Document Detail

Disease-modifying effects of phenobarbital and the NKCC1 inhibitor bumetanide in the pilocarpine model of temporal lobe epilepsy.
MedLine Citation:
PMID:  20573906     Owner:  NLM     Status:  MEDLINE    
Accumulating evidence suggests that changes in neuronal chloride homeostasis may be involved in the mechanisms by which brain insults induce the development of epilepsy. A variety of brain insults, including status epilepticus (SE), lead to changes in the expression of the cation-chloride cotransporters KCC2 and NKCC1, resulting in intracellular chloride accumulation and reappearance of immature, depolarizing synaptic responses to GABA(A) receptor activation, which may critically contribute to the neuronal hyperexcitability underlying epileptogenesis. In the present study, it was evaluated whether prolonged administration of the selective NKCC1 inhibitor, bumetanide, after a pilocarpine-induced SE modifies the development of epilepsy in adult female rats. The antiepileptic drug phenobarbital, either alone or in combination, was used for comparison. Based on pharmacokinetic studies with bumetanide, which showed extremely rapid elimination and low brain penetration of this drug in rats, bumetanide was administered systemically with different dosing protocols, including continuous intravenous infusion. As shown by immunohistochemistry, neuronal NKCC1 expression was markedly upregulated shortly after SE. Prophylactic treatment with phenobarbital after SE reduced the number of rats developing spontaneous seizures and decreased seizure frequency, indicating a disease-modifying effect. Bumetanide did not exert any significant effects on development of spontaneous seizures nor did it enhance the effects of phenobarbital. However, combined treatment with both drugs counteracted several of the behavioral consequences of SE, which was not observed with single drug treatment. These data do not indicate that bumetanide can prevent epilepsy after SE, but the disease-modifying effect of this drug warrants further studies with more lipophilic prodrugs of bumetanide.
Claudia Brandt; Maia Nozadze; Nina Heuchert; Marta Rattka; Wolfgang Löscher
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  30     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-24     Completed Date:  2010-07-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8602-12     Citation Subset:  IM    
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, D-30559 Hannover, Germany.
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MeSH Terms
Amygdala / chemistry,  drug effects,  metabolism
Analysis of Variance
Anticonvulsants / pharmacology
Behavior, Animal / drug effects
Bumetanide / analysis,  pharmacology*
Cell Count
Cerebral Cortex / chemistry,  drug effects,  metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Administration Schedule
Epilepsy, Temporal Lobe / chemically induced,  drug therapy*,  metabolism
Hippocampus / chemistry,  drug effects,  metabolism
Motor Activity / drug effects
Neurons / drug effects,  metabolism*
Phenobarbital / analysis,  pharmacology*
Rats, Sprague-Dawley
Sodium-Potassium-Chloride Symporters / metabolism*
Status Epilepticus / chemically induced,  drug therapy,  metabolism
Reg. No./Substance:
0/Anticonvulsants; 0/Sodium-Potassium-Chloride Symporters; 0/sodium-potassium-chloride cotransporter 1 protein; 28395-03-1/Bumetanide; 50-06-6/Phenobarbital; 92-13-7/Pilocarpine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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