Search Results (613)

Background/Objectives: Hippocampal neuroinflammation (HNF) is a key pathological feature in neurodegenerative disorders. Milk-derived exosomes, as bioactive extracellular vesicles, have underexplored potential in regulating brain neuroinflammatory responses. This study aimed to characterize desert milk exosomes (D-Exo) and investigate their neuroprotective and anti-neuroinflammatory effects in LPS-induced HNF mice model and an LPS-stimulated BV2 microglia. Methods: Exosomes were isolated from desert and non-desert milk (ND-Exo) for proteomic analysis. After pretreating BV2 cells with exosomes and stimulating with LPS, their inflammatory responses and polarization were assessed by RT-PCR. Balb/c mice were orally gavaged with D-Exo or 0.9% NaCl for 28 days before LPS injection. Cognitive function was assessed via behavioral tests, with microglial/astrocyte activation analyzed by immunofluorescence. Results: D-Exo exhibited superior stability and a unique proteomic profile enriched with proteins linked to neuroinflammation and blood-brain barrier (BBB) integrity, notably within the AMPK signaling pathway. In vitro, D-Exo shifted LPS-stimulated microglia from the M1 to the M2 phenotype. In vivo, it alleviated HNF and cognitive decline, reduced Aβ_1-42 and Tau deposition, elevated BDNF and MAP2, and suppressed neuroinflammation and glial activation. Conclusions: D-Exo is enriched with specific proteins, attenuates neuroinflammation and cognitive decline by regulating microglial M1/M2 polarization and AMPK pathway, highlighting its preventive potential. 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

The global aging population has led to a rising prevalence of cognitive impairment, posing a significant public health challenge. Resistance training (RT) is a non-pharmacological intervention that has been increasingly investigated for its potential to support cognitive function in older adults. Clinical evidence suggests that RT may be associated with benefits in certain cognitive domains, including memory, executive function, processing speed, and visuospatial ability. However, findings across studies remain heterogeneous, with several trials reporting neutral outcomes. Most intervention studies involve structured RT programs conducted at moderate to high intensity and performed multiple times per week. However, optimal training parameters have not yet been clearly established due to variability in study design and the absence of formal dose–response analyses. Emerging evidence suggests that the cognitive effects of RT may be mediated, at least in part, through muscle–brain axis signaling involving exercise-induced myokines. Factors such as irisin, brain-derived neurotrophic factor, interleukin-6, interleukin-15, and insulin-like growth factor-1 have been implicated in processes related to neuroplasticity, neuroinflammatory regulation, and neurovascular function, primarily based on preclinical and translational research. This review synthesizes current evidence on RT-related molecular mechanisms and clinical findings to provide an integrative perspective on the potential role of resistance training in mitigating age-related cognitive decline. Full article

Women exhibit a higher prevalence of depression, anxiety, stress-related disorders, and autoimmune conditions compared to men, yet the biological mechanisms underlying this sex difference remain incompletely understood. Growing evidence identifies neuroinflammation as a central mediator of psychiatric vulnerability in women, shaped by interactions between sex hormones, immune activation, and neural circuit regulation. Throughout the female lifespan, fluctuations in estrogen and progesterone, such as those occurring during puberty, the menstrual cycle, pregnancy, postpartum, and perimenopause, modulate microglial activity, cytokine release, and neuroimmune signaling. These hormonal transitions create windows of heightened sensitivity in key brain regions involved in affect regulation, including the amygdala, hippocampus, and prefrontal cortex. Parallel variations in systemic inflammation, mitochondrial function, and hypothalamic–pituitary–adrenal (HPA) axis responsivity amplify stress reactivity and autonomic imbalance, contributing to increased risk for mood and anxiety disorders in women. Emerging data also highlight sex-specific interactions between the immune system and monoaminergic neurotransmission, gut–brain pathways, endothelial function, and neuroplasticity. This review synthesizes current neuroscientific evidence on the sex-dependent neuroinflammatory mechanisms that bridge hormonal dynamics, brain function, and psychiatric outcomes in women. We identify critical periods of vulnerability, summarize converging molecular pathways, and discuss novel therapeutic targets including anti-inflammatory strategies, estrogen-modulating treatments, lifestyle interventions, and biomarkers for personalized psychiatry. Understanding neuroinflammation as a sex-specific process offers a transformative perspective for improving diagnosis, prevention, and treatment of psychiatric disorders in women. Full article

