Mechanisms of cognitive impairment associated with cerebral infarction. DOI
Qing Yin, Yang Li

PubMed, Journal Year: 2024, Volume and Issue: 49(10), P. 1692 - 1699

Published: Oct. 28, 2024

Cerebral infarction is a common type of stroke with high incidence and disability rates, most patients experience varying degrees cognitive impairment. The manifestations severity post-infarction impairment are influenced by multiple interacting factors, its pathophysiological mechanisms highly complex, involving pericyte degeneration, excessive generation reactive oxygen species (ROS), overproduction glutamate, overactivation autophagy. After cerebral infarction, abnormal function activates neuroinflammation facilitates the entry inflammatory mediators into brain; detachment pericytes from blood vessels disrupts integrity blood-brain barrier. Although angiogenesis glial scar formation may alleviate injury, scarring can inhibit neuronal regeneration. Excessive ROS trigger oxidative stress, leading to mitochondrial dysfunction, ferroptosis, suppression endothelial nitric oxide synthase/nitric signaling, thereby damaging neurons. An surge in glutamate release, coupled insufficient clearance, results accumulation intercellular space, excitotoxicity; influx calcium ions subsequently proteases apoptotic pathways, causing death. Overactivation autophagy alters lysosomal membrane permeability leakage enzymes; oligodendrocyte necrosis then leads severe demyelination, further exacerbating brain although promoting autophagic clearance damaged mitochondria ameliorate deficits arising dysfunction.

Language: Английский

Membrane transporters in drug development and as determinants of precision medicine DOI
Aleksandra Galetin, Kim L. R. Brouwer,

Donald Tweedie

et al.

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(4), P. 255 - 280

Published: Jan. 24, 2024

Language: Английский

Citations

93
Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy DOI Creative Commons
Ana Paula de Araújo Boleti, Pedro Henrique de Oliveira Cardoso, Breno Emanuel Farias Frihling

et al.

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(1), P. 71 - 71

Published: Jan. 10, 2024

Epilepsy represents a condition in which abnormal neuronal discharges or the hyperexcitability of neurons occur with synchronicity, presenting significant public health challenge. Prognostic factors, such as etiology, electroencephalogram (EEG) abnormalities, type and number seizures before treatment, well initial unsatisfactory effects medications, are important considerations. Although there several third-generation antiepileptic drugs currently available, their multiple side can negatively affect patient quality life. The inheritance etiology epilepsy complex, involving underlying genetic epigenetic mechanisms. Different neurotransmitters play crucial roles maintaining normal physiology different neurons. Dysregulations neurotransmission, due to transmitter levels changes receptors, result seizures. In this review, we address played by various receptors pathophysiology epilepsy. Furthermore, extensively explore neurological mechanisms involved development progression epilepsy, along its risk factors. highlight new therapeutic targets, pharmacological non-pharmacological strategies employed treatment epileptic syndromes, including drug interventions clinical trials related

Language: Английский

Citations

17
Comprehensive review of amino acid transporters as therapeutic targets DOI
Ran Xia,

Hai-Feng Peng,

Xing Zhang

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 260, P. 129646 - 129646

Published: Jan. 23, 2024

Language: Английский

Citations

9
A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases DOI Creative Commons
Igor C. Fontana, Débora Guerini de Souza, Diogo O. Souza

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(4), P. 2330 - 2346

Published: Feb. 14, 2023

The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - major neurotransmitter mammalian brain. EAAT2 loss/dysfunction triggers cascade neurodegenerative events, comprising glutamatergic excitotoxicity neuronal death. Nevertheless, our current knowledge regarding diseases, such as amyotrophic lateral sclerosis (ALS) Alzheimer's disease (AD), is restricted to post-mortem analysis brain tissue experimental models. Thus, detecting living human might be crucial improve diagnosis/therapy for ALS AD. This perspective article describes physio/pathological processes provides structure–activity relationship EAAT2-binders, bringing two perspectives: therapy (activators) diagnosis (molecular imaging tools).

Language: Английский

Citations

21
Symport and antiport mechanisms of human glutamate transporters DOI Creative Commons
Biao Qiu,

Olga Boudker

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 4, 2023

Excitatory amino acid transporters (EAATs) uptake glutamate into glial cells and neurons. EAATs achieve million-fold transmitter gradients by symporting it with three sodium ions a proton, countertransporting potassium ion via an elevator mechanism. Despite the availability of structures, symport antiport mechanisms still need to be clarified. We report high-resolution cryo-EM structures human EAAT3 bound neurotransmitter symported ions, alone, or without ligands. show that evolutionarily conserved occluded translocation intermediate has dramatically higher affinity for countertransported than outward- inward-facing plays crucial role in coupling. propose comprehensive coupling mechanism involving choreographed interplay between solutes, conformations motifs, movements gating hairpin substrate-binding domain.

Language: Английский

Citations

19
A novel multipotent conjugate bearing tacrine and donepezil motifs with dual cholinergic inhibition and neuroprotective properties targeting Alzheimer’s disease DOI
A.F. Yepes, Wilson Cardona‐G, Angie Herrera‐Ramírez

et al.

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

In this work, we developed potential multifunctional agents to combat Alzheimer's disease.

