scholarly journals Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

2021 ◽  
Vol 22 (21) ◽  
pp. 11899
Author(s):  
Ruchira M. Jha ◽  
Anupama Rani ◽  
Shashvat M. Desai ◽  
Sudhanshu Raikwar ◽  
Sandra Mihaljevic ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Phase Iii ◽  
Sulfonylurea Receptor ◽  
Cns Injury ◽  
Transient Receptor Potential Melastatin ◽  
Cord Injury ◽  
Sulfonylurea Receptor 1

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials.

scholarly journals 17β-Estradiol Inhibits MMP-9 and SUR1/TrpM4 Expression and Activation and Thereby Attenuates BSCB Disruption/Hemorrhage After Spinal Cord Injury in Male Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (5) ◽  
pp. 1838-1850 ◽  
Author(s):  
Jee Y. Lee ◽  
Hae Y. Choi ◽  
Won H. Na ◽  
Bong G. Ju ◽  
Tae Y. Yune
Keyword(s):  
Spinal Cord ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Matrix Metalloprotease ◽  
Sulfonylurea Receptor ◽  
Transient Receptor Potential Melastatin ◽  
Cord Injury ◽  
17Β Estradiol ◽  
Sulfonylurea Receptor 1 ◽  
Transient Receptor

Blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage after spinal cord injury (SCI) lead to secondary injury and the subsequent apoptosis and/or necrosis of neuron and glia, causing permanent neurological deficits. In this study, we examined the effect of 17β-estradiol (E2) on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI. After a moderate contusion injury at the 9th thoracic segment of spinal cord, E2 (300 μg/kg) was administered by iv injection immediately after SCI, and the same dose of E2 was then administered 6 and 24 hours after injury. Our data show that E2 attenuated BSCB permeability and hemorrhage and reduced the infiltration of neutrophils and macorphages after SCI. Consistent with this finding, the expression of inflammatory mediators was significantly reduced by E2. Furthermore, E2 treatment significantly inhibited the expression of sulfonylurea receptor 1 and transient receptor potential melastatin 4 after injury, which are known to mediate hemorrhage at an early stage after SCI. Moreover, the expression and activation of matrix metalloprotease-9 after injury, which is known to disrupt BSCB, and the degradation of tight junction proteins, such as zona occludens-1 and occludin, were significantly inhibited by E2 treatment. Furthermore, the protective effects of E2 on BSCB disruption and functional improvement were abolished by an estrogen receptor antagonist, ICI 182780 (3 mg/kg). Thus, our study provides evidence that the neuroprotective effect of E2 after SCI is, in part, mediated by inhibiting BSCB disruption and hemorrhage through the down-regulation of sulfonylurea receptor 1/transient receptor potential melastatin 4 and matrix metalloprotease-9, which is dependent on estrogen receptor.

scholarly journals Sulfonylurea Receptor 1 in Central Nervous System Injury: A Focused Review

2012 ◽  
Vol 32 (9) ◽  
pp. 1699-1717 ◽  
Author(s):  
J Marc Simard ◽  
S Kyoon Woo ◽  
Gary T Schwartzbauer ◽  
Volodymyr Gerzanich
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Cell Swelling ◽  
Necrotic Cell Death ◽  
Sulfonylurea Receptor ◽  
Necrotic Cell ◽  
Secondary Hemorrhage ◽  
Cord Injury ◽  
Sulfonylurea Receptor 1

The sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of ‘accidental necrotic cell death’ in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NCCa-ATP channel in acute ischemic, traumatic, and inflammatory injury to the CNS.

scholarly journals The Sulfonylurea Receptor 1 (Sur1)-Transient Receptor Potential Melastatin 4 (Trpm4) Channel

2012 ◽  
Vol 288 (5) ◽  
pp. 3655-3667 ◽  
Author(s):  
Seung Kyoon Woo ◽  
Min Seong Kwon ◽  
Alexander Ivanov ◽  
Volodymyr Gerzanich ◽  
J. Marc Simard
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Sulfonylurea Receptor ◽  
Transient Receptor Potential Melastatin ◽  
Sulfonylurea Receptor 1 ◽  
Transient Receptor ◽  
Trpm4 Channel

scholarly journals The neuroprotection effects of exosome in central nervous system injuries: A new target for therapeutic intervention

2021 ◽  
Author(s):  
Li Zhang ◽  
Lei Mao ◽  
Handong Wang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurological Disorders ◽  
Therapeutic Agents ◽  
Great Promise ◽  
Nuclear Factor ◽  
Cns Injury ◽  
Cord Injury ◽  
Extracellular Regulated Protein Kinases ◽  
Light Chain Enhancer

