Inhibition of the Na+–K+–2Cl−-cotransporter in choroid plexus attenuates traumatic brain injury-induced brain edema and neuronal damage

Lu, Kwok Tung; Wu, Chang Yen; Cheng, Nai Chi; Wo, Yu Yuan P.; Yang, Jing‐Tang; Yen, Hao Han; Yang, Yi

doi:10.1016/j.ejphar.2006.07.048

Cited by 60 publications

(48 citation statements)

References 43 publications

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“…Combined treatment with phenobarbital and bumetanide for 2 weeks after SE did not enhance the disease-modifying effect obtained with phenobarbital alone, although we used dosing protocols of bumetanide that had previously been reported to exert anticonvulsant or neuroprotective effects in rats (Dzhala et al, 2005;Lu et al, 2006Lu et al, , 2007. However, pharmacokinetic analyses showed that bumetanide is extremely rapidly eliminated in adult rats, substantiating previous pharmacokinetic experiments with this drug in rats (Busch et al, 1979;Kim and Lee, 2001).…”

Section: Discussionmentioning

confidence: 60%

“…Bumetanide is a highly potent loop diuretic that selectively blocks NKCC1 at submicromolar concentrations, thereby reducing intracellular chloride concentration (Hannaert et al, 2002;Payne et al, 2003). Bumetanide has been shown to exert neuroprotective effects in rat models of traumatic brain injury (Lu et al, 2006(Lu et al, , 2007, but whether this drug also exerts antiepileptogenic activity in models of TLE with spontaneous recurrent seizures (SRS) is not known. In newborn rats, in which GABA is excitatory, administration of bumetanide, either alone or in combination with the antiepileptic drug phenobarbital, exerted an anticonvulsant effect on neonatal seizures, but the combination of both drugs was more efficacious than bumetanide alone (Dzhala et al, 2005(Dzhala et al, , 2008.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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

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“…Preliminary studies suggest that bumetanide may be used at doses that provide specific inhibition of CNS NKCC1, without producing significant diuresis. The ionic regulation of cell volume via this channel may have implications in the treatment of edema in a wide range of neurological diseases, such as traumatic brain injury [61][62][63], ischemic stroke [55,64,65], hemorrhagic stroke [66], and tumor [67,68]. The design of trials to evaluate its effect on edema in brain injured states, such as stroke and traumatic brain injury, is underway.…”

Section: Nkcc1mentioning

confidence: 99%

Novel Treatment Targets for Cerebral Edema

2012

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Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl(−) co-transporter (NKCC1) and the SUR1-regulated NC Ca-ATP (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A-and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis.Keywords Cerebral edema . Hyponatraemia . Osmotherapy . NKCC1 . SUR1/TRPM4 . Vaptan . Glyburide Overview of Perturbations in Brain Fluid HomeostasisCerebral edema in the neurointensive care setting can occur with a heterogenous group of neurological diseases, which typically fall under the categories of metabolic [1, 2], infectious [3], neoplastic [4], cerebrovascular [5][6][7], and traumatic [8,9] brain injury. Irrespective of the inciting process, cerebral edema results in the pathological accumulation of fluid in the brain's intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 distinct fluid compartments within the cranium; fluid is present within: 1) the blood in the cerebral blood vessels, 2) the cerebrospinal fluid in the ventricular system and subarachnoid space, 3) the interstitial fluid of the brain parenchyma, and 4) the intracellular fluid of the neurons and glia. These fluid compartments are not isolated, and specific movements of solutes and water from one compartment to another occur under normal conditions. When dysregulation of this normally tightly controlled fluid balance...

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“…A recent study showed that administration of bumetanide, either prior to or during ischemia, significantly reduces brain edema in rats (Yan et al, 2001). Activation of NKCC1 was shown to contribute to brain edema after traumatic brain injury (Staub et al, 1994;Lu et al, 2006;Lu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The NKCC2 isoform is localized exclusively to the kidney (Ecelbarger et al, 1996;Payne and Forbush, 1994). NKCC1 activation was shown to contribute to astrocyte swelling/brain edema in ischemia and to brain edema after traumatic brain injury (MacVicar et al, 2002;Su et al, 2002a;Su et al, 2002b;Staub et al, 1994;Lu et al, 2006;Lu et al, 2007). Its role in astrocyte swelling after manganese treatment and in the brain edema in fulminant hepatic failure, however, is not known.…”

Section: Introductionmentioning

confidence: 99%

Na-K-Cl Cotransporter-1 as a Regulator of Manganese-induced Astrocyte Swelling

Ramakrishnan¹,

Raghavendra²,

Prabhakaran³

et al. 2014

Sci. Technol. Arts Res. J.

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Article InformationAstrocyte swelling leads to brain edema, intracranial pressure, brain herniation and acute liver failure (fulminant hepatic failure) which is the major cause of death in this condition. Manganese has been strongly implicated as an important factor in astrocyte swelling. Manganese in excess is neurotoxic and causes a CNS disorder that resembles Parkinson's disease (manganism). Manganese highly accumulates in astrocytes, which renders these cells more vulnerable to its toxicity. In addition to manganism, increased brain levels of manganese have been found in hepatic encephalopathy. Manganese is known to cause cell swelling in cultured astrocytes, although the means by which this occurs has not been fully elucidated. A disturbance in one or more of these systems may result in loss of ion homeostasis and cell swelling. In particular, activation of the Na-K-Cl cotransporter-1 (NKCC1) has been shown to be involved in cell swelling in several neurological disorders. We therefore examined the effect of manganese on NKCC activity and its potential role in the swelling of astrocytes. Cultured astrocytes were exposed to manganese (50 M), and NKCC activity was measured. Manganese increased NKCC activity at 24 h. Inhibition of this activity by bumetanide diminished manganese-induced astrocyte swelling. Manganese (Mn) also increased total as well as phosphorylated NKCC1. These results suggest that activation of NKCC1 is an important factor in the mediation of astrocyte swelling by manganese and that such activation appears to be mediated by NKCC1 abundance.

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Inhibition of the Na+–K+–2Cl−-cotransporter in choroid plexus attenuates traumatic brain injury-induced brain edema and neuronal damage

Cited by 60 publications

References 43 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

Novel Treatment Targets for Cerebral Edema

Na-K-Cl Cotransporter-1 as a Regulator of Manganese-induced Astrocyte Swelling

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