiment (3 h) (Fig. 1A). The time to reach phase V from phase II in Sp pretreated animals increased, as did the time to reach loss of posture (po0.05) (Fig. 1A). Seizure duration with Sp pretreatment was prolonged, but not significantly different from the control group, and a tendency toward a higher survival rate was observed in animals pretreated with Sp in comparison with the PTZ control group (68.64726.16 vs. 18.3772.6 min, respectively). In addition, pretreatment with Sp reduced the mortality rate compared with the PTZ control group (75% vs. 100%, respectively; po0.05) (Fig. 1A). Animals administered Pilo had progressive convulsive behavior according to the Racine (1972), but in Sp pretreated animals, a non-significant delay in the onset of each phase (1–4) was observed, and the convulsive behavior was prolonged (Fig. 1B). However, Sp pretreatment reduced the mortality rate in comparison with the control group (17% vs. 80%), and there was also an increase in survival time (164.9715.08 vs. 115.7722.18 min, respectively; po0.05) (Fig. 1B). The convulsive behavior was progressive in the group treated with KA. Sp pretreatment in the animals significantly delayed the onset of convulsive behavior in scales 1–3 (po0.05) (Fig. 1C). In addition, Sp pretreatment decreased seizure duration in the experimental animals compared with the control group (142.776.65 vs. 169.573.14 min, respectively; po0.05). The mortality was 0% in both groups.
2.2.
EEG analysis
During basal recording (30 min) in all of the studied groups, the EEG activity showed slow activity characterized by low amplitude and frequency, without evidence of pathological activity (Table 1). Similar EEG activity was found after SS and Sp administration. No significant differences between basal EEG activity and EEG activity after SS and Sp administration were observed (Table 1). The epileptiform activity of the PTZ group was characterized by rhythmic spike waves with discharge trains of high amplitude and frequency. In the animals pretreated with Sp, this pattern was preserved but there was a significant reduction in the amplitude and frequency of the discharge trains during status compared with controls (Fig. 2). In both groups, the epileptiform activity was initiated in the fronto-parietal region (Fig. 2). Regarding the number and duration of discharge trains during status, no significant differences were found in the first segments, but at the end of the experiment, there were not discharge trains in 28% of the experimental animals. The onset of partial and widespread epileptiform
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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activity was delayed with Sp pretreatment, but the delay was not significant (Fig. 3). In Pilo treated animals as well as in animals pretreated with Sp, the epileptiform activity was characterized by the presence of rhythmic spike waves and discharge trains during status of high amplitude and frequency; in both groups, the epileptiform activity began in the fronto-parietal region (Fig. 4). The amplitude and frequency of discharge trains during status was significantly reduced in Sp pretreated animals (Fig. 4; po0.05). The onset of partial and widespread epileptiform activity was delayed in animals pretreated with Sp, but the delay was not significant. There was a trend toward a decrease in the number of discharge trains during status with Sp pretreatment, but the effect was not significant (Fig. 4). In addition, one Sp treated rat did not present epileptiform activity post-Pilo administration during the 3 h of the experiment. Animals treated with KA showed epileptiform activity characterized by poly-spike and spike-wave patterns that began in the fronto-parietal region (Fig. 5). The amplitude and frequency of the discharge trains during status were significantly decreased with Sp pretreatment (Fig. 5; po0.05). The onset of partial and widespread epileptiform activity was delayed, and there was a trend toward a decrease in the duration of the discharge trains during status, but the effect was not significant, and no significant changes in the number of discharge trains during status with Sp pretreatment were found (Fig. 5).
3.
