Glyburide confers neuroprotection against age-related macular degeneration (AMD).

Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular ("dry") age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our in vitro results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD.

Covalent organic framework based cytoprotective therapy after ischemic stroke.

Cytoprotection has emerged as an effective therapeutic strategy for mitigating brain injury following acute ischemic stroke (AIS). The sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel plays a pivotal role in brain edema and neuroinflammation. However, the practical use of the inhibitor glyburide (GLB) is hindered by its low bioavailability. Additionally, the elevated reactive oxygen species (ROS) after AIS exacerbate SUR1-TRPM4 activation, contributing to irreversible brain damage. To overcome these challenges, GLB and superoxide dismutase (SOD) were embedded in a covalent organic framework (COF) with a porous structure and great stability. The resulting S/G@COF demonstrated significant improvements in survival and neurological functions. This was achieved by eliminating ROS, preventing neuronal loss and apoptosis, suppressing neuroinflammation, modulating microglia activation, and ameliorating blood-brain barrier (BBB) disruption. Mechanistic investigations revealed that S/G@COF concurrently activated the Wnt/ß-catenin signaling pathway while suppressing the upregulation of SUR1-TRPM4. This study underscores the potential of employing multi-target therapy and drug modification in cytoprotective strategies for ischemic stroke.

Resveratrol Prevents Cell Swelling Through Inhibition of SUR1 Expression in Brain Micro Endothelial Cells Subjected to OGD/Recovery.

The SUR1-TRPM4-AQP4 complex is overexpressed in the initial phase of edema induced after cerebral ischemia, allowing the massive internalization of Na+ and water within the brain micro endothelial cells (BMEC) of the blood-brain barrier. The expression of the Abcc8 gene encoding SUR1 depends on transcriptional factors that are responsive to oxidative stress. Because reactive oxygen species (ROS) are generated during cerebral ischemia, we hypothesized that antioxidant compounds might be able to regulate the expression of SUR1. Therefore, the effect of resveratrol (RSV) on SUR1 expression was evaluated in the BMEC cell line HBEC-5i subjected to oxygen and glucose deprivation (OGD) for 2 h followed by different recovery times. Different concentrations of RSV were administered. ROS production was detected with etidine, and protein levels were evaluated by Western blotting and immunofluorescence. Intracellular Na+ levels and cellular swelling were detected by imaging; cellular metabolic activity and rupture of the cell membrane were detected by MTT and LDH release, respectively; and EMSA assays measured the activity of transcriptional factors. OGD/recovery increased ROS production induced the AKT kinase activity and the activation of SP1 and NFκB. SUR1 protein expression and intracellular Na+ concentration in the HBEC-5i cells increased after a few hours of OGD. These effects correlated with cellular swelling and necrotic cell death, responses that the administration of RSV prevented. Our results indicate that the ROS/AKT/SP1-NFκB pathway is involved in SUR1 expression during OGD/recovery in BMEC of the blood-brain barrier. Thus, RSV prevented cellular edema formation through modulation of SUR1 expression.

Abcc8 (sulfonylurea receptor-1) knockout mice exhibit reduced axonal injury, cytotoxic edema and cognitive dysfunction vs. wild-type in a cecal ligation and puncture model of sepsis.

Sepsis-associated brain injury (SABI) is characterized by an acute deterioration of mental status resulting in cognitive impairment and acquisition of new and persistent functional limitations in sepsis survivors. Previously, we reported that septic mice had evidence of axonal injury, robust microglial activation, and cytotoxic edema in the cerebral cortex, thalamus, and hippocampus in the absence of blood-brain barrier disruption. A key conceptual advance in the field was identification of sulfonylurea receptor 1 (SUR1), a member of the adenosine triphosphate (ATP)-binding cassette protein superfamily, that associates with the transient receptor potential melastatin 4 (TRPM4) cation channel to play a crucial role in cerebral edema development. Therefore, we hypothesized that knockout (KO) of Abcc8 (Sur1 gene) is associated with a decrease in microglial activation, cerebral edema, and improved neurobehavioral outcomes in a murine cecal ligation and puncture (CLP) model of sepsis. Sepsis was induced in 4-6-week-old Abcc8 KO and wild-type (WT) littermate control male mice by CLP. We used immunohistochemistry to define neuropathology and microglial activation along with parallel studies using magnetic resonance imaging, focusing on cerebral edema on days 1 and 4 after CLP. Abcc8 KO mice exhibited a decrease in axonal injury and cytotoxic edema vs. WT on day 1. Abcc8 KO mice also had decreased microglial activation in the cerebral cortex vs. WT. These findings were associated with improved spatial memory on days 7-8 after CLP. Our study challenges a key concept in sepsis and suggests that brain injury may not occur merely as an extension of systemic inflammation. We advance the field further and demonstrate that deletion of the SUR1 gene ameliorates CNS pathobiology in sepsis including edema, axonal injury, neuroinflammation, and behavioral deficits. Benefits conferred by Abcc8 KO in the murine CLP model warrant studies of pharmacological Abcc8 inhibition as a new potential therapeutic strategy for SABI.

