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

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Авг. 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.

Язык: Английский

---

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Апрель 9, 2024

Cerebrovascular diseases and their sequalae, such as ischemic stroke, chronic cerebral hypoperfusion, vascular dementia are significant contributors to adult disability cognitive impairment in the modern world. Astrocytes an integral part of neurovascular unit CNS play a pivotal role homeostasis, including ionic p H balance, neurotransmission, blood flow, metabolism. respond insults, inflammation, through unique molecular, morphological, functional changes, collectively known reactive astrogliosis. The function astrocytes has been subject debate. Initially, were thought primarily supportive maintaining structure nervous system. However, recent studies suggest that may have both beneficial detrimental effects. For example, can cause oligodendrocyte death demyelination. In this review, we will summarize (1) roles ion transporter cascade astrogliosis, (2) related dementias, (3) potential therapeutic approaches for dementing disorders targeting astrocytes. Understanding relationship between cascade, cerebrovascular reveal mechanisms targets development therapies brain associated with

Язык: Английский

---

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

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Апрель 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.

Язык: Английский

---

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, Год журнала: 2024, Номер 14(3), С. 290 - 290

Опубликована: Март 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

Язык: Английский

---

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

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Май 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.

Язык: Английский

---

The role of metal ions in stroke: current evidence and future perspectives

Ageing Research Reviews, Год журнала: 2024, Номер 101, С. 102498 - 102498

Опубликована: Сен. 6, 2024

Язык: Английский

---

Functions and Mechanisms of the Voltage-Gated Proton Channel Hv1 in Brain and Spinal Cord Injury

Frontiers in Cellular Neuroscience, Год журнала: 2021, Номер 15

Опубликована: Апрель 9, 2021

The voltage-gated proton channel Hv1 is a newly discovered ion that highly conserved among species. It known not only expressed in peripheral immune cells but also one of the major channels tissue-resident microglia central nervous systems (CNS). One key role for its interaction with NADPH oxidase 2 (NOX2) to regulate reactive oxygen species (ROS) and cytosolic pH. Emerging data suggest excessive ROS production increases requires currents through injured CNS, manipulations ablate expression or induce loss function may provide neuroprotection CNS injury models including stroke, traumatic brain injury, spinal cord injury. Recent demonstrating microglial Hv1-mediated signaling pathophysiology further supports idea as mechanism posttraumatic neuroinflammation neurodegeneration. In this review, we summarize main findings Hv1, pattern, cellular mechanism, aging, animal disease pathology. We discuss potential therapeutic target

Язык: Английский

---

Snapshot of microglial physiological functions

Neurochemistry International, Год журнала: 2021, Номер 144, С. 104960 - 104960

Опубликована: Янв. 18, 2021

Язык: Английский

---

Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(2), С. 1150 - 1163

Опубликована: Янв. 29, 2024

Ion channelopathies result from impaired ion channel protein function, due to mutations affecting transport across cell membranes. Over 40 diseases, including neuropathy, pain, migraine, epilepsy, and ataxia, are associated with channelopathies, impacting electrically excitable tissues significantly skeletal muscle. Gene transmembrane ionic flow strongly linked muscle disorders, particularly myopathies, disrupting excitability contraction. Electromyography (EMG) analysis performed on a patient who complained of weakness fatigue revealed the presence primary muscular damage, suggesting an early-stage myopathy. Whole exome sequencing (WES) did not detect potentially causative variants in known myopathy-associated genes but novel homozygous deletion P2RX6 gene likely function. The gene, predominantly expressed muscle, is ATP-gated receptor belonging purinergic receptors (P2RX) family. In addition, STRING pathways suggested correlation more proteins having plausible role No previous studies have reported implication this Further needed patients defective pathway, use vitro functional assays suppressing expression will be required validate its role.

Язык: Английский

---

The influence of sex on neuroimmune communication, pain, and physiology

Biology of Sex Differences, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 22, 2024

Abstract With the National Institutes of Health’s mandate to consider sex as a biological variable (SABV), there has been significant increase studies utilizing both sexes. Historically, we have known that and hormones influence immunological processes now focusing on interactions between immune, endocrine, nervous systems are revealing differences pain behavior various molecular biochemical processes. Neuroendocrine-immune represent key integrative discipline will reveal critical in each field it pertains novel mechanisms necessary therapeutics. Here appraise preclinical clinical literature discuss these pathways drive cell- sex-specific immunity, pain, physiology.

Язык: Английский

---