Dysregulation of Ion Channels and Transporters and Blood-Brain Barrier Dysfunction in Alzheimer’s Disease and Vascular Dementia

Aging and Disease, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

The blood-brain barrier (BBB) plays a critical role in maintaining ion and fluid homeostasis, essential for brain metabolism neuronal function. Regulation of nutrient, water, transport across the BBB is tightly controlled by specialized transporters channels located within its unique cellular components. These dynamic processes not only influence BBB’s structure but also impact vital signaling mechanisms, optimal Disruption ion, pH, balance at associated with pathology has been implicated various neurological conditions, including stroke, epilepsy, trauma, neurodegenerative diseases such as Alzheimer’s disease (AD). However, knowledge gaps exist regarding dysregulation on function dementias. Several factors contribute to this gap: complex nature these historical research focus mechanisms technical challenges studying in vivo models lack efficient vitro dementia models. This review provides an overview current roles poses specific questions: 1) How are expression activity key altered AD vascular (VaD); 2) Do changes dysfunction progression; 3) Can restoring mitigate improve clinical outcomes. Addressing will provide greater insight into disorders.

Язык: Английский

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Nicotinic acetylcholine receptors and epilepsy

Pharmacological Research, Год журнала: 2023, Номер 189, С. 106698 - 106698

Опубликована: Фев. 14, 2023

Despite recent advances in understanding the causes of epilepsy, especially genetic, comprehending biological mechanisms that lead to epileptic phenotype remains difficult. A paradigmatic case is constituted by epilepsies caused altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions mature as well developing brain. The ascending cholinergic projections potent control forebrain excitability, and wide evidence implicates nAChR dysregulation both cause effect epileptiform activity. First, tonic-clonic seizures are triggered administration high doses agonists, whereas non-convulsive have kindling effects. Second, sleep-related epilepsy can be mutations on genes encoding subunits widely expressed (CHRNA4, CHRNB2, CHRNA2). Third, animal models acquired time-dependent alterations innervation observed following repeated seizures. Heteromeric nAChRs central players epileptogenesis. Evidence for autosomal dominant hypermotor (ADSHE). Studies ADSHE-linked expression systems suggest epileptogenic process promoted overactive receptors. Investigation ADSHE indicates mutant lifelong hyperexcitability altering i) function GABAergic populations neocortex thalamus, ii) synaptic architecture during synaptogenesis. Understanding balance effects adult networks essential plan rational therapy at different ages. Combining this knowledge with a deeper functional pharmacological properties individual will advance precision personalized medicine nAChR-dependent epilepsy.

Язык: Английский

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The epilepsy–autism phenotype associated with developmental and epileptic encephalopathies: New mechanism‐based therapeutic options

Epilepsia, Год журнала: 2025, Номер unknown

Опубликована: Фев. 22, 2025

Abstract Epilepsy and autism often co‐occur in genetic developmental epileptic encephalopathies (DEEs), but their underlying neurobiological processes remain poorly understood, complicating treatment. Advances molecular genetics understanding the neurodevelopmental pathogenesis of epilepsy–autism phenotype may lead to mechanism‐based treatments for children with DEEs autism. Several genes, including newly reported PPFIA3 , MYCBP2 DHX9 TMEM63B RELN are linked various disorders, intellectual disabilities, autistic features. These findings underscore clinical heterogeneity suggest diverse mechanisms influenced by genetic, epigenetic, environmental factors. Mechanisms linking epilepsy include γ‐aminobutyric acidergic (GABAergic) signaling dysregulation, synaptic plasticity, disrupted functional connectivity, neuroinflammatory responses. GABA system abnormalities, critical inhibitory neurotransmission, contribute both conditions. Dysregulation mechanistic target rapamycin (mTOR) pathway neuroinflammation also pivotal, affecting seizure generation, drug resistance, neuropsychiatric comorbidities. Abnormal function connectivity further phenotype. New treatment options targeting specific emerging. Genetic variants potassium channel genes like KCNQ2 KCNT1 frequent causes early onset DEEs. Personalized retigabine quinidine have been explored heterogeneous Efforts ongoing develop more effective KCNQ activators blockers. SCN1A variants, particularly Dravet syndrome, show potential symptoms low‐dose clonazepam, fenfluramine, cannabidiol, although human trials yet consistently replicate animal model successes. Early intervention before age 3 years, ‐ tuberous sclerosis complex‐related DEEs, is crucial. Additionally, mTOR shows promise control managing epilepsy‐associated Understanding distinct spectrum disorder implementing behavioral interventions essential improving outcomes. Despite advances, significant challenges persist diagnosing treating DEE‐associated phenotypes. Future should adopt precision health approaches improve

Язык: Английский

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GABAergic circuits drive focal seizures

