Search Results (1,854)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the deposition of Lewy bodies (LBs). The gut–brain axis has emerged as a potential route for the bidirectional dissemination of PD pathology, in which the enteric and central nervous systems may contribute to the spread of misfolded α-synuclein (α-Syn) and associated neuroinflammatory responses. However, neural pathways alone may not fully account for the widespread distribution of PD pathology across the brain and gut. As another major conduit connecting the gut and the brain, the peripheral circulation may provide an additional route for PD-related pathological processes. Nevertheless, how blood circulation contributes to the development and dissemination of pathology along the gut–brain axis remains underexplored. Accordingly, this narrative review examines peripheral blood as a potential additional route for pathological communication along the gut–brain axis, focusing on two potential mechanisms involving the transport of pathological α-Syn aggregates between the gut and the brain and the circulation of inflammatory signals associated with gut microbiota dysbiosis. Furthermore, to highlight the translational relevance of the gut–blood–brain axis, we briefly summarize recent advances in related blood-derived biomarkers and therapeutic strategies targeting these pathways. Full article

The blood–brain barrier (BBB) is a unique neurovascular interface essential for central nervous system homeostasis. Beyond its classical protective role, accumulating evidence points to the BBB as a dynamic structure actively involved in brain function in health and disease. The present review synthesizes clinical, molecular, and neuroimaging evidence implicating BBB dysfunction in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia. The paper was prepared in accordance with the recommendations of the Scale for the Assessment of Narrative Review Articles and was based on a PubMed search of publications published between 2000 and 2026. We summarize BBB architecture and regulation within the neurovascular unit and examine how neuroinflammation, oxidative stress, mitochondrial dysfunction, vascular-metabolic disturbances, and glucocorticoid signaling compromise tight junction, endothelial, pericyte, and astrocytic function, thereby facilitating peripheral immune signaling and sustaining central inflammation. Disorder-specific findings highlight shared and distinct mechanisms: In MDD, EZH2-mediated downregulation of claudin-5 and VEGF-driven barrier disruption are associated with increased permeability in the prefrontal cortex and hippocampus; in BD, elevated cerebrospinal fluid/serum albumin ratios and levels of S100B and matrix metalloproteinase-9-mediated tight junction degradation are associated with illness duration and neuroprogression; and in schizophrenia, reduced expression of claudin-5 and claudin-11, diminished pericyte coverage, and dysregulation of transforming growth factor-α/platelet-derived growth factor signaling are associated with neuroinflammation and treatment resistance. Therapeutic implications are discussed, including anti-inflammatory and antioxidant strategies, endothelial stabilization, and BBB-targeted delivery, as well as methodological limitations and future directions for biomarker development and neurovascular modeling. Full article

Understanding neuroimmune responses during brain infections remains challenging because the site of disease (i.e., the brain) is difficult to access, immune responses within the central nervous system (CNS) are spatially and temporally compartmentalized, and peripheral immune cells have largely served as a proxy for the neuroimmune response. Cerebrospinal fluid (CSF) occupies a unique anatomical and immunological position at the interface between the brain parenchyma, CNS border compartments, and the peripheral immune system, making it an important window through which neuroinflammatory processes can be investigated in living patients. In this review, we examine evidence from CNS infections, with particular emphasis on tuberculous meningitis, demonstrating that CSF contains cellular and transcriptional profiles that differ from those observed in peripheral blood and vary according to the anatomical sampling site. We consider how CNS-resident cells, border-associated immune populations, and recruited leukocytes contribute to the neuroimmune environment of CSF. Importantly, we distinguish evidence derived from cells directly recovered from CSF from soluble biomarkers that may reflect activity in parenchymal or border compartments, and from cellular processes inferred from transcriptomic studies. We also discuss how CSF sampling and analytical approaches influence interpretation and highlight the potential of high-dimensional profiling to resolve compartmentalized neuroimmune responses during CNS infection. Full article

