Search Results (2,580)

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na⁺-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded α-synuclein (aSyn). In addition to neuronal pathology, activated microglia are recognized as key mediators of the neuroinflammatory milieu in PD, contributing to DAergic neuron vulnerability. Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. A comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species was performed. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration, followed by neuronal regeneration and temporary CD4⁺ T-cell infiltration accompanied by an astroglial response and activation of microglia. In contrast, MPTP-treated mice showed a permanent neuronal loss, marked microglial activation, increased astrogliosis and CD8⁺ T-cell infiltration that was negatively correlated with neuronal survival. By contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis, mild activation of microglia and CD4⁺ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains exhibited DAergic degeneration, aSyn aggregation, and elevated CD3⁺ T-cell infiltration, and increased microglial activation. These changes correlated with neuronal loss and aSyn burden. These findings emphasize the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4⁺ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8⁺ or CD4⁺, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell–glial interactions to slow neurodegeneration and promote repair in PD. Full article

Gut microbial metabolites play a crucial role in modulating cognitive function. In a previous animal study, oral administration of Lactiplantibacillus plantarum MWFLp-182 (L. plantarum MWFLp-182) significantly increased inosine levels in both the serum and feces of D-galactose (D-gal)-induced mice, which was accompanied by improved cognitive performance. Building on this finding, we further investigated the neuroprotective mechanisms of inosine derived from L. plantarum MWFLp-182 in alleviating D-gal-induced neuronal damage in HT-22 cells. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze the addition of inosine (250 μg/mL, 500 μg/mL), which considerably reduces oxidative stress induced by D-gal (20 mg/mL), on the regulation of mRNA expression of the nuclear factor erythroid 2-related factor (Nrf2)/hemeoxygenase 1 (HO-1) signaling pathway factors. Compared to the D-gal group, the inosine-treated group exhibited a 4.3-fold and 8.7-fold increase in HO-1 and Nrf2 levels, respectively. Furthermore, inosine alleviates neuroinflammation by modulating the mRNA expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Compared to the D-gal group, the inosine-treated group showed reductions of 41.75%, 28.29%, and 32.17% in TLR4, MyD88, and NF-κB levels, respectively. Moreover, immunofluorescence staining revealed that inosine exhibits anti-apoptotic properties by enhancing the levels of neurotrophic factors, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), while simultaneously lowering the expression of the pro-apoptotic protein bcl-2-associated X (Bax). These findings suggest that inosine, a differentially expressed metabolite identified in a probiotic-intervention mouse model, alleviates D-gal-induced neuronal damage in HT-22 cells by modulating oxidative, inflammatory, and apoptotic pathways, providing mechanistic insights into the neuroprotective effects of this metabolite. Full article

Tauroursodeoxycholic acid (TUDCA), a bile acid conjugate, has been suggested to improve cognition in models of Alzheimer’s disease (AD), although its underlying mechanisms remain unclear. This study aimed to evaluate the effects of TUDCA and its potential pathways in APP/PS1 mice. Behavioral tests, assessments of amyloid-β (Aβ) deposition, neuroinflammation, peripheral inflammatory responses, intestinal barrier integrity, and gut microbiota composition were performed, along with pseudo-sterile mouse experiments and fecal microbiota transplantation (FMT). The expression of genes related to the TLR4/NF-κB/NLRP3 pathway was also examined. TUDCA significantly ameliorated cognitive impairments, reduced Aβ accumulation, and suppressed inflammatory responses in both the central nervous system and peripheral tissues. It improved intestinal barrier function and reshaped gut microbial composition by reducing pro-inflammatory taxa. FMT demonstrated that TUDCA-modulated microbiota contributed to improved learning and memory in AD mice, whereas antibiotic-induced pseudo-sterility indicated that TUDCA also exerted cognitive benefits independent of gut flora. Moreover, TUDCA inhibited the activation of the TLR4/NF-κB/NLRP3 pathway. In conclusion, TUDCA alleviates AD-related cognitive deficits partly through modulation of the microbiota–gut–brain axis while also acting via microbiota-independent mechanisms, supporting its potential as a promising therapeutic strategy for AD. Full article