Advances in multi-omics study of biomarkers of glycolipid metabolism disorder.

Glycolipid metabolism disorder are major threats to human health and life. Genetic, environmental, psychological, cellular, and molecular factors contribute to their pathogenesis. Several studies demonstrated that neuroendocrine axis dysfunction, insulin resistance, oxidative stress, chronic inflammatory response, and gut microbiota dysbiosis are core pathological links associated with it. However, the underlying molecular mechanisms and therapeutic targets of glycolipid metabolism disorder remain to be elucidated. Progress in high-throughput technologies has helped clarify the pathophysiology of glycolipid metabolism disorder. In the present review, we explored the ways and means by which genomics, transcriptomics, proteomics, metabolomics, and gut microbiomics could help identify novel candidate biomarkers for the clinical management of glycolipid metabolism disorder. We also discuss the limitations and recommended future research directions of multi-omics studies on these diseases.

Serum Sulfonylurea Receptor-1 Levels After Acute Supratentorial Intracerebral Hemorrhage: Implication for Prognosis.

Objective: Sulfonylurea receptor-1 (SUR1) is implicated in acute brain injury. This study was designed to determine relationship between serum SUR1 levels and severity, early neurologic deterioration (END) plus clinical outcome after intracerebral hemorrhage (ICH). Methods: Serum SUR1 levels of 131 ICH patients and 131 healthy controls were quantified in this prospective, observational study. END was defined as an increase of 4 or more points in the National Institutes of Health Stroke Scale (NIHSS) score or death within 24 hours after admission. Patients with a modified Rankin scale (mRS) score of 3-6 at 90 days following onset were considered to experience a poor outcome. Results: Serum SUR1 levels were substantially higher in patients than in controls. Serum SUR1 levels of patients were highly correlated with NIHSS score, Glasgow Coma Scale score, hematoma volume and ICH score. Compared with patients with END or mRS score of 0-2, other remainders had significantly elevated serum SUR1 levels. Serum SUR1 levels independently predicted END and 90-day poor outcome. Under receiver operating characteristic curve, serum SUR1 levels significantly predicted END and a poor outcome at 90 days after hemorrhagic stroke and its predictive value was similar to those of NIHSS score, Glasgow coma scale score, hematoma volume and ICH score. Conclusion: Serum SUR1 levels are highly correlated with severity, END and poor outcome after hemorrhagic stroke, indicating that serum SUR1 may be useful for risk stratification and prognostic prediction of ICH.

Effects of short-term food deprivation on catecholamine and metabolic-sensory biomarker gene expression in hindbrain A2 noradrenergic neurons projecting to the forebrain rostral preoptic area: Impact of negative versus positive estradiol feedback.