Piezo1 is an increasingly recognised mechanosensitive ion channel that transduces mechanical forces into electrical and biochemical signals and is expressed in peripheral sensory pathways as well as across multiple cell types within the central nervous system. Growing evidence indicates that Piezo1 contributes to nociceptive processing by influencing cellular excitability, inflammatory signalling, and neuron–glia interactions within nociceptive circuits. These actions position Piezo1 as an important contributor to amplified nociceptive transmission and circuit hyperexcitability, thereby potentially facilitating the transition from acute to chronic pain via several integrating mechanisms. In this context, Piezo1 may interact with other established mechanisms of chronic pain, including peripheral and central sensitisation and neuroinflammatory signalling, to help sustain persistent pain states. This review examines the potential roles of Piezo1 as a synergistic contributor to nociceptive hyperexcitability and considers how it may modulate nociceptive excitability, glial activation, and central sensitisation. Available findings support the view that Piezo1 participates in mechanotransduction and maladaptive plasticity relevant to chronic pain, although direct evidence for its cell-specific actions within spinal dorsal horn circuits remains limited. Piezo1 has also been implicated in tissue remodelling following spinal cord injury, suggesting that its therapeutic relevance may extend beyond pain signalling alone. Further studies will be required to clarify its mechanistic role in the mechanobiology of chronic pain and to evaluate the translational potential of targeting Piezo1 through pharmacological or genetic strategies for pain management. Full article

Background: Postnatal choline supplementation improves memory, non-verbal IQ, executive function, and white-matter microstructure in children with fetal alcohol spectrum disorder (FASD) across randomized controlled trials; however, peripheral and brain biomarkers of these effects are uncharacterized. Methods: We measured eight immune and neurotrophic biomarkers (TNFα, transferrin receptor 1 [TfR1], BDNF, ferritin, MCP-1, RANTES, CRP, and Eotaxin) in plasma and brain-derived extracellular vesicles (BDEVs) from 24 children with FASD randomized to choline (n = 13; 7 male, 6 female) or placebo (n = 11; 7 male, 4 female), before and approximately nine months after treatment (23 with paired pre/post samples). Values were log₁₀-transformed to correct for non-normal distribution. We modeled Group × Time effects with linear mixed models, adjusted for age, sex, and sample storage duration, cross-checked with cluster-robust ordinary least squares, and tested plasma-to-BDEV concordance for each analyte with linear regression adjusted for age and sex. Multiplicity was corrected by Benjamini–Hochberg FDR. Results: Plasma MCP-1 showed a nominally significant Group × Time interaction (p = 0.035, q = 0.28), rising over time in the placebo but not the choline group. Ferritin and CRP showed similar patterns that did not reach significance (interaction p = 0.099 and p = 0.118; q = 0.31 for both). RANTES and BDNF rose significantly in BDEVs over time, without evidence of a differential change by treatment group, and survived FDR correction (both q ≤ 0.02); ferritin also rose significantly (p = 0.021) but its Time effect did not survive FDR correction (q = 0.06). BDEV TfR1 was nominally lower in the choline group than placebo at both timepoints (p = 0.023; q = 0.13). Plasma levels were associated with BDEV levels for five markers (ferritin, TfR1, TNFα, Eotaxin, RANTES; all p < 0.05), independent of age, sex, time, and group; all five associations survived FDR correction (q ≤ 0.01). The plasma-BDEV association for MCP-1 became non-significant when adjusted for time and group (p = 0.134, q = 0.13). CRP and BDNF showed a between-person, but not within-person, plasma-BDEV association. Conclusions: In this small, exploratory sample of children with FASD, a condition characterized by brain iron deficiency and inflammation, choline was associated with an attenuated rise in pro-inflammatory plasma MCP-1 relative to placebo, generating a new hypothesized candidate biomarker for further study. Most BDEV markers changed over time (Pre-to-Post), not with treatment. Plasma and BDEV BDNF were not significantly associated overall, although a between-person association was present without a corresponding within-person signal, suggesting that inferring central nervous system function from plasma BDNF should proceed with caution. These hypothesis-generating findings support further, larger-scale investigation of BDEV content analysis as a candidate complement to this trial program’s cognitive and neuroimaging outcomes. Replication and expansion of the BDEV panel of analytes in a larger sample are needed. Trial registration: ClinicalTrials.Gov [NCT02735473]; registered 2 April 2016. Full article

