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

Abstract

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

On Potential Interactions between Non-selective Cation Channel TRPM4 and Sulfonylurea Receptor SUR1

“…We provide compelling evidence that in a recombinant system, TRPM4 channels are not modulated by SUR1; although we cannot discard the possibility that interaction may occur in a different cellular environment, our data do not support the hypothesis that the cationic currents measured in astrocytes and endothelial cells from rodent models for neurovascular trauma are due to TRPM4 channels under direct modulation by SUR1 subunits (9). At the foundation of this hypothesis lies the observation that these currents are apparently inhibited by sulfonylureas (11,12,45,54). It is unclear whether the effect of these drugs was tested once desensitization of TRPM4-like currents was complete and a steady-state had been reached, as done in our study (Figs.…”

“…TRPM4-mediated currents are known to be up-regulated in certain pathological situations (40 -42), and it is thus plausible that TRPM4 channels are responsible for the cationic currents that lead to post-traumatic neurovascular cell swelling and necrosis. On the other hand, Kir6.1 and Kir6.2 subunits are abundant in tissues where SUR1 is up-regulated following a stroke (54), and the possible concomitant increase in K ATP currents remains to be addressed.…”

Novel Treatment Targets for Cerebral Edema

“…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.…”

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

“…Recent studies show that the SUR1 receptor is upregulated in response to pro-inflammatory signals, and the K ATP channel blocker, glibenclamide, exerts neuroprotective effects through its action on non-neuronal cells in the MCAO model in rat [132,133] . Because glibenclamide also has non-K ATP channel effects, mechanisms underlying the effect of glibenclamide remain to be further investigated.…”