Neurobiology of Disease, Год журнала: 2023, Номер 180, С. 106102 - 106102

Опубликована: Март 26, 2023

Epilepsy is based on abnormal neuronal activities that have historically been suggested to arise from an excess of excitation and a defect inhibition, or in other words excessive glutamatergic drive not balanced by GABAergic activity. More recent data however indicate signaling defective at focal seizure onset may even be actively involved generation providing excitatory inputs. Recordings interneurons revealed they are active initiation their selective time-controlled activation using optogenetics triggers seizures more general context increased excitability. Moreover, appears mandatory many models. The main pro-ictogenic effect the depolarizing action GABAA conductance which occur when activity causes Cl- accumulation neurons. This process combine with background dysregulation Cl-, well described epileptic tissues. equilibrium maintained (Na+)/K+/Cl- co-transporters, can therefore favor effects GABA. In addition, these co-transporters further contribute this as mediate K+ outflow together extrusion, responsible for extracellular space subsequent increase local role obvious but its complex dynamics balance between flux polarity excitability still remain established, especially tissues where receptors ion regulators disrupted rather plays 2 faces Janus role.

Язык: Английский

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Anxiolytic-like effect of succinic acid: A possible GABAergic intervention

Food Bioscience, Год журнала: 2023, Номер 55, С. 103044 - 103044

Опубликована: Авг. 12, 2023

Язык: Английский

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Physiological roles of chloride ions in bodily and cellular functions

The Journal of Physiological Sciences, Год журнала: 2023, Номер 73(1)

Опубликована: Ноя. 15, 2023

Physiological roles of Cl-, a major anion in the body, are not well known compared with those cations. This review article introduces: (1) Cl- bodily and cellular functions; (2) range cytosolic concentration ([Cl-]c); (3) whether [Cl-]c could change cell volume under an isosmotic condition; (4) conditions where multiple transporters channels contribute to influx efflux state; (5) be large enough act as signals; (6) effects on cytoskeletal tubulin polymerization through inhibition GTPase activity polymerization-dependent biological activity; (7) proliferation; (8) Cl--regulatory mechanisms ciliary motility; (9) sweet/umami taste receptors; (10) with-no-lysine kinase (WNK); (11) regulation epithelial Na+ transport; (12) relationship between H+ body functions.

Язык: Английский

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The emergence of antidepressant drugs targeting GABAA receptors: A concise review

Biochemical Pharmacology, Год журнала: 2024, Номер 228, С. 116481 - 116481

Опубликована: Авг. 13, 2024

Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and public health system. Treatment with classical antidepressants (e.g. tricyclic selective serotonine reuptake inhibitors), primarily affect monoaminergic systems has several limitations, such as delayed onset of action moderate efficacy in relatively large proportion depressed patients. Furthermore, depression highly heterogeneus, its different subtypes, including post-partum depression, involve distinct neurobiology, warranting differential approach to pharmacotherapy. Given these shortcomings, need for novel that are superior faster fully justified. The development market introduction rapid-acting accelerated recent years. Some new act through GABAergic In this review, we discuss discovery, efficacy, limitations treatment classic antidepressants. We provide detailed discussion neurotransmission, special focus GABA

Язык: Английский

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Synaptic Plasticity Abnormalities in Fetal Alcohol Spectrum Disorders

Cells, Год журнала: 2023, Номер 12(3), С. 442 - 442

Опубликована: Янв. 29, 2023

The brain's ability to strengthen or weaken synaptic connections is often termed plasticity. It has been shown function in brain remodeling following different types of damage (e.g., drugs abuse, alcohol use disorders, neurodegenerative diseases, and inflammatory conditions). Although plasticity mechanisms have extensively studied, how neural can influence neurobehavioral abnormalities disorders (AUDs) far from being completely understood. Alcohol during pregnancy its harmful effects on the developing offspring are major public health, social, economic challenges. significant attribute prenatal exposure central nervous system (CNS), causing a range structural, functional, behavioral impairments, collectively called fetal spectrum disorder (FASD). FASD limited, emerging evidence suggests that pathogenesis involves altering set molecules involved neurotransmission, myelination, neuroinflammation. These studies identify several immediate long-lasting changes using many molecular approaches essential for cognitive function. Therefore, they offer potential targets observed FASD. In this review, we discuss substantial research progress aspects shed light mechanism dysfunction Increasing our understanding will significantly advance knowledge could provide basis finding novel therapeutic innovative treatment strategies.

Язык: Английский

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Inhibition of NKCC1 Ameliorates Anxiety and Autistic Behaviors Induced by Maternal Immune Activation in Mice

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(3), С. 1851 - 1864

Опубликована: Фев. 28, 2024

Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased for autism. Maternal immune activation (MIA) in pregnant animals produces with autistic behaviors, making MIA a useful model However, how causes behaviors not fully understood. Here, we show that NKCC1 critical mediating offspring. We confirmed induced by poly(I:C) during leads further demonstrated showed significant microglia activation, excessive dendritic spines, narrow postsynaptic density (PSD) their prefrontal cortex (PFC). Then, discovered these abnormalities may be caused overexpression offspring’s PFCs. Finally, ameliorated the using PFC microinjection inhibitor bumetanide (BTN) Our findings shed new light on pathological mechanisms autism infection.

Язык: 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, 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

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