Discussion
SE is a major clinical emergency that carries significant morbidity and mortality (Verellen and Cavazos, 2011), causes important neuronal injury, and leads to the loss and structural reorganization of interneurons and alterations in their excitatory inputs (Zhang and Buckmaster, 2009; Zhang et al., 2009). Survivors of SE have a greater risk of developing epilepsy and other neurological morbidities (i.e., depression and cognitive deficits). Over 40% of SE cases are refractory to initial treatment with two or more medications, and prolonged SE can quickly develop into refractory SE (Mayer et al., 2002; Deshpande and De Lorenzo, 2014); therefore, the development of more effective anti-SE drugs is essential to prevent the establishment of SE and to decrease the mortality related to this event. In this respect, Sp is a QA obtained from most Lupine species (Wink, 1992, 1993a). The role of Sp as an anticonvulsant drug was first observed in the PTZ model (Pothier et al., 1998), but subsequent studies have not been conducted until the present work. In this study, we found that Sp administration (13 mg/kg, i.p.) did not induce alterations in behavior and EEG activity for at least 30 min post-administration. This observation contrasts with previous reports in which Sp was found to produce neurological or systemic alterations including conQ2 vulsions (Schmitt, 1980; Tsiodras et al., 1999; Wink, 1994); however, these changes were observed after chronic administration or high doses of Sp. Moreover, some of these alterations were produced by Lupinus extracts containing a mixture of some alkaloids (synergic effects) and not pure
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compounds (Bañuelos-Pineda et al., 2005). Additionally, previous studies have found 36 mg/kg and 55–67 mg/kg i.p. doses of Sp to be lethal in 50% of animals (Yovo et al., 1984; Wink, 1994) and a lethality of 100% for doses of 100 mg/kg i.p. in mice (Pothier et al., 1998). In Wistar rats, 100% mortality was found for concentrations of 30 mg/kg s.c., administered at postnatal days 1–3 (Flores-Soto et al., 2006). The concentration of Sp used in the present work was below these reported concentrations. In the present study, the anticonvulsant effect of Sp on acute seizures was demonstrated through its ability to delay the onset of convulsive behavior and decrease its severity in the three models of SE (PTZ, Pilo and KA), although a decrease in the mortality of animals treated with PTZ and Pilo was found. These findings are consistent with the results reported by Pothier et al. (1998) for animals treated with Sp (13 mg/kg, i.p.) 30 min before PTZ (125 mg/kg, s.c.) administration, where Sp delayed the onset of convulsive behavior and prolonged the survival time. Additionally, in this work, EEG activity in the Sp treated animals was characterized by slow activity of low amplitude and frequency, as observed in the control groups; however, it was not possible to compare our EEG results during Sp administration given the absence of similar experiments in the literature, highlighting the novelty of these finding. Further, analysis of the EEG recordings showed that Sp decreased the amplitude and frequency of epileptiform activity (discharge trains during status) induced by PTZ, Pilo and KA; in the PTZ model, Sp even completely blocked epileptiform activity at 105 min post-PTZ administration. In contrast, in the Pilo model, in 16% of animals, Sp blocked this activity throughout the entire experiment. In addition, Sp prevented the establishment of SE in some animals in the three models of SE studied, which also demonstrates the anticonvulsive effect of Sp on acute seizures. Similarly, these results also cannot be compared with other in vivo studies given the absence of comparable experiments in the literature; therefore, the mechanism through which Sp exerts its anticonvulsant action is not well known. However, it has been reported that Sp produces hyperexcitability through activation of the m1 and m3 subtypes of mAChR, which increase DAG and IP3 through activation of phospholipase C (PLC). These second messengers block Kþ channels (M current activated by the Kþ channel TREK/ TASK) and increase intracellular calcium concentrations (Hamilton et al., 1997; Taylor and Brown, 2006; Bista et al., 2014). Another mechanism by which Sp causes hyperexcitability is the activation of nicotinic acetylcholine receptors, in particular the α3β2 conformation of nicotinic receptors found in the CNS, which produces an influx of Naþ and an efflux of Kþ as well as an increase in glutamate release (Daly, 2005; Taylor and Brown, 2006; Salamone et al., 2014). Additionally, it has been demonstrated that either of these two mechanisms produce persistent morphologic changes, excitotoxicity, neural damage and neurodegeneration (Yovo et al., 1984; Bañuelos-Pineda et al., 2005; FloresSoto et al., 2006; Oda and Tanaka, 2014). However, according to our better understanding, the only probable mechanism by which Sp decreases hyperexcitability is through the activation of m2 and m4 subtypes of mAChR; these receptors decrease adenylate cyclase-cAMP production, which decreases acetylcholine release and increases gamma aminobutyric acid (GABA) release (Taylor and Brown, 2006; Tzavara et al., 2003). This mechanism would
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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brain research ] (]]]]) ]]]–]]]
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431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Table 1 – EEG analysis of control groups and before convulsive drug administration. Group
SS PTZ SpþPTZ Pilo SpþPilo KA SpþKA
Basal recording (30 min)
Post-Sp recording (30 min)
Post-SS recording (3 h)
Amplitude (μV)
Frequency (Hz)
Amplitude (μV)
Frequency (Hz)
Amplitude (μV)
Frequency (Hz)
220715.3 217718.9 250720.2 210722.1 222715.3 264717.4 178.6733.2
1.4070.08 1.5570.11 1.6670.11 1.7470.07 1.3970.08 1.7370.04 1.7770.09
— — 246.2717.8 — 237.4716.2 — 212.2739.5
— — 1.9370.12 — 2.0770.14 — 1.97 70.14
212718.1 — — — — — —
1.1970.11 — — — — — —
The values represent the mean7SEM. Abbreviations: SS, saline solution (0.9%); Sp, sparteine (13 mg/kg, i.p.); PTZ, pentylenetetrazole (90 mg/ kg; i.p.; n ¼8); Pilo, pilocarpine (370 mg/kg; i.p.; n ¼ 5); KA, kainic acid (9 mg/kg; i.p.; n ¼5).
