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British Journal of Pharmacology May 2018Bumetanide has anxiolytic effects in rat models of conditioned fear. As a loop diuretic, bumetanide blocks cation-chloride co-transport and this property may allow...
BACKGROUND AND PURPOSE
Bumetanide has anxiolytic effects in rat models of conditioned fear. As a loop diuretic, bumetanide blocks cation-chloride co-transport and this property may allow bumetanide to act as an anxiolytic by modulating GABAergic synaptic transmission in the CNS. Its potential for the treatment of anxiety disorders deserves further investigation. In this study, we evaluated the possible involvement of the basolateral nucleus of the amygdala in the anxiolytic effect of bumetanide.
EXPERIMENTAL APPROACH
Brain slices were prepared from Wistar rats. extracellular recording, stereotaxic surgery, fear-potentiated startle response, locomotor activity monitoring and Western blotting were applied in this study.
KEY RESULTS
Systemic administration of bumetanide (15.2 mg·kg , i.v.), 30 min prior to fear conditioning, significantly inhibited the acquisition of the fear-potentiated startle response. Phosphorylation of ERK in the basolateral nucleus of amygdala was reduced after bumetanide administration. In addition, suprafusion of bumetanide (5 or 10 μM) attenuated long-term potentiation in the amygdala in a dose-dependent manner. Intra-amygdala infusion of bumetanide, 15 min prior to fear conditioning, also blocked the acquisition of the fear-potentiated startle response. Finally, the possible off-target effect of bumetanide on conditioned fear was excluded by side-by-side control experiments.
CONCLUSIONS AND IMPLICATIONS
These results suggest the basolateral nucleus of amygdala plays a critical role in the anxiolytic effects of bumetanide.
Topics: Animals; Bumetanide; Conditioning, Classical; Fear; Male; Motor Activity; Rats; Rats, Wistar; Reflex, Startle
PubMed: 29235092
DOI: 10.1111/bph.14125 -
Brain and Behavior Nov 2022Sevoflurane acts as a gamma-aminobutyric acid subtype A receptor agonist and can induce widespread apoptosis of immature dentate granule cells in postnatal day 21 mice....
INTRODUCTION
Sevoflurane acts as a gamma-aminobutyric acid subtype A receptor agonist and can induce widespread apoptosis of immature dentate granule cells in postnatal day 21 mice. The dentate granule cells of postnatal day 21 mice undergo a developmental stage when gamma-aminobutyric acid (GABA) shifts from inducing the depolarization of neurons to causing hyperpolarization. However, it is unclear whether sevoflurane induces apoptosis of immature granule cells by facilitating the depolarization or hyperpolarization of neurons.
METHODS
We utilized bumetanide, an Na -K -2Cl cotransporter isoform 1 (NKCC1) antagonist, to determine whether the NKCC1-mediated GABA depolarization of neurons plays a role in sevoflurane-induced neuroapoptosis. We also investigated whether sevoflurane exposure is related to long-term cognitive dysfunction in postnatal day 21 mice and explored the possible protective effects of bumetanide.
RESULTS
Bumetanide attenuated the sevoflurane-induced apoptosis of dentate granule cells in postnatal day 21 mice. Exposure to sevoflurane at postnatal day 21 mice did not affect their motor ability or anxiety level, and it had no effect on spatial learning or memory functions. However, sevoflurane exposure at postnatal day 21 impaired the pattern separation ability in the contextual fear discrimination test; bumetanide mitigated this effect of sevoflurane as well.
CONCLUSION
Bumetanide attenuates sevoflurane-induced apoptosis and is a promising prospect for protecting against anesthesia-induced neurotoxicity in the developing brain.
Topics: Animals; Mice; Sevoflurane; Bumetanide; Discrimination Learning; Animals, Newborn; gamma-Aminobutyric Acid; Dentate Gyrus; Fear
PubMed: 36184814
DOI: 10.1002/brb3.2768 -
International Journal of Clinical and... 2014Bumetanide has been reported to attenuate ischemia-evoked cerebral edema. However, whether bumetanide can protect cerebral ischemia-reperfusion injury (IRI) in vivo is...