Purpose: This study aimed to evaluate the effects of active transcranial direct current stimulation (tDCS) compared with sham stimulation on circulating brain-derived neurotrophic factor (BDNF), pain-related outcomes, working memory, and inflammatory and neuroplasticity biomarkers. Methods: PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov were searched from inception to May 2026. Randomized and controlled clinical trials comparing active with sham tDCS in adults were included. The primary outcome was post-treatment BDNF concentration. Secondary outcomes included pain intensity, pain catastrophizing, pain-related disability and functional interference, working memory, and circulating inflammatory or neuroplasticity biomarkers. Risk of bias was assessed using the revised Cochrane risk-of-bias tool. Mean differences (MDs) with 95% confidence intervals (CIs) were pooled using random-effects models. Serum and plasma BDNF were analyzed separately. Results: Twenty-one studies were included in the systematic review, of which 15 contributed to at least one quantitative synthesis and 12 study comparisons contributed to the primary BDNF analyses. Active tDCS did not significantly affect serum BDNF (MD = −0.01 [−0.15, 0.13], p = 0.890) or plasma BDNF (MD = 0.02 [−0.25, 0.29], p = 0.870) compared with sham stimulation. In contrast, active tDCS was associated with lower pain intensity (MD = −1.79 [−2.34, −1.23], p < 0.00001). No statistically significant difference was observed in the PCS total score or in the helplessness, magnification, or rumination subscales, although the point estimates generally favored active tDCS. For pain-related disability and functional interference, active tDCS was associated with lower PCP:S total scores and lower emotional interference, whereas no significant differences were observed for interference with daily activities or pain frequency. No significant differences were observed for working memory, interleukins, tumor necrosis factor-alpha, glial cell line-derived neurotrophic factor, interleukin-18, or soluble tumor necrosis factor receptors. Substantial heterogeneity was present in several pain-related and inflammatory biomarker analyses. Conclusions: Active tDCS was not associated with consistent differences in circulating serum or plasma BDNF or in the assessed peripheral inflammatory and neuroplasticity biomarkers compared with sham stimulation; however, these null peripheral findings should not be interpreted as evidence of absent central neuroplastic effects, because circulating measures may not adequately capture localized or transient biological changes within the central nervous system. Active tDCS was associated with improvements in some pain-related outcomes; however, the limited number of studies, substantial heterogeneity, and low certainty of the available evidence preclude firm conclusions regarding its clinical effectiveness for pain management. Full article

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article

Major depressive disorder (MDD) is associated with complex neurobiological alterations in which oxidative stress may play a central role; however, direct evidence linking redox biomarkers to alterations in brain chemistry remains limited. This systematic review aimed to synthesize the available evidence on the relationships between oxidative stress and neuroimaging alterations in individuals with MDD. A search was conducted in PubMed, Scopus, and Web of Science (2016–2026) following the PRISMA guidelines, including human studies assessing oxidative biomarkers (central or peripheral) alongside neuroimaging or neurofunctional measures. Four studies met the inclusion criteria (case–control, cross-sectional, and interventional designs). These studies collectively indicate that antioxidant enzymes, glutathione, and malondialdehyde are associated with altered brain activity and connectivity, prefrontal neurochemical changes, and cognitive performance. Overall, the findings support the existence of associations between redox disruption and central nervous system (CNS) alterations in MDD. However, methodological heterogeneity and the limited number of studies highlight the need for further longitudinal and multimodal research to clarify the directionality and clinical relevance of these findings. Full article

Orofacial pain is a complex and multifactorial condition that affects quality of life and presents important diagnostic and therapeutic challenges. Advances in neuroimaging techniques have enabled the investigation of nervous system alterations associated with pain perception and modulation. This review synthesizes current evidence on structural, functional, and neurochemical brain alterations identified through magnetic resonance imaging (MRI) in individuals with acute and chronic orofacial pain conditions. A comprehensive literature search of PubMed, Web of Science, and Scopus identified MRI studies (structural, diffusion, functional) in adults with temporomandibular disorders, trigeminal neuralgia, persistent dentoalveolar pain, or experimental pain. The main results demonstrated alterations along peripheral trigeminal pathways, brainstem nuclei, and central pain processing networks. Additionally, it was also possible to verify altered gray- and white matter integrity, causing disrupted connectivity within large-scale networks related to pain modulation and cognitive processing. While acute pain reflects transient activation of these pathways, chronic and neuropathic conditions can involve persistent structural and functional reorganization across sensory, affective, and cognitive networks. These findings support the involvement of distributed neural mechanisms and neuroplastic changes in many chronic orofacial pain conditions, while emphasizing that peripheral, central, psychosocial, and contextual factors may contribute to varying degrees across disorders and individuals. Multimodal MRI may provide a basis for future diagnostic, prognostic, and treatment response biomarkers, although most advanced MRI-derived markers remain investigational. Full article