Fucoidan, a complex sulfated polysaccharide derived from marine brown seaweeds, exhibits broad biological activities, including anticoagulant, antitumor, antiviral, anti-inflammatory and lipid-lowering effects. Fucoidan confers neuroprotection in animal models of a broad spectrum of brain disorders such as Parkinson’s disease (PD) and depression. However, the effect of fucoidan on gut-derived neuroinflammation and associated behavioral changes has been scarcely investigated. In comparison to fucoidan from other brown seaweeds, that from Fucus vesiculosus exhibited a better neuroprotective effect in vivo and more potent radical scavenging activity in vitro. Fucoidan from Laminaria japonica ameliorates behavioral disorders related to acute ulcerative colitis (UC) in aged mice. It is of interest to assess the effects of fucoidan administration on intestinal and brain inflammation in the acute colitis mouse model. Fucoidan treatment ameliorated DSS-induced intestinal pathology, reduced the inflammatory mediator expression in the gut and brain, and activated intestinal macrophages and cortical microglia in the UC mice. It also protected the intestinal mucosal barrier and blood–brain barrier as well as prevented neuronal damage, while alleviating anxiety-like behavior in UC mice. These results suggest fucoidan supplementation may help prevent brain disorders, such as depression and PD, potentially involving gut–brain axis-related mechanisms, as fucoidan suppresses gut-derived neuroinflammation. Full article

Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. Here, we identify Akhirin (AKH) as a critical regulator that preserves the integrity of the NSC niche during mouse brain development. At embryonic day 14.5, AKH is secreted and enriched at the apical surface of choroid plexus epithelial cells and the ventricular lining. Loss of AKH leads to increases the inflammatory cytokine expression in the CSF and disrupts NSC niche homeostasis. Furthermore, AKH is cleaved upon inflammatory stimulation, and its LCCL domain directly binds bacteria, thereby preventing their spread. These findings reveal that AKH functions as a protective barrier molecule within the developing neurogenic niche, providing immune protection and preserving NSC niche homeostasis during periods when the innate immune defenses are still immature. Full article

Late-onset sporadic Alzheimer’s disease (LOAD) is the most common form of dementia. The disease is characterized by progressive loss of memory and behavioral changes followed by neurodegeneration of all cortical areas. While the contribution of genetic and environmental factors is important, advanced aging remains the most important disease risk factor. Because LOAD does not naturally occur in most animal species, except humans, studies have traditionally relied on the use of transgenic mouse models recapitulating early-onset familial Alzheimer’s disease (EOAD). Hence, the development of more representative LOAD models through reprograming of patient-derived cells into neuronal, glial, and immune cells became a necessity to better understand the disease’s origin and pathophysiology. Herein, and focusing on neurons, we review current work in the field and compare results obtained with two different reprograming methods to generate LOAD patient’s neuronal cells: the induced pluripotent stem cell and induced neuron technologies. We also evaluate if these models can faithfully mimic cellular and molecular pathologies observed in LOAD patients’ brains. Full article

Background/Objectives: Astrocytes are key regulators of brain energy homeostasis, integrating glucose metabolism with antioxidant support for neuronal function. Dysregulation of these processes contributes to neurodegenerative diseases, including Alzheimer’s disease. Andrographolide, a bioactive diterpenoid from Andrographis paniculata, has been reported to exert neuroprotective effects through the modulation of Wnt/β–catenin signaling and neuronal metabolism; however, its actions on astrocytic metabolic pathways remain insufficiently characterized. Methods: Here, we investigated the effects of andrographolide on metabolic and redox parameters in primary mouse cortical astrocytes. Results: Andrographolide increased glucose uptake and antioxidant capacity without affecting AMPK activation or the activity of core glycolytic enzymes. Instead, it selectively enhanced glucose-6-phosphate dehydrogenase activity, promoting glucose flux through the pentose phosphate pathway in a partially Wnt-dependent manner. This metabolic reprogramming was associated with increased NADPH availability and glutathione levels, together with a reduced ATP/ADP ratio, consistent with a shift toward redox maintenance rather than maximal energy production. Conclusions: Collectively, these findings highlight astrocytic metabolic plasticity as a relevant and underexplored target of andrographolide and support the concept that natural compounds can enhance brain resilience by modulating glial redox metabolism. Full article

