Search Results (501)

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer’s disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases. Full article

Industrial development has increased environmental dioxin concentrations, sparking concern about human health impacts. Examining dioxin neurotoxicity has highlighted associations with cognitive impairment and behavioral abnormality. Dioxins are ligands of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor; it is speculated that dioxin-induced AHR activation is pivotal for toxic effects. Accurate AHR-expressing cell identification is therefore indispensable for understanding the molecular and cellular mechanisms of dioxin toxicity. Herein, current knowledge regarding AHR expression in the mammalian brain is summarized, and dioxin neurotoxicity mechanisms are discussed. Histological studies show AHR-expressing neurons in multiple brain regions, including the hippocampus and cerebral cortex. Dopaminergic and noradrenergic neurons exhibit AHR expression, suggesting possible roles in the monoaminergic system. AHR overactivation evokes dendritic arborization atrophy, whereas its deficiency increases complexity, implying that AHR-mediated signaling is crucial for neuronal growth and maturation. AHR is also involved in neurogenesis and neuronal precursor migration. Collectively, these findings support the notion that dioxin-induced AHR overactivation in individual neurons disrupts neural circuit structure, ultimately leading to impaired brain function. However, as AHR downstream signaling is intertwined with various molecules and pathways, the precise mechanisms remain unclear. Further studies on the expression, signaling, and roles of AHR are needed to clarify dioxin neurotoxicity. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB. Full article

Astrocytes, which proliferate after brain injury, represent a promising target for cellular reprogramming due to their abundance and ability to support brain repair. In this study, we investigated the in vitro reprogramming of primary cortical astrocytes from neonatal rats into neuronal precursor cells (NPCs) using the transcription factors Oct4, Sox2, and Klf4 (OSK), delivered via lentiviral vectors. We designed a reporter system to trace the conversion of astrocytes to NPCs and neurons by using GFAP-driven iCre and Nestin- or Synapsin1-driven fluorescent reporters. After transduction, we observed morphological changes and the expression of neuronal markers in some cells, while many cells remained in a transitional state, expressing both astrocytic and neuronal features. Importantly, the study was not designed to quantify reprogramming efficiency or demonstrate full astrocyte-to-neuron conversion but rather to establish and evaluate a traceable reporter system. Our data suggest that OSK-mediated reprogramming in this in vitro model can initiate conversion of astrocytes to neuronal precursor-like cells, although the process is complex and incomplete within the one-week timeframe. We also highlight limitations in co-transduction efficiency and potential silencing of the reporter system during reprogramming. These findings provide an initial technical platform to explore astrocyte reprogramming in vitro and inform future studies aiming to refine these methods and apply them in vivo. Full article

We aimed to simulate tau abnormalities—specifically hyperphosphorylation and aggregation—that are hallmarks of tauopathies, including Alzheimer’s disease, to evaluate tau-targeting therapies. To model pathological p-tau accumulation at early disease stages, we exposed mouse cortical cultures to redox-active iron from hemin (Hm), a breakdown product of hemoglobin, or challenged them with the excitatory neurotransmitter glutamate. Using the AT8 phospho-specific antibody, we demonstrate that a subtoxic concentration of Hm (3 µM) promotes pathological p-tau accumulation in a subpopulation of cultured cortical neurons and their proximal neurites. Uric acid (UA; 0.1–200 µM), the metabolic end-product of purines in humans, prevented p-tau build-up. Neither xanthine, the immediate precursor of UA, nor allantoin, its oxidized product, reproduced this effect. Live cell imaging studies revealed that UA operates by repressing iron-driven lipid peroxidation. DOT (3 µM), a brain-permeant tetracycline (TC) without antibiotic activity, mimicked UA’s anti-tau and antioxidant effects. Interestingly, both UA and DOT remained effective in preventing p-tau accumulation induced by glutamate (10 µM). To simulate tau aggregation at more advanced disease stages, we conducted a Thioflavin-T aggregation assay. Our findings revealed that UA and DOT prevented tau aggregation seeded by heparin. However, only DOT remained effective when heparin-assembled tau fibrils were used as the seeding material. In summary, our results indicate that UA-elevating agents may hold therapeutic utility for tauopathies. The non-purine compound DOT could serve as an effective alternative to UA-related therapies. Full article

