Dysfunctional K+ Homeostasis as a Driver for Brain Inflammation DOI Creative Commons
Nagihan Ozsoy, Mark Dallas

Encyclopedia, Journal Year: 2024, Volume and Issue: 4(4), P. 1681 - 1699

Published: Nov. 18, 2024

The central nervous system (CNS) relies on precise regulation of potassium ion (K+) concentrations to maintain physiology. This involves complex cellular and molecular mechanisms that work in concert regulate both intracellular extracellular K+ levels. Inflammation, a key physiological response, encompasses series cell-specific events leading inflammasome activation. Perturbations K+-sensitive processes can result either chronic or uncontrolled inflammation, highlighting the intricate relationship between homeostasis inflammatory signalling. review explores targets influence have been implicated cascades, offering potential therapeutic avenues for managing inflammation. We examine common across different cell types, providing comprehensive overview interplay inflammation CNS. By elucidating these mechanisms, we identify leads drug discovery programmes aimed at modulating responses. Additionally, highlight consequences targeting individual entities purposes, emphasizing need nuanced approach developing anti-inflammatory strategies. considers current knowledge within CNS, critical insights into underpinnings interventions. Our findings underscore importance considering development targeted therapies conditions

Language: Английский

A framework for translating tauopathy therapeutics: Drug discovery to clinical trials DOI Creative Commons
Howard Feldman,

Jeffrey L. Cummings,

Adam L. Boxer

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(11), P. 8129 - 8152

Published: Sept. 24, 2024

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. primary meet the definition rare diseases in United States. There is no approved treatment for tauopathies. In this context, designing most efficient development programs to translate promising targets and treatments from preclinical studies early-phase clinical trials vital. September 2022, Rainwater Charitable Foundation convened an international expert workshop focused on translation tauopathy therapeutics through trials. Our report recommends framework principled drug companion lexicon facilitate communication focusing reproducibility achieving common elements. Topics include selection targets, drugs, biomarkers, participants, study designs. maturation pharmacodynamic biomarkers demonstrate target engagement surrogate disease crucial unmet need. HIGHLIGHTS: Experts provided (discovery trials). "5 Rights" (target, drug, biomarker, trial). Current research frontotemporal degeneration, progressive supranuclear palsy, corticobasal syndrome includes 32 (37% biologics) Tau being tested Alzheimer's disease; have large

Language: Английский

Citations

6
Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases DOI Creative Commons

Md Shamim Rahman,

Rabia Islam, Mohammad Iqbal H. Bhuiyan

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: April 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

Language: Английский

Citations

5
Hypertension linked to Alzheimer’s disease via stroke: Mendelian randomization DOI Creative Commons
Chao Tang, Yayu Ma,

Xiaoyang Lei

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Dec. 7, 2023

This study aimed to investigate the relationship between hypertension and Alzheimer's disease (AD) demonstrate key role of stroke in this using mediating Mendelian randomization. AD, a neurodegenerative characterized by memory loss, cognitive impairment, behavioral abnormalities, severely affects quality life patients. Hypertension is an important risk factor for AD. However, precise mechanism underlying unclear. To we used mediated randomization method screened variables AD setting instrumental variables. The results analysis showed that stroke, as variable, plays causal Specifically, indirect effect value obtained multivariate MR was 54.9%. implies approximately 55% owing can be attributed stroke. suggest increased through finding not only sheds light on but also indicates novel methods prevention treatment By identifying critical link provides insights into potential interventions could mitigate impact help develop personalized treatments improve patients with who suffer from hypertension.

Language: Английский

Citations

11
Role of aquaporins in brain water transport and edema DOI Creative Commons
Yuyuan Li, Yanfang Wang, Xiao Huang

et al.

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Jan. 29, 2025

Water serves as the primary substance in all living cells and is an essential molecule involved numerous biological processes critical for maintaining homeostasis central nervous system (CNS). Disruptions water balance can occur conditions such cerebral edema, where fluid accumulation results increased intracranial pressure (ICP). Aquaporins (AQPs) are transmembrane proteins that play a vital role rapid transport of across cell membranes. Various subtypes AQPs (AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, AQP11) have been identified brain tissue. This review summarizes latest advancements our understanding regulating edema. Abundant evidence indicates most prevalent AQP CNS, regulates contributes to both cytotoxic vasogenic suggesting AQP4 may serve potential therapeutic target Additionally, some studies indicated AQP1 plays significant formation cerebrospinal (CSF) maintenance steady-state ICP. However, date, these findings not translated into clinical practice. There urgent need develop specific inhibitors activators explore benefits modulating functions context

Language: Английский

Citations

0
Associations of late‐life blood pressure with CERAD, Braak, and Thal: Findings from the National Alzheimer's coordinating center neuropathology dataset DOI Creative Commons
Mo‐Kyung Sin,

N. Maritza Dowling,

Jeffrey M. Roseman

et al.

