Evaluation of bumetanide as a potential therapeutic agent for Alzheimer’s disease

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 4, 2023

Therapeutics discovery and development for Alzheimer’s disease (AD) has been an area of intense research to alleviate memory loss the underlying pathogenic processes. Recent drug approaches have utilized in silico computational strategies candidate selection which opened door repurposing drugs AD. Computational analysis gene expression signatures patients stratified by APOE4 risk allele AD led FDA-approved bumetanide as a top agent that reverses transcriptomic brain improves deficits animal models Bumetanide is loop diuretic inhibits kidney Na + -K -2Cl − cotransporter isoform, NKCC2, treatment hypertension edema cardiovascular, liver, renal disease. Electronic health record data revealed exposed lower incidences 35%–70%. In brain, proposed antagonize NKCC1 isoform mediates cellular uptake chloride ions. Blocking neuronal leads decrease intracellular thus promotes GABAergic receptor mediated hyperpolarization, may ameliorate conditions associated with GABAergic-mediated depolarization. expressed neurons all cells including glia (oligodendrocytes, microglia, astrocytes) vasculature. consideration repurposed AD, this review evaluates its pharmaceutical properties respect estimated levels across doses can improve neurologic distinguish between non-NKCC1 mechanisms. The available indicate efficacy occur at are below those required inhibition transporter implicates mechansims improvement dysfunctions deficits. Alternatively, peripheral mechanisms involve outside central nervous system (e.g., epithelia immune system). Clinical improved neurological reviewed. Regardless mechanism, model potential reduce incidence provide support clinical investigation therapeutic agent.

Language: Английский

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The immunometabolic reprogramming of microglia in Alzheimerʼs disease

Neurochemistry International, Journal Year: 2023, Volume and Issue: 171, P. 105614 - 105614

Published: Sept. 23, 2023

Language: Английский

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Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: May 17, 2024

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca 2+ flow through membrane. Among all channels, key regulators of neuronal excitability voltage-gated potassium (K V ), largest family K + channels. Due to ROS high levels in aging brain, might be affected by oxidative agents neurodegeneration processes. This review provides new insight about channelopathies most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson’s Huntington Disease or Spinocerebellar Ataxia. The main these diseases 1, 2.1, 3, 4 7. Moreover, order prevent repair development diseases, previous channel modulators have been proposed therapeutic targets.

Language: Английский

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Microglia TRPC1 SUMOylation drives neuroinflammation after stroke by modulating NLRP3 activity via increasing TRPC1 interaction with ARRB2

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: 206, P. 106833 - 106833

Published: Feb. 6, 2025

Microglial canonical transient receptor potential channel 1 (TRPC1) has been proposed to influence neuroinflammation after cerebral ischemia and reperfusion injury (CIRI), however, the underlying mechanism remains poorly understood. This study demonstrates that TRPC1 is modified by small ubiquitin-related modifier (SUMO)ylation. Our findings suggest a notable increase in microglial SUMOylation within both middle artery occlusion (MCAO/R) model vitro oxygen-glucose deprivation/regeneration model. Mice with loss of microglia exhibited improved stroke outcomes including reduced behavior deficits, infarct volume, blood brain barrier damage as well neuronal apoptosis. Mechanistically, exacerbated neutrophil infiltration into peri-infarct area. Additionally, SUMOylated activates Nod-like protein (NLRP) 3 signaling pathway stimulates multiple CC-chemokine ligands C-X-C motif ligand chemokines MCAO/R. facilitates interaction between β-arrestin2 (ARRB2), negative regulator NLRP3 inflammasome, which disrupts NLPR3/ARRB2 complex activation NLPR3 pathway. Furthermore, ARRB2 directly binds residues 46 61 N terminus, enhanced SUMOylation. Collectively, our demonstrate previously unidentified regulates leukocyte stroke, suggesting inhibition may provide therapeutic benefits for CIRI.

Language: Английский

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Glucose-to-potassium ratio as a predictor for early post-traumatic epilepsy: a retrospective cohort study

Frontiers in Neurology, Journal Year: 2025, Volume and Issue: 16

Published: April 15, 2025

Background Post-traumatic epilepsy (PTE) is a common complication following traumatic brain injury (TBI). Early PTE refers to the appearance of seizure symptoms within 7 days injury. The glucose-to-potassium ratio (GPR) has emerged as potential biomarker for predicting risk. This study aimed evaluate association between GPR and risk PTE, assess predictive value through various analyses. Methods A total 2,049 TBI patients were included in analysis, with evaluated both continuous categorical variable. Logistic regression, trend tests, Kaplan-Meier (KM) curve analyses performed relationship PTE. Subgroup conducted explore effect modifiers, restricted cubic spline (RCS) used examine non-linear associations. Adjustments made demographic, clinical, biochemical factors. Results demonstrated significant risk, turning point at = 2.835. Patients > 2.835 exhibited higher epilepsy, indicated by KM analysis ( P < 0.0001). regression revealed that was an independent predictor unadjusted adjusted models. In fully model, remained significantly associated early (OR: 1.499, 95% CI: 1.188–1.891, 0.001). identified gender, hypertension, diabetes modifiers. Trend tests dose-response quartiles highest quartile showing partially models 0.017). Conclusions robust levels strongly increased epilepsy. variations across subgroups underscore clinical utility stratification personalized management patients.