Background: Alzheimer’s disease (AD), a progressive brain disorder, is the most common form of dementia and necessitates the development of effective intervention strategies. Ginseng-Natto composite fermentation products (GN) have demonstrated beneficial bioactivities in mouse models of AD; however, the underlying mechanism of action through which GN ameliorates AD requires further elucidation. Methods: Mice received daily intragastric administration of low- or high-dose GN for 4 weeks, followed by intraperitoneal injection of scopolamine to induce the AD model. The pharmacological effects of GN were systematically evaluated using the Morris water maze test, ELISA, and H&E staining. To further investigate the underlying mechanisms, 16S rRNA gene sequencing and metabolomics were employed to analyze the regulatory effects of GN on the gut–brain axis. Additionally, Western blotting was performed to assess the impact of GN on blood–brain barrier (BBB) integrity. Results: GN intervention significantly ameliorated cognitive deficits and attenuated neuropathological injury in AD mice, restoring the brain levels of acetylcholine (ACh), acetylcholinesterase (AChE), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) to normal ranges. GN reshaped the gut microbiota by promoting beneficial bacteria and inhibiting pro-inflammatory strains. It also regulated key metabolic pathways related to amino acid and unsaturated fatty acid metabolism. This metabolic remodeling restored the compromised BBB integrity by upregulating tight junction proteins (ZO-1, Occludin and Claudin-1). Conclusions: Our findings demonstrate that GN ameliorates AD through a gut-to-brain pathway, mediated by reshaping the microbiota-metabolite axis and repairing the BBB. Thus, GN may represent a promising intervention candidate for AD. Full article

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic disorder of gut–brain interaction characterized by intestinal dysmotility. Central sensitization has a proposed role in intestinal dysmotility, yet the precise neural circuits and mechanisms remain poorly understood. In this study, we established a neonatal maternal deprivation plus restraint stress (NMD + RS) mouse model that recapitulates key diarrhea-like phenotypes. Neural activation mapping revealed a significant upregulation of c-Fos expression within the medial prefrontal cortex (mPFC) and locus coeruleus (LC), which was predominantly localized to glutamatergic neurons. Chemogenetic inhibition of mPFC glutamatergic neurons suppressed intestinal dysmotility, whereas the activation of mPFC glutamatergic neurons evoked intestinal dysmotility in control mice. Furthermore, viral tracing revealed direct projections from mPFC neurons to glutamatergic neurons in the LC. Subsequent chemogenetic manipulation of these LC glutamatergic neurons receiving projection from mPFC neurons similarly regulated intestinal motility, demonstrating a functional downstream node. Critically, selective activation of the mPFC-LC glutamatergic circuit significantly induced intestinal dysmotility in CON mice. In contrast, inhibition of the mPFC-LC glutamatergic circuit significantly ameliorated intestinal dysmotility in NMD + RS mice. Our findings proved that the enhanced activity of the mPFC-LC circuit led to intestinal dysmotility in NMD + RS mice, hopefully providing new mechanistic perspectives and a potential neuromodulatory target for clinical management of IBS. Full article