explain the decrease in the severity of convulsive behavior and the reduction in the amplitude and frequency of epileptiform activity found in the present study. In addition, it has been reported that Sp has higher affinity for muscarinic than nicotinic acetylcholine receptors (IC50 21 vs. 331 μM, respectively), as measured by the displacement of radiolabeled ligands (Schmeller et al., 1994), Sp and Ach also compete for a common binding site (Voitenko et al., 1991). The distribution of mAChR subtypes, particularly in cerebral cortex and hippocampus (Levey et al., 1995; Tohyama and Takatsuji, 1998) also supports our hypothesis of the mediation of the anticonvulsive effect of Sp on acute seizures through m2/m4 receptors. Further, the study by Flores-Soto et al. (2006), provides other indirect evidence supports this hypothesis, showing a decrease in the mRNA of m1, m2, and m3 subunits as well as a decrease in the protein of the m1 and m2 subunits and an increase in the mRNA of the m4 subunit of the mAChR was observed in the cortex of animals treated with Sp (25 mg/kg, s.c. at postnatal days 1–3) at postnatal days 7 and 14; these changes in the expression of mAChR subunits represent a compensatory mechanism by which the hyperexcitability induced by the activation of m1 and m3 mAChRs is diminished and m4-dependent inhibition is facilitated, in accordance with our hypothesis. However, to support our hypothesis, it is necessary to carry out more experiments in which the administration of antagonists of m2 and m4 mAChR subtypes counteracts anticonvulsant effect of Sp. Also, the classical anticonvulsive drugs most frequently prescribed in the clinical treatment of
epilepsy are the valproate (valproic acid), carbamazepine, phenytoin, lamotrigine and levetiracetam (Harit et al., 2015; FernandezSuarez et al., 2015). The anticonvulsants carbamazepine, phenytoin and lamotrigine cause a use-dependent reduction in voltagedependent Naþ channels (Westbrook, 2000), while the mechanism of action of valproic acid has been linked to blockade of voltage-dependent Naþ channels as well as the potentiation of GABAergic transmission (Ogungbenro et al., 2014). However, Sp has another mechanism of action that allows a partial anticonvulsant effect on acute seizures as demonstrated in this study and has not previously been used in other studies of basic biomedical research, highlighting the novelty of these finding. In addition, in the present study, the effects of Sp in convulsive behavior were slightly variable in the three models of SE; this may be due to genetic variability in the animals as well as differences in the susceptibility of the animals to convulsive drugs and the mechanism of action of PTZ, Pilo and KA. Also in the present study, the anticonvulsant effect of Sp on acute seizures was observed at a concentration of 13 mg/kg (i.p.), which is below the non-lethal concentration (30 mg/kg, i.p.); thus, it would be interesting to perform a dose–response curve with different non-lethal concentrations of Sp to determine if Sp at higher concentrations has a greater anticonvulsive effect on acute seizures compared with the Sp concentration used in the present study. Similarly, intracerebral administration of specific doses of Sp could eliminate its systemic effects and address the anticonvulsant effect of Sp on acute seizures mediated by
Fig. 1 – Analysis of convulsive behavior in three status epilepticus models. The bars show the mean7SEM of all parameters analyzed. (A) The first graph shows the onset of different phases of convulsive behavior in the experimental group pretreated with sparteine (Sp; 13 mg/kg, i.p.) plus pentylenetetrazole (PTZ, 90 mg/kg, i.p.; n¼ 8) compared with the control group with only PTZ (n ¼ 7), according to Velisek's scale (1992): I, isolated myoclonic jerks; II, only some components presenting atypical minimal seizures; III, minimal seizures (characterized as isolated myoclonic jerks and clonic seizures accompanied by facial and front extremity muscle clonus); IV, major seizures without a tonic phase; and V, complete major seizures (characterized by head, neck and tail extension with loss of the tonic flexor reflex and