Dynamics of interstitial and intracellular pH in evolving brain infarct

Nedergaard, Maiken; Kraig, Richard P.; Tanabe, Jody; Pulsinelli, William A.

doi:10.1152/ajpregu.1991.260.3.r581

Cited by 156 publications

(175 citation statements)

References 31 publications

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“…We found that constant infusion of low-dose glibenclamide caused only slight reduction of serum glucose, but was highly effective in reducing cerebral edema, infarct volume and mortality in rodent models of stroke. Three features combine to maximize beneficial effects while minimizing potential side effects of glibenclamide: (i) its molecular target resides within the lipid plasmalemmal membrane 11,12 ; (ii) as a weak acid, its lipophilicity, which determines its ability to reach its target, increases in acidic medium; and (iii) targeted ischemic tissues are acidic 13 . Thus, the safety of glibenclamide, as borne out by decades of use in humans, and the efficacy of glibenclamide, as shown here, indicate that glibenclamide may be particularly attractive for translational use in human stroke.…”

Section: Discussionmentioning

confidence: 99%

“…It is the un-ionized form of the weak acid, glibenclamide (pK a 6.3), however, that is responsible for channel block 11,12 , and at pH 7.4, only 7% is un-ionized. We reasoned that the apparent potency of glibenclamide would increase at the acidic pH found in ischemic brain 13 . In the same neurons from the core, reducing the pH to 6.8 decreased the open probability with 50 nM glibenclamide to 12.0 ± 4.4% of baseline values (Fig.…”

Section: Nc Ca-atp Channel In Neurons After Mcaomentioning

confidence: 99%

“…Labeling in peri-infarct tissues reflected not only an increase in SUR1 glibenclamide-binding sites, which show femtomolar binding affinity for glibenclamide 22,23 , but also indicated that normal permeability barriers no longer excluded the drug. Selective distribution of drug to peri-infarct tissues may have been facilitated by breakdown of the blood-brain barrier, but was undoubtedly driven by an increase in lipid solubility of the weak acid, glibenclamide, as a result of the low pH of ischemic periinfarct tissues 13 .…”

Section: Tissue Distribution Of Glibenclamide In Mce Modelmentioning

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

390

523

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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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Section: Discussionmentioning

confidence: 99%

Section: Nc Ca-atp Channel In Neurons After Mcaomentioning

confidence: 99%

Section: Tissue Distribution Of Glibenclamide In Mce Modelmentioning

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

390

523

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“…Accumulation of lactic acid, alone with increased H + release from ATP hydrolysis, causes a decrease in brain pH, or acidosis. During brain ischemia, pH o falls to 6.5 or lower [2,35].…”

Section: Asic1a Activation In Acidosis-mediated and Ischemic Neuronalmentioning

confidence: 99%

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Xiong

Pignataro²,

et al. 2008

Current Opinion in Pharmacology

211

161

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A significant drop of tissue pH or acidosis is a common feature of acute neurological conditions such as ischemic stroke, brain trauma, and epileptic seizures. Acid-sensing ion channels, or ASICs, are proton-gated cation channels widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. Recent studies have demonstrated that activation of these channels by protons plays an important role in a variety of physiological and pathological processes such as nociception, mechanosensation, synaptic plasticity, and acidosis-mediated neuronal injury. This review provides an overview of the recent advance in electrophysiological, pharmacological characterization of ASICs, and their role in neurological diseases. Therapeutic potential of current available ASIC inhibitors is discussed.

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“…Interstitial pH undergoes multiphasic changes during normal synaptic transmission and much larger changes during seizure activity and ischemia, during which pH levels can fall by 0.2-0.6 pH units (Siesjo, 1985;Balestrino and Somjen, 1988;Nedergaard et al, 1991;Chesler and Kaila, 1992). Because neuronal injury during both seizure and ischemia is associated with glutamate release (Hirano et al, 2003) and NMDA receptor activation, mild acidification of the extracellular space in the penumbra might be expected to limit the extent of glutamate-induced neurotoxicity, although acidification in the infarct core can be harmful.…”

Section: Introductionmentioning

confidence: 99%

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H ϩ . We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 ϫ 10 9 M Ϫ1 sec Ϫ1 and 110 -196 sec Ϫ1 , respectively (K d corresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.

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Dynamics of interstitial and intracellular pH in evolving brain infarct

Cited by 156 publications

References 31 publications

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

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

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

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