Hyponatremia augments kainic-acid induced status epilepticus in the mouse: A model for dysmetabolic status epilepticus
Introduction
Status epilepticus (SE) is a dreaded neurological emergency associated with high mortality. As our understanding of SE increases, it is clear that different aetiologies of SE respond differently to treatments. Suitable experimental assays to evaluate different treatments of SE under various conditions are therefore needed.
Hyponatremia is a well-known aggravating factor for seizures (Bleck, 2009, Halawa et al., 2011, Martindale et al., 2011). The condition can arise for several reasons, for instance the use of diuretics in the elderly population, side effects of antiepileptic drug treatment, or from psychogenic polydipsia. The speed with which the hyponatremia develops affects the seizure risk, and several cases of seizures due to acute hyponatremia as a consequence of water intoxication exist in the literature (O’Connor, 1985, Primavera et al., 1995). Hyponatremia is significantly associated with SE refractory to treatment, indicating the importance of studies on this particular dysmetabolic condition (Holtkamp et al., 2005).
There is little experimental data on SE in hyponatremia. Seizures in hyponatremia have been studied mostly in the context of seizure thresholds or very severe hyponatremia causing brain oedema, herniation and death. Hypotonic hyponatremia is known to reduce the threshold for electrically induced seizures (Sofia and Barry, 1977, Swinyard et al., 1955), as well as chemically-induced seizures in relation to renal failure (Nagata et al., 2003). These studies however, did not clarify the effect of hyponatremia on SE severity or duration.
There are several models of SE in rodents. Among the simpler ones are chemoconvulsant-induced seizures, which have the advantages of not requiring a kindling setup. Several chemoconvulsants, such as pentylenetetrazole, pilocarpine, or kainic acid can be used to induce SE. Based on the literature and our previous experience (Borges et al., 2003, Huang et al., 2009, Zelano et al., 2012), KA seems comparably easy to control, robust in the induction of SE, and has an increased survival – which would potentially lessen variability. We therefore asked if KA-induced status epilepticus could be a suitable model for experiments on SE under acute hyponatremia.
We subjected mice to a moderate degree of acute hyponatremia induced by water loading–and evaluated the effect on KA-induced SE. We report that hyponatremia in itself induced epileptiform activity on EEG and that KA-induced SE was augmented in hyponatremic mice. We conclude that KA-induced SE is a suitable model for future studies on SE under dysmetabolic conditions.
Section snippets
Mice
Female mice C57/BL6 mice, more than seven-week old, from Taconic® were used. All mice were group housed, maintained on a 12-h day/light circle and cared for according to present animal regulations. The experiments were approved by the Uppsala animal ethics committee, approval number C345/11.
EEG
Electroencephalography (EEG) traces were recorded using the cable-tethered PAL-8200 system (Pinnaclet technology Inc, Lawrence, KA, USA). After anaesthesia and placement of epidural electrodes, the mice were
Results
Our first aim was to establish an acute hyponatremia. We aimed for a rapid decrease in sodium concentration to approximately 125–130 mmol/L and performed titration experiments (data not shown). Injection of sterile water with addition of dDAVP to an equivalent of 7,5% body weight resulted in sodium levels of approximately 125–130 mmol/L over the observation period of three hours (Fig. 1C).
We next induced hyponatremia and SE during monitoring in a tethered EEG-system (Fig. 1A–B). The number of
Discussion
We here report the effect of acute hyponatremia on KA-induced status epilepticus. Hyponatremia aggravated the response to the chemoconvulsant and hyponatremic mice spent significantly longer time in seizure during the observation period than non-hyponatremic mice. In addition, hyponatremia in itself evoked epileptiform activity in the form of interictal spikes and - in some animals - actual electrographic seizures.
Kainic acid-induced status epilepticus was augmented in hyponatremic mice, which
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