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: 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 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 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

Antihyperalgesic effects of vanilloid-1 and bradykinin-1 receptor antagonists following spinal cord injury in rats

2007 ◽  
Vol 6 (5) ◽  
pp. 420-424 ◽  
Author(s):  
Sharad Rajpal ◽  
Tiffany A. Gerovac ◽  
Nicholas A. Turner ◽  
Jessica I. Tilghman ◽  
Bradley K. Allcock ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Transient Receptor Potential ◽  
Treatment Strategies ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Cord Injury ◽  
Bradykinin Antagonists ◽  
Transient Receptor

Object The authors previously discovered that genes for the bradykinin-1 (B1) receptor and the transient receptor potential vanilloid subtype 1 (TRPV1) were overexpressed in animals exhibiting thermal hyperalgesia (TH) following spinal cord injury (SCI). They now report the effect of TRPV1 (AMG9810) and B1 (Lys-[Des-Arg9, Leu8]-bradykinin) antagonists on TH in animals following SCI. Methods The rats were subjected to contusion SCI and then divided into groups in which TH did or did not develop. The animals from both groups were given either AMG9810, Lys-(Des-Arg9, Leu8)-bradykinin, or the drug-specific vehicle (control groups). Animals were tested for TH preinjury and at regular intervals after SCI by using the hindlimb withdrawal latency test. Conclusions The administration of AMG9810 likely improves TH as a result of a generalized analgesic effect, whereas the effect of Lys-(Des-Arg9, Leu8)-bradykinin appears more specific to the reversal of TH. This information has potential usefulness in the development of treatment strategies for post-SCI neuropathic pain.

The TRPM7 Channel in the Nervous and Cardiovascular Systems

2020 ◽  
Vol 21 (10) ◽  
pp. 985-992 ◽  
Author(s):  
Koichi Inoue ◽  
Zhi-Gang Xiong ◽  
Takatoshi Ueki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Cellular Functions ◽  
Transient Receptor Potential Melastatin ◽  
Cation Permeability ◽  
Cardiovascular Systems ◽  
Transient Receptor ◽  
Excitatory Responses ◽  
Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

2020 ◽  
Vol 17 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Pavan Thapak ◽  
Mahendra Bishnoi ◽  
Shyam S. Sharma
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Ache Activity ◽  
Transient Receptor Potential ◽  
Mrna Level ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channels ◽  
Transient Receptor ◽  
Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

Polyphenols as Potential Therapeutics for Pain and Inflammation in Spinal Cord Injury

2020 ◽  
Vol 13 ◽  
Author(s):  
Ashif Iqubal ◽  
Musheer Ahmed ◽  
Mohammad Kashif Iqubal ◽  
Faheem Hyder Pottoo ◽  
Syed Ehtaishamul Haque
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Side Effects ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Neutrophil Infiltration ◽  
Matrix Metal ◽  
Mediators Of Inflammation ◽  
Major Player ◽  
Cord Injury

: Spinal cord injury (SCI) and associated pain and inflammation caused by the trauma or infection is one of the serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factor but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts,pericytes, Schwann cells, meningeal cells are the major player in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases and serotonin that stimulate nerve endings and manifests the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, until now, these compounds have been studied in preclinical models and shown promising results but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

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