» Articles » PMID: 20573906

Disease-modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

Overview
Journal J Neurosci
Specialty Neurology
Date 2010 Jun 25
PMID 20573906
Citations 69
Authors
Affiliations
Soon will be listed here.
Abstract

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.

Citing Articles

Loss of PV Interneurons in the BLA May Contribute to Altered Network and Behavioral States in Chronically Epileptic Mice.

Colmers P, Antonoudiou P, Basu T, Coleman E, He Y, Scapa G eNeuro. 2025; 12(1).

PMID: 39746805 PMC: 11773627. DOI: 10.1523/ENEURO.0482-23.2024.


The role of family of cation-chloride cotransporters and drug discovery methodologies.

Zhang S, Meor Azlan N, Josiah S, Zhou J, Zhou X, Jie L J Pharm Anal. 2024; 13(12):1471-1495.

PMID: 38223443 PMC: 10785268. DOI: 10.1016/j.jpha.2023.09.002.


Unilateral optogenetic kindling of hippocampus leads to more severe impairments of the inhibitory signaling in the contralateral hippocampus.

Tescarollo F, Valdivia D, Chen S, Sun H Front Mol Neurosci. 2023; 16:1268311.

PMID: 37942301 PMC: 10627882. DOI: 10.3389/fnmol.2023.1268311.


Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model.

Egawa K, Watanabe M, Shiraishi H, Sato D, Takahashi Y, Nishio S Sci Rep. 2023; 13(1):5685.

PMID: 37069177 PMC: 10110603. DOI: 10.1038/s41598-023-32376-z.


Developmental changes in brain activity of heterozygous knockout rats.

Tahara M, Higurashi N, Hata J, Nishikawa M, Ito K, Hirose S Front Neurol. 2023; 14:1125089.

PMID: 36998780 PMC: 10043303. DOI: 10.3389/fneur.2023.1125089.


References
1.
OGrady S, Palfrey H, Field M . Characteristics and functions of Na-K-Cl cotransport in epithelial tissues. Am J Physiol. 1987; 253(2 Pt 1):C177-92. DOI: 10.1152/ajpcell.1987.253.2.C177. View

2.
Clayton G, Owens G, Wolff J, Smith R . Ontogeny of cation-Cl- cotransporter expression in rat neocortex. Brain Res Dev Brain Res. 1998; 109(2):281-92. DOI: 10.1016/s0165-3806(98)00078-9. View

3.
Galanopoulou A . Developmental patterns in the regulation of chloride homeostasis and GABA(A) receptor signaling by seizures. Epilepsia. 2007; 48 Suppl 5:14-8. DOI: 10.1111/j.1528-1167.2007.01284.x. View

4.
Freichel C, Potschka H, Ebert U, Brandt C, Loscher W . Acute changes in the neuronal expression of GABA and glutamate decarboxylase isoforms in the rat piriform cortex following status epilepticus. Neuroscience. 2006; 141(4):2177-94. DOI: 10.1016/j.neuroscience.2006.05.040. View

5.
Dzhala V, Talos D, Sdrulla D, Brumback A, Mathews G, Benke T . NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005; 11(11):1205-13. DOI: 10.1038/nm1301. View