Hindbrain A2 noradrenergic neurons assimilate estrogenic and metabolic cues. In female mammals, negative- versus positive-feedback patterns of estradiol (E) secretion impose divergent regulation of the gonadotropin-releasing hormone (GnRH)-pituitary-gonadal (HPG) neuroendocrine axis. Current research used retrograde tracing, dual-label immunocytochemistry, single-cell laser-microdissection, and multiplex qPCR methods to address the premise that E feedback modes uniquely affect metabolic regulation of A2 neurons involved in HPG control. Ovariectomized female rats were given E replacement to replicate plasma hormone levels characteristic of positive (high-E dose) or negative (low-E dose) feedback. Animals were either full-fed (FF) or subjected to short-term, e.g., 18-h food deprivation (FD). After FF or FD, rostral preoptic area (rPO)-projecting A2 neurons were characterized by the presence or absence of nuclear glucokinase regulatory protein (nGKRP) immunostaining. FD augmented or suppressed mRNAs encoding the catecholamine enzyme dopamine-beta-hydroxylase (DßH) and the metabolic-sensory biomarker glucokinase (GCK), relative to FF controls, in nGKRP-immunoreactive (ir)-positive A2 neurons from low-E or high-E animals, respectively. Yet, these transcript profiles were unaffected by FD in nGKRP-ir-negative A2 neurons at either E dosage level. FD altered estrogen receptor (ER)-alpha and ATP-sensitive potassium channel subunit sulfonylurea receptor-1 gene expression in nGKRP-ir-positive neurons from low-E, but not high-E animals. Results provide novel evidence that distinct hindbrain A2 neuron populations exhibit altered versus unaffected transmission to the rPO during FD-associated metabolic imbalance, and that the direction of change in this noradrenergic input is controlled by E feedback mode. These A2 cell types are correspondingly distinguished by FD-sensitive or -insensitive GCK, which correlates with the presence versus absence of nGKRP-ir. Further studies are needed to determine how E signal volume regulates neurotransmitter and metabolic sensor responses to FD in GKRP-expressing A2 neurons.

Role of upregulation of the KATP channel subunit SUR1 in dopaminergic neuron degeneration in Parkinson's disease.

Accumulating evidence suggests that ATP-sensitive potassium (KATP ) channels play an important role in the selective degeneration of dopaminergic neurons in the substantia nigra (SN). Furthermore, the expression of the KATP channel subunit sulfonylurea receptor 1 (SUR1) is upregulated in the remaining nigral dopaminergic neurons in Parkinson's disease (PD). However, the mechanism underlying this selective upregulation of the SUR1 subunit and its subsequent roles in PD progression are largely unknown. In 3-, 6-, and 9-month-old A53T α-synuclein transgenic (α-SynA53T+/+ ) mice, only the SUR1 subunit and not SUR2B or Kir6.2 was upregulated, accompanied by neuronal damage. Moreover, the occurrence of burst firing in dopaminergic neurons was increased with the upregulation of the SUR1 subunit, whereas no changes in the firing rate were observed except in 9-month-old α-SynA53T+/+ mice. After interference with SUR1 expression by injection of lentivirus into the SN, the progression of dopaminergic neuron degeneration was delayed. Further studies showed that elevated expression of the transcription factors FOXA1 and FOXA2 could cause the upregulation of the SUR1 subunit in α-SynA53T+/+ mice. Our findings revealed the regulatory mechanism of the SUR1 subunit and the role of KATP channels in the progression of dopaminergic neuron degeneration, providing a new target for PD drug therapy.

Serum sulfonylurea receptor-1 as a biomarker of clinical severity and prognosis in patients with traumatic brain injury.

BACKGROUND: Sulfonylurea receptor-1 (Sur1) plays an important role in acute brain injury. We determine whether serum Sur1 concentrations are associated with traumatic severity and clinical outcome after traumatic brain injury (TBI). METHODS: Serum Sur1 concentrations were measured in 100 healthy controls and 138 patients with moderate to severe TBI. Glasgow coma scale (GCS) and Rotterdam computed tomography (CT) classification were recorded to assess traumatic severity. Glasgow outcome scale (GOS) score of 1-3 at posttraumatic 3 months was defined as an unfavorable outcome. RESULTS: Serum Sur1 concentrations were markedly higher in patients than in controls. Serum Sur1 concentrations of patients were highly correlated with GCS score, Rotterdam CT classification and GOS score. Patients with unfavorable outcome displayed markedly higher serum Sur1 concentrations than those presenting with favorable outcome. Under receiver operating characteristic curve, serum Sur1 concentrations significantly distinguished patients at risk of unfavorable outcome. Serum Sur1 emerged as an independent predictor for unfavorable outcome. CONCLUSIONS: Rising serum Sur1 concentrations are highly correlated with traumatic severity and are independently associated with poor prognosis after TBI, indicating that serum Sur1 may have the potential to be a useful prognostic biomarker of TBI.

The short form of the SUR1 and its functional implications in the damaged brain.