Exploring the neurogenic potential of extraneural stem cells under the actions of proneurogenic biomolecules may enhance the success of autologous cell therapy for neurodegenerative diseases such as Parkinson’s. Neural stem and progenitor cells (NSPCs) from extraneural tissues have emerged as potential sources of functional dopaminergic (DA) neurons. Background/Objectives: This study aimed to generate DA neurons from ovarian cortical cells (OCC)-derived NSPCs to elucidate whether follicle-stimulating hormone (FSH) can enhance this process and to evaluate the electrophysiological functionality of differentiated neural cells using the patch-clamp technique. Methods: OCC-NSPCs were differentiated towards the DA pathway during the neurosphere (NS) assay after two culture periods for cell expansion (CEP-1, CEP-2) with one of these media: M1 (positive control with epidermal growth factor, EGF, and fibroblast growth factor2, FGF2), M2 (control), and M3 (M2 with FSH, 50 ng/mL). Image analysis, morphometric evaluation, cell proliferation assays, and gene expression analysis of NSPC-specific transcripts were performed. After CEP-2, NS cells were cultured for 30 days in a serum-free medium containing Sonic-Hedgehog, FGF2, FGF8, and brain-derived neurotrophic factor (BDNF) for differentiation. At the end of culture, expression, and immunolocalization of GFAP, Olig2, NeuN, and tyrosine hydroxylase (TH) were analyzed in cells, along with patch-clamp recordings in differentiated neurons. Results: Cell proliferation and NS development were larger in OCC-NSPCs from groups M1 and M3 than in M2. Expression of NSPC-related transcripts was higher in M2; however, M1 and M3 cultures showed greater expression of differentiation markers NeuN, GFAP, Olig2, and TH. NeuN, GFAP, and TH were immunolocalized in differentiated cells and NS that were generated during differentiation. TH was localized in neural precursor cells, some neurons, core cells of small-, medium-, and large-sized NS, and in cells close to the outer cell layer of large NS, with greatest immunolocalization percentages in NS primed with FSH during CEP-1/2 (M3). Electrophysiological recordings revealed a major incidence of plateau potentials and a significant proportion of complete action potentials, reflecting successful functional neuronal differentiation. Conclusions: DA precursors and functional neurons can be successfully obtained after OCC-NSPCs-directed differentiation. FSH priming during the expansion period enhances the neurogenic potential of these cells towards the DA pathway. Future research will explore the eventual therapeutic use of these findings for neurodegenerative diseases. Full article

Background: Kölliker’s organ (KO), a transient structure in the cochlea, plays a critical role in the auditory maturation of mammals, particularly during embryonic and early postnatal development. This organ is essential for the proper differentiation and function of cochlear cells, acting as a pivotal source of signalling molecules that influence hair cell development and synaptic connectivity. Methods: This study systematically analyses the literature according to the PRISMA statement in order to evaluate the function roles of KO during cochlea development, reporting the molecular mechanisms and signalling pathways involved. Results: From our study, it emerged that KO supporting cells release adenosine triphosphate (ATP) through connexin hemichannels, initiating a cascade of intracellular calcium (Ca²⁺) signalling in adjacent inner hair cells (IHCs). This signalling promotes the release of glutamate, facilitating synaptic excitation of afferent nerve fibres and enhancing auditory neuron maturation prior to the onset of hearing. Additionally, the spontaneous electrical activity generated within KO supports the establishment of essential neural connections in the auditory pathway. The dynamic interplay between ATP release, Ca²⁺ signalling, and morphological changes in KO is crucial for cochlear compartmentalisation and fluid regulation, contributing to the formation of endolymph and perilymph. Furthermore, KO supports cellular plasticity and may provide a reservoir of precursor cells capable of trans-differentiating into hair cells under specific conditions. Conclusions: Dysregulation of KO function or delayed degeneration of its supporting cells has been implicated in auditory disorders, underscoring the importance of this organ in normal cochlear development and auditory function. Despite its identification over a century ago, further investigation is necessary to elucidate the molecular mechanisms underlying KO’s contributions to auditory maturation, particularly in human physiology. Full article