Abstract Central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI) and subarachnoid hemorrhage (SAH), are the most common cause of death and disability around the world. As a key subset of extracellular vesicles (EVs), exosomes have recently attracted great attentions due to their functions in remodeling extracellular matrix, and transmitting signals and molecules. A large number of studies have suggested that exosomes played an important role in brain development and involved in many neurological disorders, particularly in CNS injuries. It has been proposed that exosomes could improve cognition function, inhibit apoptosis, suppress inflammation, regulate autophagy and protect blood brain barrier (BBB) in CNS injuries via different molecules and pathways including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ph1osphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch1 and extracellular regulated protein kinases (ERK). Therefore, exosomes showed great promise as potential targets in CNS injuries. In this article, we present a review highlighting the applications of exosomes in CNS injuries. Hence, on the basis of these properties and effects, exosomes may be developed as therapeutic agents for CNS injury patients.

scholarly journals Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion

2019 ◽  
Vol 36 (7) ◽  
pp. 1060-1079 ◽  
Author(s):  
Volodymyr Gerzanich ◽  
Jesse A. Stokum ◽  
Svetlana Ivanova ◽  
Seung Kyoon Woo ◽  
Orest Tsymbalyuk ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Sulfonylurea Receptor ◽  
Sulfonylurea Receptor 1 ◽  
Transient Receptor

scholarly journals Impact of Gabapentin and Pregabalin on Neurological Outcome After Central Nervous System Injury

2020 ◽  
Vol 3 ◽  
Author(s):  
Caleb Morton ◽  
Fen-Lei Cheng
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Retrospective Chart Review ◽  
Potential Method ◽  
Cns Injury ◽  
Cell Dysfunction ◽  
Significant Difference ◽  
Cord Injury ◽  
The Central Nervous System ◽  
Short And Long Term

Background and Purpose:   Injury to the central nervous system (CNS) is often detrimental to the health, functionality, and quality of life in both the short- and long-term. Injuries that fall under this umbrella include traumatic brain injury (TBI), traumatic spinal cord injury (TSCI), and stroke. These types of injuries vary in what initiates them, but their proposed mechanisms leading to cell dysfunction and death are strikingly similar. There has been pre-clinical and limited retrospective data supporting the idea that gabapentin and pregabalin both have neuroprotective qualities and may alleviate some of the sub-acute damage initiated by these different injuries. The purpose of this study is to determine whether patients taking either gabapentin or pregabalin at the time of their injury tend to have better outcomes than patients with similar injuries who were not taking either one of the two medications.  Methods:  This is a retrospective chart review analysis of 600 patients admitted to Parkview Hospitals from 2016-2019 for TBI, TSCI, or stroke. The outcomes of patients taking either gabapentin or pregabalin with one of the prior diagnoses will be compared to patients with the same diagnosis who were not taking either of the medications mentioned. Statistical analysis will be performed to evaluate if any significant difference exists between the outcomes at discharge of patients taking either medication versus patients who were not.  Results:  Results will be listed as comparisons between patients grouped by injury, and sub-grouped by medication usage. P-values will be included to show significance of comparisons.  Conclusion and Potential Impact:   The main impact of this study is to provide evidence and support leading to a potential method to improve outcomes in patients with CNS injuries. Secondary impacts are providing basis for development of a CNS injury registry and support for developing a unified CNS injury assessment scale to allow comparison of the treatments of different CNS injuries. 

scholarly journals Molecular Mechanisms of Central Nervous System Axonal Regeneration and Remyelination: A Review

2020 ◽  
Vol 21 (21) ◽  
pp. 8116
Author(s):  
Akiko Uyeda ◽  
Rieko Muramatsu
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Motor Deficits ◽  
Cns Injury ◽  
Cellular Mechanisms ◽  
Cns Regeneration ◽  
Cord Injury ◽  
Extracellular Environment ◽  
Injury Causes

Central nervous system (CNS) injury, including stroke, spinal cord injury, and traumatic brain injury, causes severe neurological symptoms such as sensory and motor deficits. Currently, there is no effective therapeutic method to restore neurological function because the adult CNS has limited capacity to regenerate after injury. Many efforts have been made to understand the molecular and cellular mechanisms underlying CNS regeneration and to establish novel therapeutic methods based on these mechanisms, with a variety of strategies including cell transplantation, modulation of cell intrinsic molecular mechanisms, and therapeutic targeting of the pathological nature of the extracellular environment in CNS injury. In this review, we will focus on the mechanisms that regulate CNS regeneration, highlighting the history, recent efforts, and questions left unanswered in this field.