OBJECTIVE
Bumetanide has been reported to attenuate ischemia-evoked cerebral edema. However, whether bumetanide can protect cerebral ischemia-reperfusion injury (IRI) in vivo is unclear. In the present study, we aim to determine whether intravenously injection bumetanide can attenuate cerebral IRI and if its protection effect might be related to the modification of cerebral NKCC1 and KCC2 protein expression.
METHODS
Focal cerebral ischemia was induced by occluding the right middle cerebral artery (MCAO) for 2-h, followed by 3-h, 24-h or 48-h of reperfusion respectively. Brain edema, neurological deficits, and infarction volume were determined by (wet weights-dry weights)/dry weights×100, 5-point neurological function score evaluation system, and TTC staining, respectively. The expression levels of NKCC1 and KCC2 were determined by immunohistochemical staining.
RESULTS
Reperfusion increased brain edema, neurological deficits, and infarction volume. Bumetanide decreased brain edema, attenuated the neurological defects and reduced post-ischemic cerebral infarction. Cerebral ischemia-reperfusion injury increased NKCC1 expression level and decreased KCC2 expression level. Interestingly, bumetanide down-regulated the NKCC1 protein expression level without changing the KCC2 protein expression level in rat brain cortex.
CONCLUSION
These results suggest that bumetanide protects focal cerebral ischemia-reperfusion injury in rat, which might through the inhibition of NKCC1.
Topics: Animals; Brain Ischemia; Bumetanide; Cerebral Cortex; Disease Models, Animal; Injections, Intravenous; Male; Rats; Reperfusion Injury; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2; Symporters; Time Factors; K Cl- Cotransporters
PubMed: 24817944
DOI: No ID Found -
CNS Drugs Aug 2018Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests.... (Review)
Review
Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.
Topics: Autism Spectrum Disorder; Bumetanide; Disease Progression; Fecal Microbiota Transplantation; Humans; Social Behavior Disorders; Social Skills; Sodium Potassium Chloride Symporter Inhibitors; Vasopressins
PubMed: 30105528
DOI: 10.1007/s40263-018-0556-y -
Neurobiology of Disease Jul 2015GABAA receptor-mediated inhibition is active and may contribute to epileptiform synchronization. The efficacy of inhibition relies on low levels of intracellular Cl(-),...
GABAA receptor-mediated inhibition is active and may contribute to epileptiform synchronization. The efficacy of inhibition relies on low levels of intracellular Cl(-), which are controlled by KCC2 activity. This evidence has led us to analyze with field potential recordings the effects induced by the KCC2 blockers VU0240551 (10 μM) or bumetanide (50 μM) and by the KCC2 enhancer CLP257 (100 μM) on the epileptiform discharges generated by piriform and entorhinal cortices (PC and EC, respectively) in an in vitro brain slice preparation. Ictal- and interictal-like discharges along with high-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz) were recorded from these two regions during application of 4-aminopyridine (4AP, 50 μM). Blocking KCC2 activity with either VU024055 or high doses of bumetanide abolished ictal discharge in both PC and EC; in addition, these experimental procedures decreased the interval of occurrence and duration of interictal discharges. In contrast, enhancing KCC2 activity with CLP257 increased ictal discharge duration in both regions. Finally, blocking KCC2 activity decreased the duration and amplitude of pharmacologically isolated synchronous GABAergic events whereas enhancing KCC2 activity led to an increase in their duration. Our data demonstrate that in vitro ictogenesis is abolished or facilitated by inhibiting or enhancing KCC2 activity, respectively. We propose that these effects may result from the reduction of GABAA receptor-dependent increases in extracellular K(+) that are known to rest on KCC2 function.
Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bumetanide; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Excitatory Amino Acid Antagonists; Male; Rats, Sprague-Dawley; Sodium Potassium Chloride Symporter Inhibitors; Symporters; Thiazoles; Thiazolidines; Thioglycolates; Tissue Culture Techniques; K Cl- Cotransporters
PubMed: 25926348
DOI: 10.1016/j.nbd.2015.04.006 -
International Journal of Molecular... Jul 2020Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as...
Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)-NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1-NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1-NKCC1, and WNK4-SPAK-NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1-NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia.
Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Bumetanide; Hyperglycemia; Immediate-Early Proteins; Lung; Macrophages, Alveolar; Male; Pneumonia; Protein Serine-Threonine Kinases; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Signal Transduction; Solute Carrier Family 12, Member 2
PubMed: 32645929
DOI: 10.3390/ijms21134803 -
Frontiers in Immunology 2018The expression of Na-K-2Cl cotransporter 1 (NKCC1) in the alveolar epithelium is responsible for fluid homeostasis in acute lung injury (ALI). Increasing evidence...
The expression of Na-K-2Cl cotransporter 1 (NKCC1) in the alveolar epithelium is responsible for fluid homeostasis in acute lung injury (ALI). Increasing evidence suggests that NKCC1 is associated with inflammation in ALI. We hypothesized that inhibiting NKCC1 would attenuate ALI after ischemia-reperfusion (IR) by modulating pathways that are mediated by tumor necrosis-associated factor 6 (TRAF6). IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in an isolated and perfused rat lung model. The rats were randomly allotted into four groups comprising two control groups and two IR groups with and without bumetanide. Alveolar fluid clearance (AFC) was measured for each group. Mouse alveolar MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without bumetanide. Flow cytometry and transwell monolayer permeability assay were carried out for each group. Bumetanide attenuated the activation of p-NKCC1 and lung edema after IR. In the HR model, bumetanide decreased the cellular volume and increased the transwell permeability. In contrast, bumetanide increased the expression of epithelial sodium channel (ENaC) via p38 mitogen-activated protein kinase (p38 MAPK), which attenuated the reduction of AFC after IR. Bumetanide also modulated lung inflammation via nuclear factor-κB (NF-κB). TRAF6, which is upstream of p38 MAPK and NF-κB, was attenuated by bumetanide after IR and HR. Inhibition of NKCC1 by bumetanide reciprocally modulated epithelial p38 MAPK and NF-κB via TRAF6 in IR-ALI. This interaction attenuated the reduction of AFC via upregulating ENaC expression and reduced lung inflammation.
Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Bumetanide; Cell Line; Disease Models, Animal; Humans; Hypoxia; Lung; Male; Mice; NF-kappa B; Pneumonia; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Respiratory Mucosa; Signal Transduction; Solute Carrier Family 12, Member 2; TNF Receptor-Associated Factor 6
PubMed: 30271405
DOI: 10.3389/fimmu.2018.02049 -
Molecular Pharmacology Jan 2016Aquaporins (AQPs) in the major intrinsic family of proteins mediate fluxes of water and other small solutes across cell membranes. AQP1 is a water channel, and under...
Aquaporins (AQPs) in the major intrinsic family of proteins mediate fluxes of water and other small solutes across cell membranes. AQP1 is a water channel, and under permissive conditions, a nonselective cation channel gated by cGMP. In addition to mediating fluid transport, AQP1 expression facilitates rapid cell migration in cell types including colon cancers and glioblastoma. Work here defines new pharmacological derivatives of bumetanide that selectively inhibit the ion channel, but not the water channel, activity of AQP1. Human AQP1 was analyzed in the Xenopus laevis oocyte expression system by two-electrode voltage clamp and optical osmotic swelling assays. The aquaporin ligand bumetanide derivative AqB011 was the most potent blocker of the AQP1 ion conductance (IC50 of 14 μM), with no effect on water channel activity (at up to 200 μM). The order of potency for inhibition of the ionic conductance was AqB011 > AqB007 >> AqB006 ≥ AqB001. Migration of human colon cancer (HT29) cells was assessed with a wound-closure assay in the presence of a mitotic inhibitor. AqB011 and AqB007 significantly reduced migration rates of AQP1-positive HT29 cells without affecting viability. The order of potency for AQP1 ion channel block matched the order for inhibition of cell migration, as well as in silico modeling of the predicted order of energetically favored binding. Docking models suggest that AqB011 and AqB007 interact with the intracellular loop D domain, a region involved in AQP channel gating. Inhibition of AQP1 ionic conductance could be a useful adjunct therapeutic approach for reducing metastasis in cancers that upregulate AQP1 expression.