Oligodendrocytes form myelin in the central nervous system, and their dysfunction can cause severe neurological symptoms, as large-scale analyses have highlighted numerous gene expression alterations in pathological conditions. Although in vivo functional gene analyses are preferable, they have several limitations, especially in large-scale studies. Therefore, standardized in vitro systems are needed to facilitate efficient and reliable functional analyses of genes identified in such studies. Here, we describe a practical and efficient method for oligodendrocyte precursor cell (OPC) isolation from mouse brains on postnatal day 6–8 and a gene delivery method for the isolated OPCs. By modifying the magnetic-activated cell sorting (MACS) procedure with reduced processing volumes, we simplified OPC isolation, allowing simultaneous handling of multiple samples and improving workflow efficiency. We also optimized electroporation parameters to achieve robust transfection efficiency with minimal cell death. Transfected OPCs are suitable for both monoculture-based differentiation assays and co-culture with dorsal root ganglion (DRG) explants, in which they reliably differentiate into mature oligodendrocytes and myelinate along the axons. This system enables stable and reproducible in vitro analysis of oligodendrocyte function, supports investigations into both intrinsic differentiation and neuron–glia interactions, and provides a powerful platform for oligodendrocyte research with efficient and timely gene manipulation. Full article

Oligodendrocyte precursor cells (OPCs) are a dynamic and heterogeneous population of glial cells essential for brain development and myelination. Beyond their well-established role in oligodendrogenesis, emerging evidence suggests that OPCs contribute to synaptic regulation, neuronal communication, and brain plasticity. Recent studies have increasingly implicated OPC dysfunction in the pathophysiology of psychiatric disorders, particularly schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). This narrative review integrates clinical, genetic, transcriptomic, and histological findings to examine the role of OPC alterations in mental illnesses. In SCZ, OPC abnormalities predominantly affect myelination, but recent data also suggest deficits in non-canonical functions, including neuron–OPC communication. Findings in BD largely mirror those in SCZ, implying shared OPC-related mechanisms across these disorders. In contrast, OPC involvement in MDD appears more complex, with evidence supporting both myelination deficits and non-canonical dysfunctions, such as impaired neuro–glial interactions and perineuronal network alterations. The developmental timing of OPC dysfunction may represent a common denominator underlying psychiatric disorders, as early-life stress and neurodevelopmental disturbances have been linked to OPC impairments. Moreover, given the shared developmental origins of OPCs and parvalbumin-positive interneurons, disruptions in their mutual interactions may contribute to broader neural network dysregulation. Despite these insights, the field remains in its infancy. Future studies integrating independent human cohorts with robust preclinical models are needed to clarify the extent of OPC involvement in psychiatric pathophysiology. Understanding OPC dysfunction may reveal novel biomarkers and open new avenues for individualized therapeutic interventions and preventive strategies in mental health. Full article