Sulfonylurea receptor (SUR) belongs to the adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter family; however, SUR is associated with ion channels and acts as a regulatory subunit determining the opening or closing of the pore. Abcc8 and Abcc9 genes code for the proteins SUR1 and SUR2, respectively. The SUR1 transcript encodes a protein of 1582 amino acids with a mass around 140-177 kDa expressed in the pancreas, brain, heart, and other tissues. It is well known that SUR1 assembles with Kir6.2 and TRPM4 to establish KATP channels and non-selective cation channels, respectively. Abbc8 and 9 are alternatively spliced, and the resulting transcripts encode different isoforms of SUR1 and SUR2, which have been detected by different experimental strategies. Interestingly, the use of binding assays to sulfonylureas and Western blotting has allowed the detection of shorter forms of SUR (~65 kDa). Identity of the SUR1 variants has not been clarified, and some authors have suggested that the shorter forms are unspecific. However, immunoprecipitation assays have shown that SUR2 short forms are part of a functional channel even coexisting with the typical forms of the receptor in the heart. This evidence confirms that the structure of the short forms of the SURs is fully functional and does not lose the ability to interact with the channels. Since structural changes in short forms of SUR modify its affinity to ATP, regulation of its expression might represent an advantage in pathologies where ATP concentrations decrease and a therapeutic target to induce neuroprotection. Remarkably, the expression of SUR1 variants might be induced by conditions associated to the decrease of energetic substrates in the brain (e.g. during stroke and epilepsy). In this review, we want to contribute to the knowledge of SUR1 complexity by analyzing evidence that shows the existence of short SUR1 variants and its possible implications in brain function.

Emerging therapeutic targets for cerebral edema.

INTRODUCTION: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema. AREAS COVERED: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered. EXPERT OPINION: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.

The neurogliovascular unit in hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neurological complication of hepatic dysfunction and portosystemic shunting. It is highly prevalent in patients with cirrhosis and is associated with poor outcomes. New insights into the role of peripheral origins in HE have led to the development of innovative treatment strategies like faecal microbiota transplantation. However, this broadening of view has not been applied fully to perturbations in the central nervous system. The old paradigm that HE is the clinical manifestation of ammonia-induced astrocyte dysfunction and its secondary neuronal consequences requires updating. In this review, we will use the holistic concept of the neurogliovascular unit to describe central nervous system disturbances in HE, an approach that has proven instrumental in other neurological disorders. We will describe HE as a global dysfunction of the neurogliovascular unit, where blood flow and nutrient supply to the brain, as well as the function of the blood-brain barrier, are impaired. This leads to an accumulation of neurotoxic substances, chief among them ammonia and inflammatory mediators, causing dysfunction of astrocytes and microglia. Finally, glymphatic dysfunction impairs the clearance of these neurotoxins, further aggravating their effect on the brain. Taking a broader view of central nervous system alterations in liver disease could serve as the basis for further research into the specific brain pathophysiology of HE, as well as the development of therapeutic strategies specifically aimed at counteracting the often irreversible central nervous system damage seen in these patients.

Recent advances in nanomedicines for the treatment of ischemic stroke.

Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs in vivo, achieve effective drug accumulation at the target site, enhance the therapeutic effect and meanwhile reduce the side effect. In this review, we comprehensively describe the pathophysiology of stroke, traditional treatment strategies and emerging nanomedicines, summarize the barriers and methods for transporting nanomedicine to the lesions, and illustrate the latest progress of nanomedicine in treating ischemic stroke, with a view to providing a new feasible path for the treatment of cerebral ischemia.

Gliquidone ameliorates hepatic insulin resistance in streptozotocin-induced diabetic Sur1-/- rats.

Gliquidone was suggested to exert hypoglycemic effect through enhancing hepatic insulin sensitivity. However, inadequate in vivo evidences make this statement controversial. The aim of the present study was to clarify the insulin-sensitizer role of gliquidone in liver and muscle, so as to confirm its extra-pancreatic effects in vivo. TALEN technique was used to create Sur1 knockout (Sur1-/-) rats. Diabetic Sur1-/- rat models were established by high-fat diet combined with streptozotocin, and which were randomly divided into three groups: gliquidone, metformin and saline, treated for 8 weeks. Fasting blood glucose (FBG) and body mass were tested each week. IPGTT, IPITT and hyperinsulinemic-euglycemic clamp tests were used to evaluate glucose tolerance and insulin sensitivity, respectively. Key mediators of glucose metabolism in liver and skeletal muscle and the activity of AKT and AMPK in these tissues were further analyzed. We found that gliquidone decreased FBG and increased insulin sensitivity without increasing insulin secretion in diabetic Sur1-/- rats. Further exploration implied that gliquidone mainly increased hepatic glycogen storage and decreased gluconeogenesis, which were accompanied with activation of AKT, but not enhanced muscle GLUT4 expression. However, both these effects were still weaker than that of metformin. These results suggested that gliquidone could exerts an extra-pancreatic hypoglycemic effect by improving insulin sensitivity, which might be largely attributes to its additional insulin sensitizer role in hepatic glucose metabolism.

SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury.

BACKGROUND: Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. METHODS: Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. RESULTS: Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. CONCLUSION: SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

Glibenclamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Glibenclamide (GLY) is the sixth drug tested by the Operation Brain Trauma Therapy (OBTT) consortium based on substantial pre-clinical evidence of benefit in traumatic brain injury (TBI). Adult Sprague-Dawley rats underwent fluid percussion injury (FPI; n = 45), controlled cortical impact (CCI; n = 30), or penetrating ballistic-like brain injury (PBBI; n = 36). Efficacy of GLY treatment (10-µg/kg intraperitoneal loading dose at 10 min post-injury, followed by a continuous 7-day subcutaneous infusion [0.2 µg/h]) on motor, cognitive, neuropathological, and biomarker outcomes was assessed across models. GLY improved motor outcome versus vehicle in FPI (cylinder task, p < 0.05) and CCI (beam balance, p < 0.05; beam walk, p < 0.05). In FPI, GLY did not benefit any other outcome, whereas in CCI, it reduced 21-day lesion volume versus vehicle (p < 0.05). On Morris water maze testing in CCI, GLY worsened performance on hidden platform latency testing versus sham (p < 0.05), but not versus TBI vehicle. In PBBI, GLY did not improve any outcome. Blood levels of glial fibrillary acidic protein and ubiquitin carboxyl terminal hydrolase-1 at 24 h did not show significant treatment-induced changes. In summary, GLY showed the greatest benefit in CCI, with positive effects on motor and neuropathological outcomes. GLY is the second-highest-scoring agent overall tested by OBTT and the only drug to reduce lesion volume after CCI. Our findings suggest that leveraging the use of a TBI model-based phenotype to guide treatment (i.e., GLY in contusion) might represent a strategic choice to accelerate drug development in clinical trials and, ultimately, achieve precision medicine in TBI.

Resveratrol reduces cerebral edema through inhibition of de novo SUR1 expression induced after focal ischemia.

Cerebral edema is a clinical problem that frequently follows ischemic infarcts. Sulfonylurea receptor 1 (SUR1) is an inducible protein that can form a heteromultimeric complex with aquaporin 4 (AQP4) that mediate the ion/water transport involved in brain tissue swelling. Transcription of the Abcc8 gene coding for SUR1 depends on the activity of transcriptional factor SP1, which is modulated by the cellular redox environment. Since oxidative stress is implicated in the induced neuronal damage in ischemia and edema formation, the present study aimed to evaluate if the antioxidant resveratrol (RSV) prevents the damage by reducing the de novo expression of SUR1 in the ischemic brain. Male Wistar rats were subjected to 2 h of middle cerebral artery occlusion followed by different times of reperfusion. RSV (1.9 mg/kg; i.v.) was administered at the onset of reperfusion. Brain damage and edema formation were recognized by neurological evaluation, time of survival, TTC (2,3,5-Triphenyltetrazolium chloride) staining, Evans blue extravasation, and water content. RSV mechanism of action was studied by SP1 binding activity measured through the Electrophoretic Mobility Shift Assay, and Abcc8 and Aqp4 gene expression evaluated by qPCR, immunofluorescence, and Western blot. We found that RSV reduced the infarct area and cerebral edema, prevented blood-brain barrier damage, improved neurological performance, and increased survival. Additionally, our findings suggest that the antioxidant activity of RSV targeted SP transcription factors and inhibited SUR1 and AQP4 expression. Thus, RSV by decreasing SUR1 expression could contribute to reducing edema formation, constituting a therapeutic alternative for edema reduction in stroke.

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

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)-Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.