scholarly journals Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor

2014 ◽  
Vol 307 (9) ◽  
pp. R1092-R1100 ◽  
Author(s):  
Brian Kinsman ◽  
James Cowles ◽  
Jennifer Lay ◽  
Sarah S. Simmonds ◽  
Kirsteen N. Browning ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Consistent Finding ◽  
Cellular Dehydration ◽  
Genes Encoding ◽  
The Central Nervous System ◽  
Transient Receptor

Recent studies suggest the ability of the central nervous system to detect changes in osmolality is mediated by products of the genes encoding the transient receptor potential vanilloid-1 (TRPV1) or vanilloid-4 (TRPV4) channel. The purpose of the present study was to determine whether deletion of TRPV1 and/or TRPV4 channels altered thirst responses to cellular dehydration in mice. Injection of 0.5 or 1.0 M NaCl produced dose-dependent increases in cumulative water intakes of wild-type (WT), TRPV1−/−, TRPV4−/−, and TRPV1−/−V4−/− mice. However, there were no differences in cumulative water intakes between WT versus any other strain despite similar increases in plasma electrolytes and osmolality. Similar results were observed after injection of hypertonic mannitol. This was a consistent finding regardless of the injection route (intraperitoneal vs. subcutaneous) or timed access to water (delayed vs. immediate). There were also no differences in cumulative intakes across strains after injection of 0.15 M NaCl or during a time-controlled period (no injection). Chronic hypernatremia produced by sole access to 2% NaCl for 48 h also produced similar increases in water intake across strains. In a final set of experiments, subcutaneous injection of 0.5 M NaCl produced similar increases in the number of Fos-positive nuclei within the organum vasculosum of the lamina terminalis and median preoptic nucleus across strains but significantly smaller number in the subfornical organ of WT versus TRPV1−/−V4−/− mice. Collectively, these findings suggest that TRPV1 and/or TRPV4 channels are not the primary mechanism by which the central nervous system responds to cellular dehydration during hypernatremia or hyperosmolality to increase thirst.

scholarly journals Identification of clinical and radiographic predictors of central nervous system injury in genetic skeletal disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Antônio L Cunha ◽  
Ana P S Champs ◽  
Carla M. Mello ◽  
Mônica M. M. Navarro ◽  
Frederico J. C. Godinho ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Spinal Cord Injury ◽  
Nervous System ◽  
Low Back Pain ◽  
Back Pain ◽  
Low Back ◽  
Cns Injury ◽  
Cord Injury ◽  
Skeletal Disorders

AbstractSome studies report neurological lesions in patients with genetic skeletal disorders (GSDs). However, none of them describe the frequency of neurological lesions in a large sample of patients or investigate the associations between clinical and/or radiological central nervous system (CNS) injury and clinical, anthropometric and imaging parameters. The project was approved by the institution’s ethics committee (CAAE 49433215.5.0000.0022). In this cross-sectional observational analysis study, 272 patients aged four or more years with clinically and radiologically confirmed GSDs were prospectively included. Genetic testing confirmed the diagnosis in the FGFR3 chondrodysplasias group. All patients underwent blinded and independent clinical, anthropometric and neuroaxis imaging evaluations. Information on the presence of headache, neuropsychomotor development (NPMD), low back pain, joint deformity, ligament laxity and lower limb discrepancy was collected. Imaging abnormalities of the axial skeleton and CNS were investigated by whole spine digital radiography, craniocervical junction CT and brain and spine MRI. The diagnostic criteria for CNS injury were abnormal clinical and/or radiographic examination of the CNS. Brain injury included malacia, encephalopathies and malformation. Spinal cord injury included malacia, hydrosyringomyelia and spinal cord injury without radiographic abnormalities. CNS injury was diagnosed in more than 25% of GSD patients. Spinal cord injury was found in 21.7% of patients, and brain injury was found in 5.9%. The presence of low back pain, os odontoideum and abnormal NPMD remained independently associated with CNS injury in the multivariable analysis. Early identification of these abnormalities may have some role in preventing compressive CNS injury, which is a priority in GSD patients.

scholarly journals Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

2014 ◽  
Vol 34 (3) ◽  
pp. 369-375 ◽  
Author(s):  
Juan Pablo de Rivero Vaccari ◽  
W Dalton Dietrich ◽  
Robert W Keane
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Interleukin 1 ◽  
Cns Injury ◽  
Cord Injury ◽  
Cns Trauma ◽  
The Central Nervous System ◽  
Brain And Spinal Cord

The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1 β (IL-1 β) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

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