Bumetanide enhances phenobarbital efficacy in a neonatal seizure model

Dzhala, Volodymyr; Brumback, Audrey C.; Staley, Kevin J.

doi:10.1002/ana.21229

Cited by 249 publications

(257 citation statements)

References 82 publications

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“…4B) ( P = 0.86, 0.8, and 0.25, respectively, n = 5). Interseizure interval tends to gradually decrease in this preparation over time,36 but celecoxib did not revert this trend (Fig. 4B).…”

Section: Resultsmentioning

confidence: 84%

“…Extracellular field potentials were recorded in the CA1 and/or CA3 pyramidal cell layer of intact hippocampi36 and organotypic hippocampal slices in a conventional submerged chamber using tungsten‐coated microelectrodes and ISO‐DAM8A amplifier (World Precision Instruments). Oxygenated (95% O 2 and 5% CO 2 ) artificial cerebrospinal fluid containing 126 mmol/L NaCl, 3.5 mmol/L KCl, 2 mmol/L CaCl 2 , 1.3 mmol/L MgCl 2 , 25 mmol/L NaHCO 3 , 1.2 mmol/L NaH 2 PO 4 , and 11 mmol/L glucose (pH 7.4), was continuously perfused at 33 ± 0.5°C.…”

Section: Methodsmentioning

confidence: 99%

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Staged anticonvulsant screening for chronic epilepsy

Berdichevsky

Saponjian

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveCurrent anticonvulsant screening programs are based on seizures evoked in normal animals. One‐third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high‐throughput in vitro models to low‐throughput in vivo models.MethodsEpileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure‐like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings.ResultsWe screened 407 compound‐concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy.InterpretationThe use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure‐like activity and seizure‐induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models.

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“…4B) ( P = 0.86, 0.8, and 0.25, respectively, n = 5). Interseizure interval tends to gradually decrease in this preparation over time,36 but celecoxib did not revert this trend (Fig. 4B).…”

Section: Resultsmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Staged anticonvulsant screening for chronic epilepsy

Berdichevsky

Saponjian

Park

et al. 2016

Ann Clin Transl Neurol

Self Cite

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“…Another study found bumetainde to enhance the anticonvulsant action of phenobarbitone in immature brain by alteration of Cl-transport. Seizures were abolished in 70% and significantly reduced the frequency, duration and power of seizures in the remaining 30% when both drugs used in conjunction (106) .…”

Section: Neonatal Seizures 39mentioning

confidence: 99%

Neonatal Seizures

Al-Zwaini¹

2011

Epilepsy in Children - Clinical and Social Aspects

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“…As a result, during early stages of development, the GABA-A receptor-mediated opening of Cl -channels leads to an outward Cl -flow and, thus, to excitation [122]. One of the presumed consequences of GABA acting as an excitatory neurotransmitter early in life is the ineffectiveness of GABAergic antiepileptic drugs [122,123] on the one hand, and the antiepileptic effects of NKCC1 blockers on the other hand. Indeed, the NKCC1 blocker bumetanide exerted acute anticonvulsant effects in immature animals [123].…”

Section: Rapid Kindling: a Model Of Epileptogenesis In The Developingmentioning

confidence: 99%

“…One of the presumed consequences of GABA acting as an excitatory neurotransmitter early in life is the ineffectiveness of GABAergic antiepileptic drugs [122,123] on the one hand, and the antiepileptic effects of NKCC1 blockers on the other hand. Indeed, the NKCC1 blocker bumetanide exerted acute anticonvulsant effects in immature animals [123]. Under conditions of rapid kindling applied to immature animals across different ages, bumetanide exerted potent antiepileptogenic effect in all but few neonatal rats, yet it was completely ineffective in pre-adolescent subjects.…”

Section: Rapid Kindling: a Model Of Epileptogenesis In The Developingmentioning

confidence: 99%

Novel Animal Models of Pediatric Epilepsy

et al. 2012

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When mimicking epileptic processes in a laboratory setting, it is important to understand the differences between experimental models of seizures and epilepsy. Because human epilepsy is defined by the appearance of multiple spontaneous recurrent seizures, the induction of a single acute seizure without recurrence does not constitute an adequate epilepsy model. Animal models of epilepsy might be useful for various tasks. They allow for the investigation of pathophysiological mechanisms of the disease, the evaluation, or the development of new antiepileptic treatments, and the study of the consequences of recurrent seizures and neurological and psychiatric comorbidities. Although clinical relevance is always an issue, the development of models of pediatric epilepsies is particularly challenging due to the existence of several key differences in the dynamics of human and rodent brain maturation. Another important consideration in modeling pediatric epilepsy is that "children are not little adults," and therefore a mere application of models of adult epilepsies to the immature specimens is irrelevant. Herein, we review the models of pediatric epilepsy. First, we illustrate the differences between models of pediatric epilepsy and models of the adulthood consequences of a precipitating insult in early life. Next, we focus on new animal models of specific forms of epilepsies that occur in the developing brain. We conclude by emphasizing the deficiencies in the existing animal models and the need for several new models.

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Bumetanide enhances phenobarbital efficacy in a neonatal seizure model

Abstract: Thus, alteration of Cl- transport by bumetanide enables the anticonvulsant action of phenobarbital in immature brain. This is a mechanistic demonstration of rational anticonvulsant polypharmacy. The combination of these agents may comprise an effective therapy for early-life seizures.

Cited by 249 publications

References 82 publications

Staged anticonvulsant screening for chronic epilepsy

Staged anticonvulsant screening for chronic epilepsy

Neonatal Seizures

Novel Animal Models of Pediatric Epilepsy

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