Topics: Animals; Aquaporin 1; Bumetanide; Cell Movement; Dose-Response Relationship, Drug; Female; HT29 Cells; Humans; Ion Channel Gating; Protein Structure, Secondary; Xenopus laevis
PubMed: 26467039
DOI: 10.1124/mol.115.101618 -
British Journal of Clinical Pharmacology Aug 19781. The pharmacological actions of a new short acting loop diuretic were investigated in nine healthy male subjects and compared with those of frusemide and bumetanide.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. The pharmacological actions of a new short acting loop diuretic were investigated in nine healthy male subjects and compared with those of frusemide and bumetanide. Subjects received 6 mg piretanide/day, 40 mg frusemide/day or 1 mg bumetanide/day for a period of 1 week. 2. Comparison of effects following the first dose administered showed that 6 mg piretanide is of similar potency to 40 mg frusemide in terms of diuresis, natriuresis and kaliuresis but is less potent than 1 mg bumetanide. 3. All three diuretics caused a decrease in urate excretion and a rise in serum uric acid. 4. Piretanide was well tolerated. Further investigation is required to ascertain what clinical advantage it offers over frusemide and bumetanide.
Topics: Adult; Bumetanide; Diuretics; Electrolytes; Furosemide; Humans; Male; Potassium; Sodium; Time Factors; Uric Acid
PubMed: 678389
DOI: 10.1111/j.1365-2125.1978.tb00837.x -
Molecular Pharmaceutics Sep 2017Monocarboxylate transporter 6 (MCT6; SLC16A5) has been recognized for its role as a xenobiotic transporter, with characterized substrates probenecid, bumetanide, and...
Monocarboxylate transporter 6 (MCT6; SLC16A5) has been recognized for its role as a xenobiotic transporter, with characterized substrates probenecid, bumetanide, and nateglinide. To date, the impact of commonly ingested dietary compounds on MCT6 function has not been investigated, and therefore, the objective of this study was to evaluate a variety of flavonoids for their potential MCT6-specific interactions. Flavonoids are a large group of polyphenolic phytochemicals found in commonly consumed plant-based products that have been recognized for their dietary health benefits. The uptake of bumetanide in human MCT6 gene-transfected Xenopus laevis oocytes was significantly decreased in the presence of a variety of flavonoids (e.g., quercetin, luteolin, phloretin, and morin), but was not significantly affected by flavonoid glycosides (e.g., naringin, rutin, phlorizin). The IC values of quercetin, phloretin, and morin were determined to be 25.3 ± 3.36, 17.3 ± 2.37, and 33.1 ± 3.29 μM, respectively. The mechanism of inhibition of phloretin was reversible and competitive, with a K value of 22.8 μM. Furthermore, typical MCT substrates were also investigated for their potential interactions with MCT6. Substrates of MCTs 1, 2, 4, 8, and 10 did not cause any significant decrease in MCT6-mediated bumetanide uptake, suggesting that MCT6 has distinct compound selectivity. In summary, these results suggest that dietary aglycon flavonoids may significantly alter the pharmacokinetics and pharmacodynamics of bumetanide and other MCT6-specific substrates, and may represent potential substrates for MCT6.
Topics: Animals; Bumetanide; Flavonoids; Humans; Luteolin; Monocarboxylic Acid Transporters; Oocytes; Phloretin; Quercetin; Xenopus laevis
PubMed: 28513167
DOI: 10.1021/acs.molpharmaceut.7b00264