Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure

Abstract

Astrocyte swelling (cytotoxic brain edema) is the major neurological complication of acute liver failure (ALF), a condition in which ammonia has been strongly implicated in its etiology. Ion channels and transporters are known to be involved in cell volume regulation and a disturbance in these systems may result in cell swelling. One ion channel known to contribute to astrocyte swelling/brain edema in other neurological disorders is the ATP-dependent, non-selective cation channel (NCCa-ATP channel). We therefore examined its potential role in the astrocyte swelling/brain edema associated with ALF. Cultured astrocytes treated with 5 mM ammonia showed a 3-fold increase in the sulfonylurea receptor type 1 (SUR1) protein expression, a marker of NCCa-ATP channel activity. Blocking SUR1 with glibenclamide significantly reduced the ammonia-induced cell swelling in cultured astrocytes. Additionally, overexpression of SUR1 in ammonia-treated cultured astrocytes was significantly reduced by co-treatment of cells with BAY 11-7082, an inhibitor of NF-κB, indicating the involvement of an NF-κB-mediated SUR1 upregulation in the mechanism of ammonia-induced astrocyte swelling. Brain SUR1 mRNA level was also found to be increased in the thioacetamide (TAA) rat model of ALF. Additionally, we found a significant increase in SUR1 protein expression in rat brain cortical astrocytes in TAA-treated rats. Treatment with glibenclamide significantly reduced the brain edema in this model of ALF. These findings strongly suggest the involvement of NCCa-ATP channel in the astrocyte swelling/brain edema in ALF, and that targeting this channel may represent a useful approach for the treatment of the brain edema associated with ALF.

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…Unlike many other constitutively expressed SUR1 regulated channels in various systemic tissues, SUR1-TRPM4 is unique in that it is not normally present in the CNS, but undergoes de novo upregulation after CNS injury [36]. Upregulation of SUR1 with or without TRPM4 (hereafter SUR1±TRPM4) has been demonstrated in multiple CNS cell types (neurons, astrocytes, endothelial cells, macrophages, microglia) and models of injury, including ischemic stroke [56][57][58][59], TBI [50,[60][61][62], spinal cord injury (SCI) [63,64], intracerebral hemorrhage (ICH) [65], subarachnoid hemorrhage (SAH) [66,67], CNS metastases [68], cardiac arrest [69,70], hepatic failure [71], and encephalomyelitis [72][73][74] ( Figure 1A). The increased expression in several cell-types of the neurovascular unit renders SUR1-TRPM4 a likely contributor across the spectrum of cerebral edema endotypes (reviewed elsewhere [14,15,75]), including cellular/cytotoxic edema, ionic edema, vasogenic edema, and eventually hemorrhagic transformation/progression with complete disintegration of the BBB and oncotic death of endothelial cells ( Figure 1C) [14,15,76].…”

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

“…Recently, the stimulation of ion transporters, including the Na 33,34 and the nonselective cation (NCCa-ATP) channel, 35 as well as an increase in the level of the astrocytic plasma membrane protein aquaporin-4, 36 have all been shown to be involved in the mechanism of ammonia neurotoxicity, particularly in the development of the cytotoxic brain edema associated with acute HE. While the signaling systems that are stimulated in acute HE are well established, evidence for the involvement of signaling factors in chronic HE remains sparse.…”

Glibenclamide Is Comparable to Target Temperature Management in Improving Survival and Neurological Outcome After Asphyxial Cardiac Arrest in Rats

“…In recent years, GBC has been proved to be neuroprotective in several disease models, including cerebral infraction, traumatic brain injury, subarachnoid hemorrhage, hemorrhagic encephalopathy of prematurity, spinal cord injury, hepatic encephalopathy, and multiple sclerosis 10, 11, 12, 13, 14, 15, 16. Moreover, the use of sulfonylureas (to treat diabetes) around the time of acute ischemic stroke has been associated with less neurological deficit and lower risk of hemorrhagic conversion 17, 18.…”