Background: While intravenous administration of nanoparticles (NPs) is effective for targeting the lungs and liver, directing them to other organs and tissues remains challenging. Methods: Here, we report alternative administration routes that improve organ-specific accumulation of poly (lactic-co-glycolic acid) (PLGA) NPs (100 nm, negatively charged) loaded with the near-infrared dye Cyanine 7 (Cy7). NP cytotoxicity was evaluated in HEK293, mMSCs, C2C12, L929, and RAW264.7 cells. Hemocompatibility was assessed using WBCs and RBCs. NPs were administered via the tail vein, carotid, renal, and femoral arteries in BALB/c mice. Administration safety was evaluated by laser speckle contrast imaging and histological analysis. NP biodistribution and accumulation were assessed using in vivo and ex vivo fluorescence tomography and confocal microscopy of cryosections. Results: PLGA-Cy7 NPs demonstrate low cytotoxicity even at high doses and exhibit good hemocompatibility. Administration of NPs through the mouse carotid, renal, and femoral arteries significantly increases accumulation in the target ipsilateral brain hemisphere (31.7-fold) and salivary glands (28.3-fold), kidney (13.7-fold), and hind paw (3.6-fold), respectively, compared to intravenous administration. Injection of NPs through arteries supplying the target organs and tissues does not result in significant changes in blood flow, morphological alterations, or irreversible embolization of vessels, provided the procedure is performed correctly and the optimal dosage is used. Conclusions: These results highlight the potential of intra-arterial delivery of NPs for organ-specific drug targeting, underscoring the synergistic impact of advances in materials science, minimally invasive endovascular surgery, and nanomedicine. Full article

One highly consequential presentation of Venezuelan equine encephalitis virus (VEEV) infection is encephalitis. Here we considered anti-inflammatory interventions to limit the effects of this using a BALB/c subcutaneously challenged mouse model of disease. This disease model nearly ubiquitously presents with severe encephalitis, where viral neuroinvasion correlates with much of the outward clinical signs of disease. A selection of already licenced, commonly used anti-inflammatory drugs were tested in mice developing encephalitis (starting treatment at $24 \mathrm{h}$ post challenge). Drug regimens were used that had previously been shown to have pharmacodynamic effects in mice for unrelated conditions. None of the treatment regimens tested reduced brain inflammation. A single anti-inflammatory drug (dexamethasone) was further tested utilising ascending doses in an effort to provide an effective anti-inflammatory regimen. Higher doses of dexamethasone ($20$ and $50 \mathrm{m}\mathrm{g}/\mathrm{k}\mathrm{g}$) reduced inflammatory markers in the brain and lowered weight loss and clinical signs early on during infection. However, the $50 \mathrm{m}\mathrm{g}/\mathrm{k}\mathrm{g}$ regimen also caused the disease to become more severe at later time points when compared to controls. When combined with the antiviral drug molnupiravir, the negative effects of the dexamethasone treatment ($20$ and $50 \mathrm{m}\mathrm{g}/\mathrm{k}\mathrm{g}$) were absent, and the positive disease severity-reducing effects remained. When combined with a specific VEEV monoclonal antibody (1A3B7), dexamethasone significantly reduced the antibody’s protective effects. These data present currently unique insights into how anti-inflammatory approaches might benefit patients with VEEV disease and where caution might be advised. Full article

Water deprivation triggers coordinated physiological responses to preserve body fluid balance, yet the molecular mechanisms that regulate aquaporin-mediated water transport under dehydration remain incompletely understood. Aquaporin-4 (AQP4), the main water channel in the brain and a basolateral water pathway in the kidney collecting duct, exists in multiple isoforms, including the translational readthrough variant AQP4ex, whose regulatory role is only beginning to be defined. Here, we investigated the effects of acute water deprivation (6–12 h) on AQP4 isoform expression and phosphorylation in a mouse kidney and brain. While total AQP4 and AQP4ex protein levels remained largely unchanged in both tissues, dehydration induced a marked and divergent regulation of the phosphorylated form of AQP4ex. Levels increased in the kidney medulla, consistent with enhanced antidiuretic water transport, but decreased in the cerebral cortex, suggesting a protective reduction in perivascular water permeability. No changes were detected in the cerebellum. These findings identify phosphorylation of AQP4ex as a rapid, tissue-specific regulatory mechanism that adjusts water flux according to the physiological needs of each organ, revealing an additional layer of control in systemic water homeostasis and highlighting AQP4ex as a potential target in dehydration-related and osmotic disorders. Future studies could explore the signaling pathways regulating AQP4ex phosphorylation and investigate its potential involvement in pathological conditions, such as diabetes insipidus or cerebral edema. Full article

