Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d2442148e118">Objective</h5> <p id="P1">We investigated the role of chloride homeostasis in seizure progression and development of pharmacoresistant status epilepticus (SE) by pharmacologically targeting the Na-K-Cl cotransporter (NKCC1) with bumetanide. We also investigated the ability of bumetanide to restore the efficacy of diazepam following SE. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d2442148e123">Methods</h5> <p id="P2">Kainic acid (KA)–induced SE in vivo and 0-Mg <sup>2+</sup>-induced seizure-like events (SLEs) in vitro were monitored using electroencephalography (EEG) recordings in freely moving adult male mice and extracellular field potential recordings in acute entorhinal cortex-hippocampus slices, respectively. The ability of bumetanide to decrease epileptiform activity and prevent the development of pharmacoresistance to diazepam following SE was evaluated. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d2442148e131">Results</h5> <p id="P3">Bumetanide treatment significantly reduced KA-induced ictal activity in vivo and SLEs in vitro. In addition, bumetanide restored the efficacy of diazepam in decreasing ictal activity following SE in both the in vivo and in vitro models. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d2442148e136">Significance</h5> <p id="P4">Our data demonstrate an anticonvulsant effect of bumetanide on KA-induced seizures in adult mice, suggesting a role for chloride plasticity in seizure progression. These data also demonstrate that the erosion of inhibition during seizure progression could underlie the development of pharmacoresistant SE and implicate a role for chloride plasticity in this process. </p> </div>

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Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

Gilles Huberfeld, Lucia Wittner, Stéphane Clémenceau … (2007)

Changes in chloride (Cl-) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl- homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA(A) receptor-mediated postsynaptic events, indicating a perturbed Cl- homeostasis. We assessed possible contributions of changes in expression of the potassium-chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from approximately 30% of CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium-sodium-chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA(A) reversal potentials and suppressed interictal activity. Changes in Cl- transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

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Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety.

Jamie Maguire, Brandon Stell, Mahsan Rafizadeh … (2005)

Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by delta subunit-containing GABA(A) receptors (deltaGABA(A)Rs). Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of deltaGABA(A)Rs in individuals with catamenial epilepsy or PMDD.

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Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus.

David Naylor, Hantao Liu, Claude Wasterlain (2005)

During status epilepticus (SE), GABAergic mechanisms fail and seizures become self-sustaining and pharmacoresistant. During lithiumpilocarpine-induced SE, our studies of postsynaptic GABA(A) receptors in dentate gyrus granule cells show a reduction in the amplitude of miniature IPSCs (mIPSCs). Anatomical studies show a reduction in the colocalization of the beta2/beta3 and gamma2 subunits of GABA(A) receptors with the presynaptic marker synaptophysin and an increase in the proportion of those subunits in the interior of dentate granule cells and other hippocampal neurons with SE. Unlike synaptic mIPSCs, the amplitude of extrasynaptic GABA(A) tonic currents is augmented during SE. Mathematical modeling suggests that the change of mIPSCs with SE reflects a decrease in the number of functional postsynaptic GABA(A) receptors. It also suggests that increases in extracellular [GABA] during SE can account for the tonic current changes and can affect postsynaptic receptor kinetics with a loss of paired-pulse inhibition. GABA exposure mimics the effects of SE on mIPSC and tonic GABA(A) current amplitudes in granule cells, consistent with the model predictions. These results provide a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines, as a reduction of available functional GABA(A) postsynaptic receptors. Novel therapies for SE might be directed toward prevention or reversal of these losses.