Functional Coupling between Sulfonylurea Receptor Type 1 and a Nonselective Cation Channel in Reactive Astrocytes from Adult Rat Brain

Chen, Mingkui; Dong, Yafeng; Simard, J. Marc

doi:10.1523/jneurosci.23-24-08568.2003

Cited by 151 publications

(208 citation statements)

References 36 publications

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“…The opening of SUR1/TRPM4 channels causes complete depolarization and cell blebbing, characteristic of cytotoxic (cellular) edema. Depolarization and blebbing induced by depletion of ATP are prevented by glibenclamide, consistent with a crucial role for SUR1/ TRPM4 channels in cytotoxic edema [71,72]. SUR1/ TRPM4 channels represent an important path for sodium flux required for formation of edema, and independent of Na + -K + -ATPase inactivity seen in ischemia.…”

Section: Nkcc1mentioning

confidence: 54%

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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Section: Nkcc1mentioning

confidence: 54%

Novel Treatment Targets for Cerebral Edema

2012

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“…Opening of NC Ca-ATP channels causes complete depolarization and cell blebbing, characteristic of cytotoxic edema. Depolarization and blebbing induced by depletion of ATP are prevented by glibenclamide, and are reproduced without depletion of ATP by diazoxide, consistent with a crucial role for NC Ca-ATP channels in cytotoxic edema 3 .…”

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confidence: 59%

“…2b). Apart from its involvement in K ATP channels, SUR1 also forms the regulatory subunit of NC Ca-ATP channels 3 . As the pore-forming subunit of the NC Ca-ATP channel has not been cloned, we used its biophysical properties for identification.…”

Section: Nc Ca-atp Channel In Neurons After Mcaomentioning

confidence: 99%

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Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke

Simard

Chen

Tarasov

et al. 2006

Nat Med

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Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC Ca-ATP channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC Ca-ATP but not K ATP channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC Ca-ATP channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.Edema complicates many conditions that affect the central nervous system (CNS), including stroke and trauma. Edema worsens neurological function and can threaten life. Swelling resulting from malignant cerebral edema after a large middle cerebral artery (MCA) stroke is responsible for the high mortality of 60−80% of the patients 1 . Molecular mechanisms of cerebral edema are poorly understood, and available treatments are nonspecific and only moderately effective 1 .SUR1 is a regulatory subunit that associates with Kir6.x pore-forming subunits to form heterooctameric K ATP channels 2 . SUR1 confers sensitivity to sulfonylurea inhibitors such as glibenclamide and to channel activators such as diazoxide. Apart from involvement with

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“…These results suggested that mitochondrial ATP-sensitive potassium channels served as the target for diazoxide in the astrocytes [13]. On the other hand, another recent investigation has revealed the possibility that ATP-sensitive non-selective cation channels on the surface of reactive astrocytes could be regulated by sulfonylurea receptor-1, which is the site of action of diazoxide [3]. These data suggest that diazoxide can target both mitochondrial and surface cation channels on the astrocytes, thereby modulating the astrocytic function, which could explain our present data.…”

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confidence: 97%

Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain

Farkas

Annaházi

Institóris

et al. 2005

Neuroscience Letters

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Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain Farkas, E; Annahazi, A; Institoris, A; Mihaly, A; Luiten, PGM; Bari, F Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Farkas, E., Annahazi, A., Institoris, A., Mihaly, A., Luiten, P. G. M., & Bari, F. (2005). Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain. Neuroscience Letters, 373(3), 195-199. DOI: 10.1016/j.neulet.2004 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. AbstractAging and dementia are accompanied by cerebral white matter (WM) injury, which is considered to be of ischemic origin. A causal link between cerebral ischemia and WM damage has been demonstrated in rats; however, few attempts appear to have been made to test potential drugs for the alleviation of ischemia-related WM injury.We induced cerebral hypoperfusion via permanent, bilateral occlusion of the common carotid arteries of rats. A mitochondrial ATP-sensitive potassium channel opener diazoxide (5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) was administered i.p. (0.25 ml) on 5 consecutive days after surgery. Sham-operated animals served as control for surgery, and non-treated rats as controls for treatments. Thirteen weeks after surgery, the animals were sacrificed and astrocytes and microglia were labeled immunocytochemically in the internal capsule, the corpus callosum and the optic tract.The astrocytic proliferation was enhanced by cerebral hypoperfusion in the optic tract, and reduced by diazoxide in DMSO, but not by DMSO alone in the corpus callosum. After carotid artery occlusion, microglial activation was enhanced two-fold in the corpus callosum and four-fold in the optic tract. DMSO decreased microglial activation in the optic tract, while diazoxide in DMSO, but not DMSO alone, restored microglial activation to the control level in the corpus callosum.In summary, the rat optic tract appeared to be particularly vulnerable to ischemia, while the effect of diazoxide was restricted to the corpus callosum. We conclude that diazoxide dissolved in DMSO can moderate ischemia-related neuroinflammation by suppressing glial reaction in selective cerebral WM areas.

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Functional Coupling between Sulfonylurea Receptor Type 1 and a Nonselective Cation Channel in Reactive Astrocytes from Adult Rat Brain

Cited by 151 publications

References 36 publications

Novel Treatment Targets for Cerebral Edema

Novel Treatment Targets for Cerebral Edema

Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke

Diazoxide and dimethyl sulphoxide alleviate experimental cerebral hypoperfusion-induced white matter injury in the rat brain

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