Long-term expressional changes of Na+–K+–Cl− co-transporter 1 (NKCC1) and K+–Cl− co-transporter 2 (KCC2) in CA1 region of hippocampus following lithium-pilocarpine induced status epilepticus (PISE)

Li, Xiubin; Zhou, Jueqian; Chen, Ziyi; Chen, Shuda; Zhu, Fei-qi; Zhou, Liemin

doi:10.1016/j.brainres.2008.04.047

Cited by 80 publications

(55 citation statements)

References 31 publications

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“…KCC2 expression was significantly decreased at 1 and 2 weeks after SE (earlier time points were not examined). In the present study, by using immunohistochemical analysis of NKCC1 expression, we found that neuronal NKCC1 is upregulated shortly after SE in rats, substantiating previous experiments with pilocarpine in mice (Li et al, 2008). Two to three weeks after pilocarpine-induced SE, no significant alterations in NKCC1 expression were determined in subiculum or dentate gyrus of rats (Bragin et al, 2009).…”

Section: Discussionsupporting

confidence: 91%

“…First, behavioral hyperexcitability of SE rats in response to the infusion setup (see Results) restricted the duration of infusion. Second, more importantly, several lines of evidence indicate that hippocampal increases in NKCC1 expression and E GABA shift occur within 24 h after pilocarpine-induced SE and that E GABA recovers to control values within 1-2 weeks after SE [Pathak et al, 2007;Li et al, 2008;present data (see Results)]. …”

Section: Methodsmentioning

confidence: 84%

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

Brandt¹,

Nozadze²,

Heuchert³

et al. 2010

Journal of Neuroscience

164

166

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 84%

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

Brandt¹,

Nozadze²,

Heuchert³

et al. 2010

Journal of Neuroscience

164

166

View full text Add to dashboard Cite

show abstract

“…Experiments performed in pilocarpine-treated rats have also demonstrated that pharmacologically isolated, GABA A receptor-mediated IPSPs have more positive reversal potentials in neurons recorded in vitro from the epileptic subiculum, peirhinal cortex and amygdala (de Guzman et al, 2006;Benini and Avoli, 2005;Benini et al, 2011); these data often correlated with reduced levels of mRNA expression and immunoreactivity of the neuron-specific cotransporter KCC2. In line with the view that altered homeostasis of intracellular [Cl − ] is associated with epileptogenesis, NKCC1 mRNA and proteins in the mouse CA1 subfiled are up-regulated up to 45 days following pilocarpine-induced status epilepticus, while KCC2 is down-regulated (Li et al, 2008). Laschet et al (2007) have also demonstrated that GABAergic inhibition is more lable in human epileptogenic tissue than in non-epileptogenic tissue, a functional difference that appears to result from an intrinsic deficiency of GABA A receptor endogenous phosphorylation.…”

Section: Gaba a Receptor-mediated Inhibition In Temporal Lobe Epilepsysupporting

confidence: 64%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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“…A downregulation of KCC2 could be one reason for a depolarizing or even an excitatory GABA action. A decrease of KCC2 expression was described in the aforementioned studies 12,13,[15][16][17] and further after pilocarpine-induced epilepsy, 18 as well as in cortical malformations associated with epilepsy. 19 A downregulation of KCC2 expression was also revealed under ischemic conditions, particularly after oxygen glucose deprivation in hippocampal slices 20 and in an in vivo model of global ischemia.…”

mentioning

confidence: 85%

Downregulation of Potassium Chloride Cotransporter KCC2 After Transient Focal Cerebral Ischemia

Jaenisch

Witte

Frahm

2010

Stroke

110

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Background and Purpose-The potassium chloride cotransporter 2 (KCC2) is the main neuronal chloride extruder in the adult nervous system. Therefore, KCC2 is responsible for an inwardly directed electrochemical gradient of chloride that leads to hyperpolarizing GABA-mediated responses. Under some pathophysiological conditions, GABA has been reported to be depolarizing because of a downregulation of KCC2. This is the first study to our knowledge analyzing the expression of KCC2 after a focal cerebral ischemia. Methods-Mild and severe ischemia were induced in rats by a transient occlusion of the middle cerebral artery for 30 and 120 minutes, respectively. KCC2 mRNA and protein expression were studied in the ischemic hemisphere after different reperfusion times (2 hour, 1 day, 7 days, 30 days, 168 days) by using quantitative polymerase chain reaction, Western blotting, and immunohistological staining. Results-We found a substantial decrease of KCC2 mRNA and protein levels in the ischemic hemisphere, with a stronger downregulation of KCC2 after severe vs mild ischemia. Long-term surviving cells expressing KCC2 could be detected in the infarct core. These cells were identified as GABAergic interneurons mainly expressing parvalbumin. Conclusions-Our study revealed a substantial neuron-specific downregulation of KCC2 after focal cerebral ischemia. (Stroke.2010;41:e151-e159.)

show abstract

Long-term expressional changes of Na+–K+–Cl− co-transporter 1 (NKCC1) and K+–Cl− co-transporter 2 (KCC2) in CA1 region of hippocampus following lithium-pilocarpine induced status epilepticus (PISE)

Cited by 80 publications

References 31 publications

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

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

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Downregulation of Potassium Chloride Cotransporter KCC2 After Transient Focal Cerebral Ischemia

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