{"title":"Pre-Clinical Models of Acquired Neonatal Seizures: Differential Effects of Injury on Function of Chloride Co-Transporters.","authors":"Sk Kang, Sd Kadam","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>Hypoxic-ischemic encephalopathy [HIE] represents the most common acquired pathology associated with neonatal seizures. HIE-associated neonatal seizures are often difficult to control, due to their refractoriness to traditional anti-seizure agents. Developmentally regulated chloride gradients during early development make the neonatal brain more seizure-susceptible by depolarizing GABA<sub>A</sub>R-mediated currents, and therefore hindering inhibition by conventional anti-seizure drugs such as phenobarbital [PB] and benzodiazepines. Pharmaco-modulation of chloride co-transporters has become a current field of research in treating refractory neonatal seizures, and the basis of two clinical trials [NCT01434225; NCT00380531]. However, the recent termination of NEMO study [NCT01434225] on bumetanide, an NKCC1 antagonist, suggests that clinical utilization of bumetanide as an adjunct to treat neonatal seizures with PB may not be a viable option. Hence, re-evaluation of bumetanide as an adjunct through pre-clinical studies is warranted. Additionally, the model-specific variability in the efficacy of bumetanide in the pre-clinical models of neonatal seizures highlights the differential consequences of insults used to induce seizures in each pre-clinical model as worth exploration. Injury itself can significantly alter the function of chloride co-transporters, and therefore the efficacy of anti-seizure agents that follow.</p>","PeriodicalId":90444,"journal":{"name":"Austin journal of cerebrovascular disease & stroke","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290373/pdf/nihms644394.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Austin journal of cerebrovascular disease & stroke","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Hypoxic-ischemic encephalopathy [HIE] represents the most common acquired pathology associated with neonatal seizures. HIE-associated neonatal seizures are often difficult to control, due to their refractoriness to traditional anti-seizure agents. Developmentally regulated chloride gradients during early development make the neonatal brain more seizure-susceptible by depolarizing GABAAR-mediated currents, and therefore hindering inhibition by conventional anti-seizure drugs such as phenobarbital [PB] and benzodiazepines. Pharmaco-modulation of chloride co-transporters has become a current field of research in treating refractory neonatal seizures, and the basis of two clinical trials [NCT01434225; NCT00380531]. However, the recent termination of NEMO study [NCT01434225] on bumetanide, an NKCC1 antagonist, suggests that clinical utilization of bumetanide as an adjunct to treat neonatal seizures with PB may not be a viable option. Hence, re-evaluation of bumetanide as an adjunct through pre-clinical studies is warranted. Additionally, the model-specific variability in the efficacy of bumetanide in the pre-clinical models of neonatal seizures highlights the differential consequences of insults used to induce seizures in each pre-clinical model as worth exploration. Injury itself can significantly alter the function of chloride co-transporters, and therefore the efficacy of anti-seizure agents that follow.