SUR1-TRPM4 channels, not KATP, mediate brain swelling following cerebral ischemia.

BACKGROUND: Preclinical and emerging clinical data show that glibenclamide reduces space occupying edema and brain swelling following cerebral ischemia. Glibenclamide is a potent inhibitor of numerous sulfonylurea receptor (SUR)-regulated channels, including KATP (SUR1-KIR6.2, SUR2A-KIR6.2, SUR2B-KIR6.2, SUR2B-KIR6.1) and SUR1-TRPM4. Here, we used molecularly specific oligodeoxynucleotides (ODNs) to investigate the role of various SUR-regulated ion channel subunits in post-ischemic brain swelling. METHODS: Focal cerebral ischemia was induced in adult male rats by permanent middle cerebral artery occlusion (pMCAo). We used this model to study the effects of antisense-ODNs (AS-ODNs) directed against Abcc8/SUR1, Trpm4/TRPM4, Kcnj8/KIR6.1 and Kcnj11/KIR6.2 on hemispheric swelling, with sense or scrambled ODNs used as controls. We used antibody-based Förster resonance energy transfer (immuno-FRET) and co-immunoprecipitation to study the co-assembly of SUR1-TRPM4 heteromers. RESULTS: In the combined control groups administered sense or scrambled ODNs, pMCAo resulted in uniformly large infarct volumes (mean ± SD: 57.4 ± 8.8 %; n = 34) at 24 h after onset of ischemia, with no effect of AS-ODNs on infarct size. In controls, hemispheric swelling was 23.9 ± 4.1 % (n = 34), and swelling was linearly related to infarct volume (P < 0.02). In the groups administered anti-Abcc8/SUR1 or anti-Trpm4/TRPM4 AS-ODN, hemispheric swelling was significantly less, 11.6 ± 3.9 % and 12.8 ± 5.8 % respectively (P < 0.0001), and the relationship between infarct volume and swelling was reduced and not significant. AS-ODNs directed against Kcnj8/KIR6.1 and Kcnj11/KIR6.2 had no significant effect on hemispheric swelling (23.3 ± 5.4 % and 22.9 ± 5.8 % respectively). Post-ischemic tissues showed co-assembly of SUR1-TRPM4 heteromers. CONCLUSIONS: Post-ischemic hemispheric swelling can be decoupled from infarct volume. SUR1-TRPM4 channels, not KATP, mediate post-ischemic brain swelling.

Glimepiride and glibenclamide have comparable efficacy in treating acute ischemic stroke in mice.

Glibenclamide protects against ischemic injury in both preclinical and clinical studies, presumably by blocking the de novo assembled sulfonylurea receptor 1-transient receptor potential M4 (Sur1-Trpm4) channel induced by ischemia. However, glibenclamide may cause unexpected serious hypoglycemia. Here, we tested whether glimepiride, another sulfonylurea with better safety, has comparable efficacy with glibenclamide and whether gene deletion of Trpm4 (Trpm4-/-) exerts similar effect. Wild-type (WT) mice subjected to temporary middle cerebral artery occlusion (tMCAO) were randomized to receive glibenclamide (an initial dose of 10 µg/kg and additional doses of 1.2 µg every 8 h), three different doses of glimepiride (10 µg/kg, 100 µg/kg and 1 mg/kg) or vehicle after ischemia, while tMCAO-treated Trpm4-/- mice were randomized to receive vehicle or glimepiride. Neurological function, infarct volume, edema formation, the integrity of blood-brain barrier and inflammatory reaction were evaluated at 24 h after ischemia. In tMCAO-treated WT mice, 10 µg/kg and 100 µg/kg glimepiride had comparable efficacy with glibenclamide in improving longa score and grip test score, reducing infarct volume, mitigating brain edema, lessening extravasation of Evans blue dye and IgG, restoring tight junction protein expression as well as suppressing inflammatory cytokines. Compared with WT mice, Trpm4-/- mice showed less neurological deficit, smaller cerebral infarction, lighter brain edema and more integrity of blood-brain barrier. As expected, glimepiride did not provide additional neuroprotection compared with vehicle in the tMCAO-treated Trpm4-/- mice. Glimepiride shows comparable efficacy with glibenclamide in alleviating brain injury after ischemic stroke in mice, possibly via targeting the Sur1-Trpm4 channel.