tonic flexion-extension following the protracted clonus). The time of the loss of posture, convulsive behavior time, survival time and % of survival are also shown. (B) The graphs show similar parameters as in (A) but in animals pretreated with Sp plus pilocarpine (Pilo; 370 mg/kg i.p.; n ¼ 6) compared with the Pilo control group (n ¼ 5). The convulsive behavior was analyzed with the Racine scale (1972): 0, no behavioral changes; 1, facial movements and ear and facial twitching; 2, myoclonic convulsions without rearing; 3, myoclonic convulsions with rearing; 4, clonic convulsions with loss of posture; and 5, generalized tonic-clonic seizures. (C) The graphs show similar parameters as in (B), in experimental animals pretreated with Sp plus kainic acid (KA; 9 mg/kg, i.p.; n ¼6) compared with the KA control group (n¼ 3), *po0.05. Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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nicotinic or muscarinic receptors, in accordance with its affinity for these particular receptors. In addition, analysis of the expression of mAChR subtypes during the acute anticonvulsant effect of Sp (1–3 h after its administration) could support the
principal role of these receptors in mediating the anticonvulsive effect of Sp on acute seizures. In conclusion, this is the first study in which the anticonvulsant effect of Sp on acute seizures pretreatment
Fig. 2 – Amplitude (lV) and frequency (Hz) of EEG activity in animals treated with pentylenetetrazole (PTZ) and pretreated with sparteine (Sp). The X-axes of the graphs show the time in minutes: -30 to 0 min, time of Sp pretreatment administration; 0 min, time of saline solution (SS, 0.9%) or PTZ (90 mg/kg i.p.) administration. The Y-axes of the graphs show the amplitude and frequency of the EEG activity of each animal of the three groups treated with SS, PTZ and Sp (13 mg/kg, i.p.) plus PTZ; *po0.05. The composition of the EEG traces shows the EEG activity for 30 s after SS, Sp and PTZ administration; the epileptiform activity (PTZ and SpþPTZ) was characterized by rhythmic spike waves, with a decrease in their amplitude and frequency in experimental animals pretreated with Sp. Abbreviations: F, frontal; P, parietal; T, temporal; and O, occipital. Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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(13 mg/kg, i.p.), applied 30 min before PTZ, Pilo and KA, was observed on convulsive behavior (decrease of severity) and epileptiform activity (decrease in amplitude and frequency). However, it is necessary to perform more experiments to determine the precise mechanism through which Sp produces an anticonvulsant effect at this concentration.
4.
Experimental procedures
4.1.
Animal surgery
Thirty-eight adult male Wistar rats (250–350 g in weight) were used in the present study. All rats were maintained in individual cages in a temperature-controlled room on a 12-h light/dark cycle with ad libitum access to food and water. All experimental procedures were designed to minimize animal suffering and the
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total number of animals used. This protocol conformed to the Rules for Research in Health Matters (Mexican Official Norms NOM-062-ZOO-1999, NOM-033-ZOO-1995), and it was approved by the local Animal Care Committee. Rats were first anesthetized with isoflurane in 100% O2 and then secured in a Stoelting stereotaxic frame with the incisor bar positioned at 3.3 mm. Two stainless steel screws were attached to the skull, first above bregma and second below lambda, which served as the ground and reference electrodes, respectively. Eight surface electrodes with the same characteristics as the electrodes described above were implanted into the skull: in the right and left frontal cortex (rFC, lFC), the right and left parietal cortex (rPC, lPC), the right and left occipital cortex (rOC, lOC), and the right and left temporal cortex (rTC, lTC). The surface electrode wires were attached to a socket connector and fixed to the skull with acrylic dental cement. This procedure was applied in animals from the control and experimental groups to evaluate the EEG recordings.