Language: Английский

Citations

0
Study of Intracellular Peptides of the Central Nervous System of Zebrafish (Danio rerio) in a Parkinson’s Disease Model DOI Open Access
Louise Oliveira Fiametti, Carlos Franco, Letícia Oliveira Catarin Nunes

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2017 - 2017

Published: Feb. 26, 2025

Although peptides have been shown to biological functions in neurodegenerative diseases, their role Parkinson's disease has understudied. A previous study by our group, which used a 6-hydroxydopamine zebrafish model, suggested that nine intracellular may play part this condition. In context, aim is better understand the of five these peptides. The selection was made based on precursor proteins, are fatty acid binding protein 7, mitochondrial ribosomal S36, MARCKS-related 1-B, excitatory amino transporter 2 and thymosin beta-4. were chemically synthesized solid phase characterized high-performance liquid chromatography mass spectrometry. Circular dichroism performed determine secondary structure each peptide, showed all maintain random aqueous solutions studied. Two molecules show helical profile trifluoroethanol, known structuring agent. Cell viability MTT assay indicates not cytotoxic concentrations tested both mouse human cell lines. Behavioral using 6-OHDA larvae model suggest help recovery motor function with 24 h treatment at two concentrations. Three complete from 6-OHDA-induced impairment. Further studies needed mechanism action whether they truly potential ally against disease.

Language: Английский

Citations

0
The severity of SLC1A2-associated neurodevelopmental disorders correlates with transporter dysfunction DOI Creative Commons
Peter Kovermann, Allan Bayat, Christina Fenger

et al.

EBioMedicine, Journal Year: 2025, Volume and Issue: 114, P. 105648 - 105648

Published: April 1, 2025

Excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate and a key mediator of excitatory neurotransmission in human brain. Here we present cohort 18 individuals harbouring 13 different SLC1A2 variants, who all with neurodevelopmental impairment variable symptoms disease severities, delineate impact these variants on EAAT2 function. The consequences nine novel missense for expression, transport anion channel properties expressed mammalian cells were characterized by confocal microscopy, enzyme-linked immunosorbent [3H]-D-aspartate uptake assays, electrophysiological recordings. Ten mediated significant changes to expression and/or These molecular phenotypes classified into three categories: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), mixed loss-of-transport/gain-of-anion-channel (G82R, L85R, L85P, P289R). In contrast, L37P, H542R I546T did not mediate or Although specific clinical outcomes carrying within each category varied somewhat, categories translated distinct terms phenotypic traits severity. observed associations between functional effects produced offer valuable insights future predictions progression severity SLC1A2-associated disorders. Furthermore, variant-induced could assist tailoring personalized treatments This work was funded German Ministry Education Research Lundbeck Foundation.

Language: Английский

Citations

0
Structural basis of excitatory amino acid transporter 3 substrate recognition DOI Creative Commons
Biao Qiu,

Olga Boudker

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(16)

Published: April 18, 2025

Excitatory amino acid transporters (EAATs) reside on cell surfaces and uptake substrates, including L-glutamate, L-aspartate, D-aspartate, using ion gradients. Among five EAATs, EAAT3 is the only isoform that can efficiently transport L-cysteine, a substrate for glutathione synthesis. Recent studies suggest also transports oncometabolite R-2-hydroxyglutarate (R-2HG). Here, we examined structural basis of recognition by determining cryogenic electron microscopy (cryo-EM) structures bound to different substrates. We found L-cysteine binds in thiolate form, recognizes substrates fine-tuning local conformations coordinating residues. However, purified human EAAT3, could not observe R-2HG binding or transport. Imaging revealed several conformational states, an outward-facing state with semi-open gate disrupted sodium-binding site. These demonstrate full closure, coupled last sodium ion, occurs after binding. Furthermore, observed affect how transporter distributes between fully conformation intermediate occluded states path inward-facing conformation, suggesting translocation rates are substrate-dependent.

Language: Английский

Citations

0
Neuroprotection Role of Vitamin C by Upregulating Glutamate Transporter-1 in Auditory Cortex of Noise-Induced Tinnitus Animal Model DOI

Wanxin Cao,

Shan Xiong, Wenliang Ji

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(6), P. 1197 - 1205

Published: March 7, 2024

Vitamin C (Vc) plays a pivotal role in series of pathological processes, such as tumors, immune diseases, and neurological disorders. However, its therapeutic potential for tinnitus management remains unclear. In this study, we find that Vc relieves noise-exposed rats. the 7-day therapy groups, spontaneous firing rate (SFR) increases from 1.17 ± 0.10 Hz to 1.77 0.15 after noise exposure. effectively reduces elevated SFR 0.99 0.07 0.55 0.05 at different doses. The glutamate level auditory cortex rats (3.78 0.42 μM) relative control group (1.34 0.22 μM). High doses (500 mg/kg/day) reduce levels (1.49 0.28 Mechanistic studies show expression transporter 1 (GLT-1) is impaired following exposure treatment restores GLT-1 cortex. Meanwhile, inhibitor, dl-threo-beta-benzyloxyaspartic acid (dl-TBOA), invalidates protection Vc. Our finding shows substantially enhances clearance by upregulating consequently alleviates noise-induced tinnitus. This study provides valuable insight into novel biological target development interventions may prevent onset

Language: Английский

Citations

2