Bladder discomfort, urgency, and frequency of urination are the hallmarks of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic illness. Although the precise etiology remains unclear, numerous clinical investigations have established inflammation as a pivotal factor in its pathogenesis, encompassing uroepithelial damage, mast cell activation, and neuroinflammatory responses. This review delineates the pathological features and classification of IC/BPS, emphasizing the contribution of inflammatory mechanisms and the involvement of cytokines as key mediators in disease progression. The insights presented aim to guide the advancement of innovative treatment approaches. Full article

Background: Growing evidence indicates that oral microbiome dysbiosis contributes to systemic inflammation, immune activation, and neural dysfunction. These processes may influence the onset and progression of major neuropsychiatric and neurodegenerative disorders. This review integrates clinical, epidemiological, and mechanistic findings linking periodontal pathogens and oral microbial imbalance to Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, and anxiety. Methods: A narrative review was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar to identify recent studies examining alterations in the oral microbiota, microbial translocation, systemic inflammatory responses, blood–brain barrier disruption, cytokine signaling, and neural pathways implicated in brain disorders. Results: Evidence from human and experimental models demonstrates that oral pathogens, particularly Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, can disseminate systemically, alter immune tone, and affect neural tissues. Their virulence factors promote microglial activation, cytokine release (IL-1β, IL-6, TNF-α), amyloid-β aggregation, and α-synuclein misfolding. Epidemiological studies show associations between oral dysbiosis and cognitive impairment, motor symptoms in PD, and alterations in mood-related taxa linked to stress hormone profiles. Immunometabolic pathways, HPA-axis activation, and the oral–gut–brain axis further integrate these findings into a shared neuroinflammatory framework. Conclusions: Oral dysbiosis emerges as a modifiable contributor to neuroinflammation and brain health. Periodontal therapy, probiotics, prebiotics, synbiotics, and targeted inhibitors of bacterial virulence factors represent promising strategies to reduce systemic and neural inflammation. Longitudinal human studies and standardized microbiome methodologies are still needed to clarify causality and evaluate whether restoring oral microbial balance can modify the course of neuropsychiatric and neurodegenerative disorders. Full article

Chronic sleep deprivation (CSD) disrupts redox homeostasis and enhances neuroinflammatory activation, contributing to progressive cognitive impairment. Propyl gallate (PG), a lipophilic ester of gallic acid with established antioxidant activity, has not been investigated in the context of prolonged sleep deprivation. The current study examined whether PG alleviates CSD-induced oxidative imbalance, inflammatory activation, and associated behavioral deficits. Male ICR mice were subjected to 14 days of CSD using a rolling-drum apparatus and received oral PG (50, 100, or 200 mg/kg) or Ginkgo biloba extract (GBE, 40 mg/kg). Behavioral outcomes were assessed through a battery of tests, including the open-field, novel-object recognition, step-through, and Morris water maze paradigms. Oxidative and inflammatory biomarkers were assessed in serum and hippocampus, and Western blotting quantified the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2). PG improved CSD-induced impairments in exploration, recognition memory, and spatial learning; restored antioxidant capacity; reduced lipid peroxidation; enhanced Nrf2-associated antioxidant signaling; and suppressed NF-κB-mediated inflammatory activation. These findings indicate that PG alleviates cognitive deficits induced by CSD through the modulation of redox homeostasis and neuroinflammatory responses, supporting its potential as an antioxidant derivative under chronic sleep-deprivation conditions. Full article

Neuroinflammation is a defining feature of many neurological disorders, including neurodegenerative diseases, traumatic brain injury, and demyelinating conditions. Glial cells play a central role in this process by initiating, modulating, and resolving inflammatory responses in the CNS. This review examines the diverse roles of glial cells in neuroinflammation, focusing on their molecular and cellular interactions, context-dependent activation states, and phenotypic plasticity. It discusses how microglial activation can result in both neuroprotective and neurotoxic effects, while astrocytes contribute to immune regulation, blood–brain barrier integrity, and neuronal survival. The review also highlights interactions between glial cells and peripheral immune components, which may exert synergistic or antagonistic effects. Finally, it outlines emerging preclinical and clinical strategies targeting glial pathways to modulate several neuroinflammatory outcomes, emphasizing that a detailed understanding of glial dynamics is essential for developing effective CNS therapies. Full article