Neuropathology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Mid‐life high blood pressure (BP) is a risk factor for Alzheimer's disease (AD). CERAD amyloid β (Aβ) plaques, Braak tau neurofibrillary tangles, and Thal Aβ plaque location are major scoring systems quantifying neuropathological features of AD. We examined the association late‐life systolic BP (SBP) with CERAD, Braak, in National Coordinating Center (NACC) Neuropathology Dataset. Of 1978 participants data on 762 had scores 0–1 (none to sparse) 1216 2–3 (moderate frequent). 1947 411 stages 0–II (normal mild) 1536 III–VI (moderately very severe). 2132 Thal, 438 phases 0–I, 428 II–III, 1266 IV–V. Using mean last four SBP before death, was categorized into <120 (references), 120–139, ≥140 mmHg. Age‐sex‐adjusted ORs (95% CIs) associated mmHg were 1.37 (1.03, 1.83, P = 0.03) 1.26 (0.89, 1.78, 0.20), respectively. Similar observed II–III These associations essentially remained unchanged after additional adjustment APOE Lewy Body pathology. findings suggest that higher markers presence severity Further studies larger sample sizes necessary confirm findings.

Language: Английский

Citations

0
Drugs targeting APOE4 that regulate beta‐amyloid aggregation in the brain: Therapeutic potential for Alzheimer's disease DOI
Joan Poblano, Ileana Castillo‐Tobías, Lia Berlanga

et al.

Basic & Clinical Pharmacology & Toxicology, Journal Year: 2024, Volume and Issue: 135(3), P. 237 - 249

Published: July 17, 2024

Abstract Alzheimer's disease is characterized by progressive cognitive decline, and behavioural psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts effectively treat disease, only seven drugs approved for its treatment, two these prevent progression. This highlights need identify new pharmacological options. review focuses on mimetic peptides, small molecule correctors HAE‐4 antibodies that target ApoE. These reduce β‐amyloid‐induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide furosemide show potential prevalence humans, antidepressants imipramine improve function individuals diagnosed with Consistent this, both classes have been shown exert neuroprotective effects inhibiting ApoE4‐catalysed Aβ aggregation Moreover, peroxisome proliferator‐activated receptor ligands, particularly pioglitazone rosiglitazone, ApoE4‐induced animal However, they do not decline allele carriers. Finally, ApoE4 impairs integrity blood–brain barrier haemostasis. On this basis, modulation promising avenue treatment late‐onset

Language: Английский

Citations

3
Can bumetanide be a miraculous medicine for autism spectrum disorder: Meta-analysis evidence from randomized controlled trials DOI

Hongli Xiao,

Han Zhu,

Jia-Qi Jing

et al.

Research in autism spectrum disorders, Journal Year: 2024, Volume and Issue: 114, P. 102363 - 102363

Published: March 9, 2024

Language: Английский

Citations

2
Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease DOI Creative Commons
Jasmine Morales, Nico Gabriel, Loki Natarajan

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5236 - 5246

Published: June 21, 2024

Abstract INTRODUCTION Bumetanide, a loop diuretic, was identified as candidate drug for repurposing Alzheimer's disease (AD) based on its effects transcriptomic apolipoprotein E signatures. Cross‐sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence AD; however, temporality between exposure and AD development has not been established. METHODS We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association time‐dependent use time first diagnosis while controlling patient characteristics. Multiple sensitivity were conducted test robustness findings. RESULTS sampled 833,561 beneficiaries, 60.8% female, mean (standard deviation) age 70.4 (12). Bumetanide significantly risk (hazard ratio 1.05; 95% confidence interval, 0.99–1.10). DISCUSSION Using nationwide dataset retrospective cohort study design, we able identify effect lowering risk. Highlights (AD). AD. used accounted duration use.

Language: Английский

Citations

1
NKCC1 inhibition reduces periaxonal swelling, increases white matter sparing, and improves neurological recovery after contusive SCI DOI Creative Commons

Spencer Ames,

Jesse Brooks,

Emma S. Jones

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 199, P. 106611 - 106611

Published: July 18, 2024

Ultrastructural studies of contusive spinal cord injury (SCI) in mammals have shown that the most prominent acute changes white matter are periaxonal swelling and separation myelin away from their axon, axonal swelling, spheroid formation. However, underlying cellular molecular mechanisms cause functional consequences poorly understood. We hypothesized loss connectivity between axo-myelinic interface impedes neurological recovery by disrupting conduction velocity, glial to trophic support resulting Utilizing vivo longitudinal imaging Thy1YFP+ axons labeled with Nile red, we reveal significantly increases acutely following a SCI (T13, 30 kdyn, IH Impactor) versus baseline recordings (laminectomy only) often precedes In addition, using determine fate myelinated fibers after SCI, show ∼73% present at 1 h post ∼ 51% those transition spheroids 4 SCI. Next, assessed whether cation-chloride cotransporters within internode contributed modulation would increase sparing improve moderate (T9, 50 kdyn). Mechanistically, activation cotransporter KCC2 did not survival, but chronic tissue sparing. distinction, NKKC1 antagonist bumetanide improved recovery, sparing, part through preventing disruption interface. Collectively, these data novel neuroprotective target prevent

Language: Английский

Citations

1
Interleukin-18 interacts with NKCC1 to mediate brain injury after intracerebral hemorrhage DOI Creative Commons

Beibei Xu,

Hao Li, Zheng He

et al.

Brain Behavior & Immunity - Health, Journal Year: 2024, Volume and Issue: 42, P. 100890 - 100890

Published: Oct. 18, 2024

Language: Английский

Citations

0