Fig. 3 – Analysis of EEG activity in animals treated with pentylenetetrazole (PTZ) and pretreated with sparteine (Sp). The Xaxes in the graphs show the time in minutes: 0 min, time of PTZ administration (90 mg/kg, i.p.). The Y-axis in the first graph shows the duration of discharge trains in periods of 15 min (data shown for each rat). In the period of 120–180 min, no discharge trains were found in Sp pretreated animals (n¼ 2, *po0.05). In the graph of the number of discharge trains, there was a tendency for the number to decrease. No significant difference in the time to reach partial and widespread epileptiform activity was observed. The bars show the mean7SEM. Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Fig. 4 – Analysis of EEG activity in animals treated with pilocarpine (Pilo) and pretreated with sparteine (Sp). The bars in the graphs show the mean7SEM, *po0.01. Amplitude (μV) and frequency (Hz) decreased significantly in animals treated with Pilo (370 mg/kg, i.p., n ¼5) and pretreated with Sp (13 mg/kg, i.p.). No significant differences were found in the onset of epileptiform activity (partial and widespread seizures) or in the duration and number of discharge trains. The composition of the EEG traces shows the EEG activity for 30 s after the administration of saline solution (SS; 0.9%), Sp and Pilo; the epileptiform activity (Pilo and SpþPilo) was characterized by rhythmic spike waves, with a decrease in their amplitude and frequency in experimental animals pretreated with Sp. In addition, one of the Sp pretreated animals did not present epileptiform activity. Abbreviations: F, frontal; P, parietal; T, temporal; and O, occipital.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Fig. 5 – Analysis of EEG activity in animals treated with kainic acid (KA) and pretreated with sparteine (Sp). The bars in the graphs show the mean7SEM, *po0.01. Amplitude (μV) and frequency (Hz) decreased significantly in animals treated with KA (9 mg/kg, i.p.; n¼ 6) and pretreated with Sp (13 mg/kg, i.p.). No significant differences were found in the onset of epileptiform activity (partial and widespread seizures) or in the duration and number of discharge trains. The composition of the EEG traces shows the EEG activity for 30 s after the administration of saline solution (SS; 0.9%), Sp and KA; the epileptiform activity (KA and SpþKA) was characterized by rhythmic poly-spikes and spike waves, with a decrease in their amplitude and frequency in experimental animals pretreated with Sp. Abbreviations: F, frontal; P, parietal; T, temporal; and O, occipital.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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4.2.
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EEG recordings and drug administration
All drugs were obtained from Sigma (St. Louis, MO, USA), dissolved in SS (0.9%) and administered i.p. The rats were place in a container 24–72 h after surgery and connected to a cable fixed on a balance arm. EEG activity was recorded using a Grass polygraph model 6 with a low-frequency filter at 1 Hz and a high-frequency filter at 300 Hz, and it was sampled at 100 Hz/ channel (eight channels). The data were stored on a computer hard disk and analyzed with AcqKnowledge software from Biopac Systems MP150 (Biopac Systems, Inc., CA, USA). After 30 min (basal recording), the animals of the first control group received SS (2 ml, n¼ 3) and were observed continuously; EEG signals were also captured for 180 min. The animals of the other control groups received PTZ (90 mg/kg, 2 ml, n¼ 8; Erdogan et al., 2014; Moezi et al., 2012; Homayoun et al., 2015), KA (9 mg/kg, 2 ml, n¼ 6; Kotaria et al., 2013) or Pilo (370 mg/kg, 2 ml, n¼6; Turski et al., 1983); they were observed continuously, and EEG recordings were performed for 180 min or until the time of survival. The animals of the experimental groups were injected with Sp (13 mg/kg, 2 ml; according Sp effects and mortality Q3 studies previously reported; Pothier et al., 1998; Flores-Soto et al., 2006; Bañuelos-Pineda et al., 2008) 30 min before the convulsive drugs at the same doses as the control groups (three experimental groups were used, with n¼ 6 in each group). The convulsive behavior and the EEG recordings were analyzed as well. In particular, the animals treated with Pilo also received scopolamine (1 mg/kg) at the same time they received Sp.
4.3.
EEG analysis
The basal electrical activity of each group was analyzed, and the amplitude and frequency were averaged over a 5 min recording period. After Sp administration (30 min), the amplitude and frequency were averaged over a 5 min recording period. After administration of the convulsive drugs, epileptiform activity was examined in the complete EEG recording period until the animal death or at the end of the experiment (3 h), during which the amplitude, frequency and duration of every discharge trains were analyzed. Additionally, the onset of partial and widespread epileptiform activity and the number of discharge trains were analyzed. In the PTZ model, the same parameters were analyzed as previously described.
4.4.