Iron accumulation in the brain is widespread in Alzheimer’s disease (AD), the most common cause of dementia. According to numerous studies, too much iron triggers the development of neurofibrillary tangles (NFTs) and amyloid-β (Aβ) plaques, both of which accelerate the onset of AD. Iron sequestration and storage were disrupted by high iron, and the pattern of interaction between iron regulatory proteins (IRPs) and iron-responsive elements (IREs) was altered. The 5′-untranslated regions (5′-UTRs) of their APP mRNA transcripts have an IRE stem-loop, which is where iron influx enhances the translation of the amyloid precursor protein (APP). Iron regulated APP expression via the release of the repressor interaction of APP mRNA with IRP1 by a pathway similar to the iron control translation of the ferritin mRNA by the IREs in their 5′-UTRs. This leads to an uncontrolled buildup of redox active Fe²⁺, which exacerbates neurotoxic oxidative stress and neuronal death. Fe²⁺ overload upregulates the APP expression and increases the cleavage of APP and the accumulation of Aβ in the brain. The level of APP and Aβ, and protein aggregates, can be downregulated by IRPs, but are upregulated in the presence of iron overload. Therefore, the inhibition of the IRE-modulated expression of APP or Fe²⁺ chelation offers therapeutic significance to AD. In this article, I discuss the structural and functional features of IRE in the 5′-UTR of APP mRNA in relation to the cellular Fe²⁺ level, and the link between iron and AD through the amyloid translational mechanism. Although there are currently no treatments for AD, a progressive neurodegenerative disease, there are a number of promising RNA inhibitor and Fe²⁺ chelating agent therapeutic candidates that have been discovered and are being validated in April 2025 clinical trials. Future studies are expected to further show the therapeutic efficacy of iron-chelating medications, which target the APP 5′-UTR and have the ability to lower APP translation and, consequently, Aβ levels. As a result, these molecules have a great deal of promise for the development of small-molecule RNA inhibitors for the treatment of AD. Full article

Chronic periodontitis, driven by the keystone pathogen Porphyromonas gingivalis, has been increasingly associated with Alzheimer’s disease (AD) and AD-related dementias (ADRDs). However, the mechanisms through which P. gingivalis-lipopolysaccharide (LPS)-induced release of neuroinflammatory proteins contribute to the pathogenesis of AD and ADRD remain inadequately understood. Caspase-4, a critical mediator of neuroinflammation, plays a pivotal role in these processes following exposure to P. gingivalis-LPS. In this study, we investigated the mechanistic role of caspase-4 in P. gingivalis-LPS-induced IL-1β production, neuroinflammation, oxidative stress, and mitochondrial alterations in human neuronal and microglial cell lines. Silencing of caspase-4 significantly attenuated IL-1β secretion by inhibiting the activation of the caspase-4-NLRP3-caspase-1-gasdermin D inflammasome pathway, confirming its role in neuroinflammation. Moreover, caspase-4 silencing reduced the activation of amyloid precursor protein and presenilin-1, as well as the secretion of amyloid-β peptides, suggesting a role for caspase-4 in amyloidogenesis. Caspase-4 inhibition also restored the expression of key neuroinflammatory markers, such as total tau, VEGF, TGF, and IL-6, highlighting its central role in regulating neuroinflammatory processes. Furthermore, caspase-4 modulated oxidative stress by regulating reactive oxygen species production and reducing oxidative stress markers like inducible nitric oxide synthase and 4-hydroxynonenal. Additionally, caspase-4 influenced mitochondrial membrane potential, mitochondrial biogenesis, fission, fusion, mitochondrial respiration, and ATP production, all of which were impaired by P. gingivalis-LPS but restored with caspase-4 inhibition. These findings provide novel insights into the role of caspase-4 in P. gingivalis-LPS-induced neuroinflammation, oxidative stress, and mitochondrial dysfunction, demonstrating caspase-4 as a potential therapeutic target for neurodegenerative conditions associated with AD and related dementias. Full article

