Blockade of the sodium calcium exchanger exhibits anticonvulsant activity in a pilocarpine model of acute seizures in rats

Abstract

Recent evidence suggests that the sodium calcium exchanger (NCX) may contribute to the etiology of pentylenetetrazol-induced seizures. Here we further investigated the role of NCX in the etiology of seizures by quantifying the effects of KB-R7943 and SN-6, potent inhibitors of the reverse mode of NCX subtypes 3 (NCX3) and 1 (NCX1), respectively, on the occurrence of acute seizures and status epilepticus induced by intraperitoneal administration of pilocarpine, a muscarinic acetylcholine receptor agonist. Pretreatment with KB-R7943 significantly reduced the incidence of pilocarpine-induced seizures and status epilepticus in 22–56% of treated animals. In the remaining animals that exhibited seizures, KB-R7943 pretreatment delayed the onset of seizures and status epilepticus, and reduced seizure severity. Delayed onset of seizures and reduced seizure severity also were seen following pretreatment with SN-6. These findings suggest that altered NCX activity may contribute to the pathophysiology of pilocarpine-induced seizures and status epilepticus.

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

“…by gastric intubation in a volume of 0.2 ml/100 g body weight using an 18-gauge stainless steel feeding needle with a round tip (ball diameter 3 mm). The initial dose of 0.3 or 1 mg/kg was chosen based on published in vivo pharmacological studies and preliminary data (Martinez and N’Gouemo, 2010; Blokin et al, 2008). The 90 min timepoint was the most effective pretreatment window on seizure activity in our previous study (Martinez and N’Gouemo, 2010).…”

“…The NCX has been implicated in the pathophysiology of various neurological conditions, including Alzheimer’s disease (Bi et al, 2012; Sokolow et al, 2011), ischemia (Pignataro et al, 2004; Lee et al, 2005; Boscia et al, 2006), hypoxia (Secondo et al, 2007) and Parkinson’s disease (Ago et al, 2011). Although the role of the NCX in the pathogenesis of seizures and epilepsy remains poorly understood, we have reported that inhibition of Ca 2+ influx via NCX activity in the reverse mode reduced the incidence of pilocarpine-induced limbic seizures and status epilepticus (Martinez and N’Gouemo, 2010). The NCX also plays an important role in the pathogenesis of generalized seizures because genetic deletion of the NCX1 isoform suppressed the tonic flexion component of pentylenetrazole (PTZ)-induced generalized seizures in mice (Saito et al, 2009).…”

KB-R7943, an inhibitor of the reverse Na+/Ca2+ exchanger, does not modify secondary pathology in the thalamus following focal cerebral stroke in rats

“…In our study all animals were given DSMO and thus it should not bias the data. Second, the administration dose (30 mg/kg, per os) was selected based on the on the previous studies indicating axonal protection after experimental ischemia [14] and behavioral improvements after acute seizure [25]. One should note, that the used KB-R7943 dose seemed to induce some side-effects (e.g., loss of body weight and hypothermia [36]), which may mask part of therapeutic effects.…”

“…KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate) (Tocris Bioscience, Bristol, UK) was dissolved first in DMSO (dimethyl sulfoxide; Sigma-Aldrich, Seelze, Germany; final volume 5%) and then in a mixture of Arabic gum (5% solution in distilled water, Sigma, St. Louis, USA). The drug dose was selected on the basis of previous studies [14,25]. The drug treatment was started on postoperative day 2 to avoid interference with the maturation of acute ischemic damage.…”

Decreased expression of hippocampal Na+/Ca2+ exchanger isoform-1 by pentylenetetrazole kindling in mice

“…NCX has been implicated in the pathophysiology of several neurodegenerative disorders (Ago et al, 2011;Morimoto et al, 2012;Pannaccione et al, 2012). Recent studies show that the NCX inhibitors KB-R7943 and SN-6 reduce the incidence of pilocarpine-and pentylenetetrazole (PTZ)-induced seizures and status epilepticus (Martinez and N'Gouemo, 2010;N'Gouemo, 2013). Furthermore, Saito et al (2009) reported that PTZ-induced convulsions were not observed in NCX1-hetrozygote knockout mice.…”