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder in which altered microvascular circulation participates in the pathogenesis. The lack of therapeutic treatments for AD makes the development of strategies aimed at preventing or delaying the disease onset urgent. In recent years, several studies have highlighted that a diet rich in antioxidants and anti-inflammatory compounds may positively impact AD development. In this study, we assessed the impact of a diet enriched with Acebuche (ACE) oil, an extra-virgin olive oil particularly rich in antioxidants and anti-inflammatory compounds, on AD progression in the 5xFAD mouse model. Methods: After weaning, wild-type (WT) and 5xFAD mice received the standard or the ACE oil-enriched diet. At 2, 4 and 6 months, the effects of the diet were evaluated on AD-related microvascular aberrancies, beta-amyloid (Aβ) formation, hypoxic state, blood–brain barrier (BBB) alterations, neuroinflammation and cognitive impairment. Metabolic parameters were also evaluated. Results: In 5xFAD mice, the ACE oil-enriched diet prevented alterations in cerebral microcirculation. Moreover, Aβ accumulation, downregulation of Aβ-degrading enzymes, hypoxia, BBB breakdown, neuroinflammation, and cognitive deficits were delayed by the ACE oil-enriched diet. However, some of these effects were reduced at 6 months, in concomitance with systemic metabolic changes, such as hepatic steatosis, evidenced in both WT and 5xFAD mice receiving the ACE oil-enriched diet. Conclusions: Overall, the present results represent proof of concept for the validity of early dietary interventions in AD prevention. Full article

Huntington’s Disease (HD) is characterized by prominent degeneration of the principal neurons of the striatum and by progressive motor and cognitive deterioration. Striatal neurons degenerate in HD due to multiple cell-autonomous and non-autonomous factors. Impaired neurotrophin signaling by brain-derived neurotrophic factor (BDNF) and its cognate receptor Tropomyosin receptor kinase B (TrkB) is an important mechanism underlying neuronal loss in HD. Fingolimod, a clinically approved oral drug for Multiple Sclerosis, was originally developed based on its anti-inflammatory properties. Recent work suggests that fingolimod can also promote BDNF expression and enhance neurotrophic support in the brain. We hypothesized that fingolimod treatment initiated during the presymptomatic phase would increase striatal BDNF levels and protect against motor dysfunction in HD. In wild-type mice, fingolimod treatment increases striatal BDNF levels and enhances BDNF-TrkB signaling. However, chronic fingolimod therapy (0.1 mg/kg, i.p., twice per week, over 7 weeks) initiated at age 4 weeks in the R6/2 mouse model of HD failed to improve behavioral locomotor deficits and exacerbated limb clasping. Furthermore, fingolimod treatment in these presymptomatic R6/2 mice acutely decreased BDNF-TrkB signaling in the striatum in a dose-dependent manner. In contrast, acute administration of fingolimod in symptomatic 7-week-old R6/2 mice increased striatal BDNF-TrkB signaling in a dose-dependent manner, consistent with previous work suggesting that chronic fingolimod can improve motor behavior when given during the symptomatic phase. Thus, the effects of fingolimod striatal BDNF-TrkB signaling and motor behavior in HD are complex and vary with disease stage. Addressing this variability is critical for the design of neuroprotective drug trials in HD, including those utilizing sphingosine-1-phosphate receptor (S1P) modulators. Full article