Acrylamide (ACR), utilized as a precursor for producing polyacrylamide for water purification, has demonstrated neurotoxic properties. However, the mechanisms underlying its neurotoxicity remain inadequately understood. In this investigation, Caenorhabditis elegans were exposed to ACR at concentrations ranging from 250 to 1000 μg/mL and then their locomotor behavior, neuronal development, neurotransmitter concentrations, and gene expression profiles were assessed. Exposure to 250–1000 μg/mL ACR resulted in observable behaviors such as head swiveling and body bending, accompanied by a significant reduction in body size. Furthermore, ACR exposure caused damage to serotonergic, cholinergic, dopaminergic, and glutamatergic neuronal structures. In this context, elevated levels of serotonin, dopamine, acetylcholine, and glutamate were detected, along with notable upregulation of the expression of genes associated with neurotransmitters, including tph-1, cat-4, mod-1, mod-5, cat-1, ser-1, dat-1, dop-1, dop-3, unc-17, cho-1, eat-4, and glr-2. Moreover, ACR exposure elevated reactive oxygen species (ROS), O₂, and H₂O₂ levels while concurrently depleting glutathione (GSH), thereby compromising the antioxidant defense system. This led to a significant upsurge in the expression of genes involved in the nematode ACR detoxification pathway, specifically daf-16, skn-1, mlt-1, sod-3, gst-4, gcs-1, hsf-1, and hsp-16.2. Additionally, Spearman correlation analysis revealed a significant inverse relationship between certain neurotransmitter and antioxidant genes and locomotor activities, highlighting the role of these genes in mediating ACR-induced neurotoxicity in C. elegans. Collectively, this research enhances the understanding of the mechanisms related to ACR neurotoxicity. Full article

The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin that promotes neuronal survival and differentiation, its precursor, proBDNF, has the opposite effect, promoting apoptosis and neuronal death. This review highlights the new and unique aspects of BDNF/proBDNF interaction in the modulation of neuronal apoptotic pathways in neurodegenerative disorders. It systematically discusses the cross-talk in apoptotic signaling at the molecular level, whereby BDNF activates survival pathways such as PI3K/Akt and MAPK/ERK, whereas proBDNF activates p75NTR and sortilin to induce neuronal apoptosis via JNK, RhoA, NFkB, and Rac-GTPase pathways such as caspase activation and mitochondrial injury. Moreover, this review emphasizes the factors that affect the balance between proBDNF and BDNF levels within the context of neurodegeneration, including proteolytic processing, the expression of TrkB and p75NTR receptors, and extrinsic gene transcription regulators. Cellular injury, stress, or signaling pathway alterations can disrupt the balance of BDNF/proBDNF, which may be involved in apoptotic-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review provides a comprehensive framework for targeting neurotrophin signaling in the development of innovative therapies for neuronal survival and managing apoptotic-related neurodegenerative disorders, addressing the mechanistic complexity and clinical feasibility of BDNF/proBDNF interaction. Full article

The presence and function of the opioidergic system in sensory dorsal root ganglia (DRG) was demonstrated in various animal models of pain. To endorse recent functional and transcriptional evidence of opioid receptors in human DRG, this study compared morphological and transcriptional evidence in human and rat DRG using immunofluorescence confocal microscopy and mRNA transcript analysis. Specifically, it examined the neuronal expression of mu (MOR), delta (DOR), and kappa (KOR) opioid receptors, opioid peptide precursors (POMC, PENK, and PDYN), and key pain-signaling molecules. The results demonstrate abundant immunoreactivity in human DRG for key pain transduction receptors, including the thermosensitive ion channels TRPV1, TRPV4 and TRPA1, mechanosensitive PIEZO1 and PIEZO2, and the nociceptive-specific Nav1.8. They colocalized with calcitonin gene-related peptide (CGRP), a marker for peptidergic sensory neurons. Within this same subpopulation, we identified MOR, DOR, and KOR, while their ligand precursors were less abundant. Notably, the mRNA transcripts of MOR and PENK in human DRG were highest among the opioid-related genes; however, they were considerably lower than those of key pain-signaling molecules. These findings were corroborated by functional evidence in demonstrating the fentanyl-induced inhibition of voltage-gated calcium currents in rat DRG, which was antagonized by naloxone. The immunohistochemical and transcriptional demonstration of opioid receptors and their endogenous ligands in both human and rat DRG support recent electrophysiologic and in situ hybridization evidence in human DRG and confirms their potential as analgesic targets. This peripherally targeted approach has the advantage of mitigating central opioid-related side effects, endorsing the potential of future translational pain research from rodent models to humans. Full article