Behavioral analysis
Normal and convulsive behaviors were continuously observed before and after drug administration throughout the entire protocol (210 min in each group). To measure the convulsive behavior of the animals during and after PTZ administration, Velisek's scale was used as follows: 0, no changes in behavior; I, isolated myoclonic jerks; II, only some components presenting atypical minimal seizures; III, minimal seizures; IV, major seizures without a tonic phase; and V, complete major seizures. Minor attacks were characterized as isolated myoclonic jerks and clonic seizures accompanied by facial and front extremity muscle clonus, and major attacks were characterized by head, neck and tail extension with loss of the tonic flexor reflex and tonic flexion–extension following the protracted clonus (Mares et al., 1990; Velisek et al.,
1211 1212 1213 1214 1215 1216 1217 1218 4.5. Data analysis 1219 1220 The data are shown as the mean7SEM. The comparisons 1221 between the control and experimental groups were per1222 formed with unpaired Student's t test or with one-way 1223 ANOVA, followed by Tukey's post-hoc test. Comparisons 1224 were considered significant at p r0.05. 1225 1226 1227 Disclosure statement 1228 1229 The authors have no actual or potential conflicts of interest. 1230 1231 1232 Acknowledgments 1233 1234 This study was supported by CONACYT Grant CONACYT-SEP- Q4 1235 CB 106179 to LMC. 1236 1237 r e f e r e n c e s 1238 1239 1240 Ban˜uelos-Pineda, J., Nolasco-Rodrı´guez, G., Monteon, J.A., Garcı´a1241 Lo´pez, P.M., Ruiz-Lo´pez, M.A., Garcı´a-Estrada, J., 2005. 1242 Histological evaluation of brain damage caused by crude 1243 quinolizidine alkaloid extracts from lupines. Histol. Histopathol. 20, 1147–1153. 1244 Bista, P., Pawlowski, M., Cerina, M., Ehling, P., Leist, M., Meuth, P., 1245 Aissaoui, A., Borsotto, M., 2014. Differential phospholipase C1246 dependent modulation of TASK and TREK two-pore domain Q5 1247 Kþ channels in rat thalamocortical relay neurons. J. Physiol., 1248 127–144 593.1. 1249 Daly, J.W., 2005. Nicotinic agonist, antagonist, and modulation 1250 from natural sources. Cell. Mol. Neurobiol. 25, 513–552. Deshpande, L.S., De Lorenzo, R.J., 2014. Mechanisms of 1251 levetiracetam in the control of status epilepticus and epilepsy. 1252 Front. Neurol. 31, 11. 1253 Erdogan, H., Ekici, F., Katar, M., Kesici, H., Aslan, H., 2014. The 1254 protective effect of endothelin-A receptor antagonist BQ-123 1255 in pentylenetetrazole-induced seizures in rats. Hum. Exp. 1256 Toxicol. 33, 1–9. Fernandez-Suarez, E., Villa-Estebanez, R., Garcia-Martinez, A., 1257 Fidalgo-Gonzalez, J.A., Zanabili Al-Sibbai, A.A., Salas-Puig, J., 1258 2015. Prevalence, type of epilepsy and use of antiepileptic 1259 drugs in primary care. Rev. Neurol. 60, 535–542. 1260 Flores-Soto, M.E., Ban˜uelos-Pineda, J., Orozco-Sua´rez, S., Schliebs, 1261 R., Beas-Zarate, C., 2006. Neuronal damage and changes in the 1262 expression of muscarinic acetylcholine receptor subtypes in 1263 the neonatal rat cerebral cortical upon exposure to sparteine, a quinolizidine alkaloid. Int. J. Dev. Neurosci. 24, 401–410. 1264 Hamilton, S.E., Loose, M.D., Qi, M., Levey, A.I., Hille, B., Mcknight, 1265 G.S., Idzerda, R.L., Nathanson, N.M., 1997. Disruption of the 1266 m1 receptor gene ablates muscarinic receptor-dependent M 1267 current regulation and seizure activity in mice. Proc. Natl. 1268 Acad. Sci. USA 94, 13311–13316. 1269 Hansen, S.L., Sperling, B.B., Sa´nchez, C., 2004. Anticonvulsivants and antiepileptogenic effects of GABAA receptor ligands in 1270 1992). To evaluate the convulsive behavior after Pilo and KA administration, the Racine (1972) was used: 0, no behavioral changes; 1, facial movements and ear and facial twitching; 2, myoclonic convulsions without rearing; 3, myoclonic convulsions with rearing; 4, clonic convulsions with loss of posture; and 5, generalized tonic–clonic seizures.
Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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Please cite this article as: Villalpando-Vargas, F., Medina-Ceja, L., Effect of sparteine on status epilepticus induced in rats by pentylenetetrazole, pilocarpine and kainic acid. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.07.017
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