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by neuroinflammation and demyelination. Although treatment options for MS have increased over the past decade, current therapies primarily target the peripheral immune system and are often associated with significant side effects. Moreover, these therapies still do not offer solutions for the resulting neurodegeneration that accompanies the progression of the disease. Findings from research using cellular and animal models and studies in humans highlight the neuroprotective and anti-inflammatory properties of apigenin, a flavonoid present in several commonly consumed plant species, such as cabbage, orange, tea, onion, and chamomile. This review compiles chemical and current evidence on the therapeutic potential of apigenin, primarily on its ability to modulate neuroinflammation and underscore the need for further investigation into its clinical applications as an adjuvant therapy for MS. Full article

Chemotherapy-induced neurotoxicity, affecting both the central and peripheral nervous systems, is a frequent and severe adverse effect of paclitaxel (PAC) treatment with limited therapeutic options. We previously demonstrated that PAC triggers neuronal cell death via ferroptosis. αO-Conotoxin GeXIVA[1,2], a marine-derived peptide, has shown efficacy in alleviating chemotherapy-induced neuropathic pain. In the present study, we investigated whether GeXIVA[1,2] protects neurons from PAC-induced neurotoxicity by suppressing ferroptosis. Using SH-SY5Y and HT-22 neuronal cell lines, we found that GeXIVA[1,2] pretreatment rescued PAC-impaired cell viability without exhibiting cytotoxicity. GeXIVA[1,2] markedly attenuated PAC-induced reactive oxygen species (ROS) overproduction and restored intracellular glutathione (GSH) levels. Mechanistically, PAC suppressed the Nrf2/SLC7A11/GSH/GPX4 ferroptosis-defense pathway, and GeXIVA[1,2] reactivated this axis by upregulating Nrf2, SLC7A11, and GPX4 protein expression. These results reveal a novel ferroptosis-suppressive function of GeXIVA[1,2] in the context of PAC-induced neurotoxicity. Our findings provide a mechanistic foundation for developing GeXIVA[1,2] as a ferroptosis-targeted intervention against chemotherapy-induced neurotoxicity. Full article

Major depressive disorder remains a leading cause of disability worldwide, and the limited efficacy and delayed onset of conventional antidepressants have intensified interest in the microbiota–gut–brain axis as a source of therapeutic targets. Microbiota-associated candidates—short-chain fatty acids, bile acid and tryptophan metabolites, and neuroactive amines—show mood-relevant activity, yet almost none has reached the clinic. This review reframes that gap as a delivery problem. Rather than treating entry into the central nervous system as a universal requirement, we distinguish strategies intended for local intestinal, peripheral systemic, and direct central action, and we argue that delivery is a major but not exclusive translational bottleneck. We outline the barriers these agents face—upper gastrointestinal loss, poor colonic targeting, rapid metabolite turnover, first-pass exposure, and the blood–brain barrier—and synthesize delivery strategies across two fronts. Colon-targeted systems are technically established but have been validated for non-depression indications, whereas brain-directed approaches—bacterial extracellular vesicles, detoxified membrane-coated carriers, receptor-mediated transcytosis, and intranasal routes—reach the brain mainly in selected preclinical models. We foreground a paradox: microbial extracellular vesicles are at once one of the better-documented bio-derived routes for brain exposure in preclinical studies and prominent drivers of neuroinflammation, which defines a risk–opportunity continuum. We close with a route-specific validation roadmap encompassing quantitative exposure, target engagement, chronic efficacy, and safety. Full article