Language: Английский

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Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: April 21, 2022

Increase of deposits amyloid β peptides in the extracellular matrix is landmark during Alzheimer’s Disease (AD) due to imbalance production vs. clearance. This accumulation triggers microglial activation. Microglia plays a dual role AD, protective by clearing increasing phagocytic response ( CD163, IGF-1 or BDNF ) and cytotoxic role, releasing free radicals (ROS NO) proinflammatory cytokines TNF- α, IL-1 β) reactive gliosis activated aggregates. activation correlated with an increase K V 1.3 channels expression, protein levels current density. Several studies highlight importance inflammatory inhibition neural progenitor cell proliferation neuronal differentiation. However, little known about pathways this stem cells differentiation accumulation. In recent using vitro derived from mice models, it has been demonstrated that blockers inhibit microglia-mediated neurotoxicity culture reducing expression pro-inflammatory α through NF-kB p38MAPK pathway. Overall, we conclude change course AD development, further investigations are needed establish specific pathway validate use blocker as therapeutic treatment Alzheimer patients.

Language: Английский

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The α-7 Nicotinic Receptor Positive Allosteric Modulator Alleviates Lipopolysaccharide Induced Depressive-like Behavior by Regulating Microglial Function, Trophic Factor, and Chloride Transporters in Mice

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(3), P. 290 - 290

Published: March 19, 2024

Neuroinflammation contributes to the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation microglial brain-derived neurotrophic factor (BDNF), Na-K-Cl cotransporter-1 (NKCC1), and K-Cl cotransporter-2 (KCC2) due activation BDNF-tropomyosin receptor kinase B (TrkB) signaling. Allosteric modulation α7 nAChRs has not been investigated on BDNF, KCC2, NKCC1 during LPS-induced depressive-like behavior. Therefore, we examined effects PNU120596, an nAChR positive allosteric modulator, expression in hippocampus prefrontal cortex using Western blot analysis, immunofluorescence assay, real-time polymerase chain reaction. The ANA12, a TrkB antagonist, cognitive deficit behaviors were determined Y-maze, tail suspension test (TST), forced swim (FST). Pharmacological interactions between PNU120596 ANA12 also examined. Experiments conducted male C57BL/6J mice. LPS administration (1 mg/kg) resulted increased BDNF NKCC1/KCC2 ratio decreased KCC2 cortex. pretreatment (4 attenuated increase reduction these brain regions. In addition, (0.25 or 0.50 reduced measured spontaneous alternation Y-maze immobility duration TST FST. Coadministration prevented behaviors. Overall, behavior likely decreasing targeting

Language: Английский

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The Role of Glial Cells in the Pathophysiology of Epilepsy

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 94 - 94

Published: Jan. 10, 2025

Epilepsy is a chronic neurological disorder marked by recurrent seizures, significantly impacting individuals worldwide. Current treatments are often ineffective for third of patients and can cause severe side effects, necessitating new therapeutic approaches. Glial cells, particularly astrocytes, microglia, oligodendrocytes, emerging as crucial targets in epilepsy management. Astrocytes regulate neuronal homeostasis, excitability, synaptic plasticity, playing key roles maintaining the blood-brain barrier (BBB) mediating neuroinflammatory responses. Dysregulated astrocyte functions, such reactive astrogliosis, lead to abnormal activity seizure generation. They release gliotransmitters, cytokines, chemokines that may exacerbate or mitigate seizures. Microglia, innate immune cells CNS, contribute neuroinflammation, glutamate excitotoxicity, balance between excitatory inhibitory neurotransmission, underscoring their dual role promotion protection. Meanwhile, primarily involved myelination, also modulate axonal excitability neuron-glia network underlying pathogenesis. Understanding dynamic interactions glial with neurons provides promising avenues novel therapies. Targeting these improved control better clinical outcomes, offering hope refractory epilepsy.

Language: Английский

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Regulation of Blood-brain Barrier Integrity by Brain Microvascular Endothelial Cells in Ischemic Stroke: A Therapeutic Opportunity

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177553 - 177553

Published: March 1, 2025

Language: Английский

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Chlorpromazine directly inhibits Kv1.3 channels by facilitating the inactivation of channels

Molecular Brain, Journal Year: 2025, Volume and Issue: 18(1)

Published: May 8, 2025

Abstract Kv1.3 channels in microglia are pivotal regulating neuroinflammation. The antipsychotic chlorpromazine (CPZ) demonstrates anti-inflammatory effects by decreasing activity mPFC microglia. However, the precise mechanism of CPZ’s effect remains unclear, given that CPZ is known to inhibit dopamine receptors and contains various cell types with receptors. In this study, we investigate how inhibits using human channel-expressing Xenopus laevis oocytes. directly channel currents a concentration-dependent manner. CPZ-mediated inhibition not voltage-dependent, accelerates inactivation without significantly affecting its activation. Our findings suggest blocks involving other ion or receptors, including thereby contributing understanding neuroinflammation-suppressing mechanism.

Language: Английский

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