Chloride Homeostasis and GABA Signaling in Temporal Lobe Epilepsy

Miles, Richard B.; Blaesse, Peter; Huberfeld, Gilles; Wittner, Lúcia; Kaila, Kai

doi:10.1093/med/9780199746545.003.0045

Cited by 59 publications

(60 citation statements)

References 112 publications

(138 reference statements)

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“…Bumetanide inhibits the neuronal chloride cotransporter NKCC1, which acts as a chloride importer. Gamma-aminobutyric acid-mediated excitation has been observed when expression of NKCC1 is higher than expression of the chloride exporter KCC2; e.g., early during development and in the hippocampus of adults with temporal lobe epilepsy [58,59]. Based on the hypothesis that increased expression of NKCC1 may be involved in the development of neuronal hyperexcitability during epileptogenesis in adults, we evaluated whether treatment with bumetanide after pilocarpine-induced SE alters the long-term consequences of the brain insult [60].…”

Section: Examples For Synergistic Drug Combinationsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Section: Examples For Synergistic Drug Combinationsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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“…It may revert excitation mediated by GABA through modifying chloride homeostasis. It suppresses GABA-generated network activities that contribute to the rhythmic interictal events (14,15). Interictal events were not detected in the current case after bumetanide treatment.…”

Section: Discussionmentioning

confidence: 61%

Follow-up Case Report: Bumetanide Can Control Seizural Activity in Temporal Lobe Epilepsy Patient

et al. 2017

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Despite the infectiveness of conventional anti-epileptic drugs (AEDs) in refractory focal epilepsy, surgery along with medications, as the only treatment, was not successful in 30% of the cases. Recently, cysto-and histo-physiological investigations revealed the role of gamma-aminobutyric acid (GABA)-ergic system in etiopathology of temporal lobe epilepsy (TLE). Studies reported that the inhibitory action of GABA neurotransmitter due to elevated intracellular Cl-concentration through abnormal expression of Na-K-Cl cotransporter (NKCC)-1 became excessive in recurrent seizures. These primary results were confirmed in the brain tissue obtained from patients with TLE. Based on the evidence, the current study suggested the administration of bumetanide, an NKCC1 inhibitor, as a potential candidate for the treatment of intractable TLE. The previous study by authors showed a significant reduction in seizural activity of 2 out of 3 patients with TLE following the administration of bumetanide. However, result of the current study showed the control of seizure in the 3rd case of previous study by the administration of bumetanide as an adjuvant to AEDs. Moreover, his AEDs dosage after discontinuation of Bumetanide tapered without any relapse.

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“…This difference can be explained by experimental differences since Zhu et al [44] used slices that presumably expressed half of the KCC2 protein content as compared to wild-type animals [44], whereas in our study, we employed slices from normal rats with normal expression of KCC2. Underexpression of KCC2 can in fact result in Cl − homeostasis changes leading to a switch in GABA A receptor signaling from hyperpolarizing to depolarizing [19,26]. Experimental data have also shown that epileptiform activity induced by 4AP leads to downregulation of KCC2 expression [8,31].…”

Section: Modulation Of Short-and Long-lasting Events By Blocking Kcc2mentioning

confidence: 99%

On the contribution of KCC2 and carbonic anhydrase to two types of in vitro interictal discharge

Hamidi

D’Antuono

Avoli

2015

Pflugers Arch - Eur J Physiol

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GABA A receptor-mediated inhibition-which is due to Cl − and HCO 3 − currents controlled by KCC2 and carbonic anhydrase activity, respectively-contributes to short-and long-lasting interictal events recorded from the CA3 region of hippocampus during application of 4-aminopyridine (4AP, 50 μM). Here, we employed field potential recordings in an in vitro brain slice preparation to establish the effects induced by the KCC2 blockers VU0240551 (10 μM) or bumetanide (50 μM) and by the carbonic anhydrase inhibitor acetazolamide (10 μM) on the two types of interictal events. We found that blocking KCC2 activity decreased the amplitude of the short-lasting events. In addition, this pharmacological procedure increased the interval of occurrence of the long-lasting events and reduced their amplitude. Blocking carbonic anhydrase activity with acetazolamide reduced the interval of occurrence and the duration of the short-lasting events while increasing their amplitude; acetazolamide also reduced the duration and amplitude of the long-lasting events. Finally, blocking either KCC2 or carbonic anhydrase activity increased the interval of occurrence of pharmacologically isolated synchronous GABAergic events and decreased their duration and amplitude. These data substantiate further the role of GABA A receptor-mediated signaling in driving neuronal populations toward hypersynchronous states presumably by increasing extracellular [K + ].

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Chloride Homeostasis and GABA Signaling in Temporal Lobe Epilepsy

Cited by 59 publications

References 112 publications

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Follow-up Case Report: Bumetanide Can Control Seizural Activity in Temporal Lobe Epilepsy Patient

On the contribution of KCC2 and carbonic anhydrase to two types of in vitro interictal discharge

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