Background: Persistent quadriceps weakness is a common consequence of joint injury, particularly following anterior cruciate ligament (ACL) injury and reconstruction. While traditionally attributed to muscle atrophy and disuse, growing evidence suggests that neural mechanisms play a central role. Arthrogenic Muscle Inhibition (AMI) is a neurally mediated impairment in the ability to voluntarily activate periarticular musculature following joint injury, occurring within a broader neurophysiological response involving altered joint-related afferent input, spinal mechanisms, and supraspinal adaptations. Methods: A narrative review of the literature was conducted using PubMed and Scopus databases. Studies investigating the peripheral, spinal, and supraspinal mechanisms of AMI, as well as its clinical manifestations, assessment methods, and rehabilitation strategies, were reviewed. Experimental, observational, and neurophysiological studies focusing on ACL injury and related joint disorders were included. Results: Current evidence indicates that AMI is a multifactorial neurophysiological process involving altered afferent signaling, spinal reflex inhibition, and central nervous system adaptations. These mechanisms contribute to persistent quadriceps activation failure, impaired motor control, biomechanical asymmetries, and functional and biomechanical alterations that may persist during recovery. Neuroimaging and electrophysiological studies further demonstrate cortical reorganization and neuroplastic changes that may persist despite restoration of joint stability and muscle strength. Conclusions: AMI should be considered a multilevel sensorimotor dysfunction rather than an isolated muscular deficit. Recognition of its neurophysiological basis may improve rehabilitation strategies by promoting interventions that target both neural and muscular components of recovery. Full article

This study provides a comprehensive bibliometric analysis of photobiomodulation (PBM) research in peripheral nervous system (PNS) disorders, aiming to characterize its structural features and developmental trends. Using a bibliometric workflow, a final dataset of 191 unique publications across 24 standardized PNS disease entities was identified through MeSH- and ICD-11-based classification from 14,670 records retrieved from the Web of Science Core Collection. The results show that PBM research has grown steadily since 2010 but remains concentrated in specific clinical conditions, particularly carpal tunnel syndrome (CTS). Keyword co-occurrence network analysis and functional classification identified three primary domains of PBM research: (1) pain modulation, (2) nerve regeneration and structural repair, and (3) biological/mechanistic regulation. The relative emphasis of these domains differed across disease groups, with compression and entrapment neuropathies emphasizing intervention parameters and assessment, nerve injury/regeneration research showing greater representation of structural repair and biological regulation, and neuropathic pain/neuropathy research showing a prominent pain-related component. Temporal analysis indicated diversification toward a broader range of neuropathic conditions and increasing representation of pain-related and biological themes. In conclusion, PBM research exhibits distinct functional patterns across PNS disease contexts. The function-oriented classification framework provides a structured basis for identifying research gaps and disease-specific research priorities. Full article

Background/Objectives: Antiseizure drugs (ASDs) are the primary therapeutic approach for epilepsy in small animals. Although ASDs are primarily used to modulate central neuronal excitability, they are commonly administered systemically, most often by the oral route, and may therefore influence neuronal populations outside the central nervous system. Nevertheless, their functional effects on peripheral neuronal populations, including enteric and dorsal root ganglion (DRG) neurons, remain incompletely characterized at a comparative pharmacological level. This study aimed to perform a comparative functional neuropharmacological profiling of commonly used ASDs in primary cultured myenteric and DRG neurons. Methods: Changes in neuronal activity were assessed in primary cultured guinea pig myenteric and DRG neurons using voltage-sensitive dye imaging with Di-8-ANEPPS following direct ASD application under standardized in vitro conditions. Results: ASDs exerted distinct drug- and neuron-type-specific effects on peripheral neuronal excitability. Topiramate induced the most pronounced reduction in neuronal excitability in myenteric neurons, whereas phenobarbital and levetiracetam produced only minor changes compared with buffer control. Potassium bromide induced mainly excitatory effects in both enteric and DRG neurons. Overall, most ASDs predominantly increased neuronal excitability in DRG neurons. Conclusions: These findings demonstrate distinct functional response profiles of ASDs in enteric and sensory neuronal populations. This comparative in vitro approach may provide a basis for future studies investigating peripheral neuronal drug effects and may help relate experimental pharmacological profiling to clinically relevant challenges associated with ASD treatment across different disorders. Full article