Perinatal depression (PND) is a severe mood disorder affecting mothers during pregnancy and postpartum, with implications for both maternal and neonatal health. Emerging evidence suggests that gut microbiota-derived metabolites play a critical role in neuroinflammation and neurotransmission. In this study, we employed an in silico approach to evaluate the pharmacokinetic and therapeutic potential of metabolites produced by Lactobacillus helveticus and Bifidobacterium longum in targeting key proteins implicated in PND, including BDNF, CCL2, TNF, IL17A, IL1B, CXCL8, IL6, IL10. The ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles of selected microbial metabolites, including acetate, lactate, formate, folic acid, riboflavin, kynurenic acid, γ-aminobutyric acid, and vitamin B12 were assessed using computational tools to predict their bioavailability and safety. Enrichment analysis was performed to identify biological pathways and molecular mechanisms modulated by these metabolites, with a focus on neuroinflammation, stress response, and neurogenesis. Additionally, molecular docking studies were conducted to evaluate the binding affinities of these metabolites toward the selected PND-associated targets, providing insights into their potential as neuroactive agents. Our findings suggest that specific microbial metabolites exhibit favorable ADMET properties and strong binding interactions with key proteins implicated in PND pathophysiology. These results highlight the therapeutic potential of gut microbiota-derived metabolites in modulating neuroinflammatory and neuroendocrine pathways, paving the way for novel microbiome-based interventions for perinatal depression. Further experimental validation is warranted to confirm these computational predictions and explore the clinical relevance of these findings. Full article

Methylglyoxal (MG), a reactive dicarbonyl metabolite associated with diabetes and metabolic disorders, contributes to carbonyl stress, neuroinflammation, and Alzheimer-like neurodegeneration. This study investigated the neuroprotective effects of propyl gallate (PG), a phenolic antioxidant widely used as a food additive, against MG-induced cognitive impairment in mice. Male C57BL/6J mice were exposed to 1% MG in drinking water for eight weeks and orally administered PG (20, 40, or 100 mg/kg/d). Behavioral tests demonstrated that PG significantly improved spatial learning and recognition memory and alleviated anxiety-like behavior induced by MG. Histological and biochemical analyses revealed that PG reduced hippocampal neuronal damage, suppressed tau hyperphosphorylation and amyloid-β (Aβ) accumulation, and attenuated the overexpression of pro-inflammatory cytokines TNF-α and IL-6. Furthermore, PG increased PI3K expression and Akt phosphorylation while reducing activation of GSK-3β, counteracting the MG-induced suppression of this pathway and aligning with reduced tau hyperphosphorylation. These findings indicate that PG protects against MG-related cognitive dysfunction through modulation of neuroinflammatory responses and survival-related signaling pathways, highlighting its potential as a neuroprotective dietary antioxidant for metabolic stress-associated neurodegenerative disorders. Full article

Three-dimensional (3D) bioprinting is a rapidly evolving technology that uses complementary biomaterials to emulate native extracellular matrices, enabling the generation of finely patterned, multicellular tissue architectures. Autoimmune diseases (AD), which are characterized by chronic, often organ-specific, immune response, are ideally suited to these in vitro models. This review summarizes the current state of 3D bioprinting for modelling AD, focusing on rheumatoid arthritis (RA), type 1 diabetes (T1D) and inflammatory bowel disease (IBD), as well as applications to systemic lupus erythematosus (SLE), neuroinflammatory conditions such as multiple sclerosis (MS) and other AD. Bioprinting modalities, advances in immune competent bioinks, strategies for vascularization and approaches to the hybridization of printed tissues with organoids and organ-on-chip systems are reviewed. From a clinical perspective, this review focuses on applications with translational potential, including immune-competent models derived from patients for biomarker discovery, drug screening and treatment response prediction. The key challenges, notably the reconstitution of full immune complexity, stable and perfusable vasculature, and maintenance of long-term viability and function are highlighted. Finally, future directions are defined to enhance the clinical utility and impact of 3D bioprinting across preclinical development and precision medicine. Full article

Chronic pain is increasingly regarded as a condition of glia–neuronal dysregulation driven by persistent neuroinflammatory signaling. Following injury to nerves or tissues, glial cells, including astrocytes or satellite glial cells, undergo changes in their phenotype, thereby amplifying painful stimuli mediated by cytokines, chemokines, or ATP signaling. In response to injuries, activated microglia release several mediators such as BDNF, IL-1β, or TNF-α, thereby disrupting chloride homeostasis and inducing disinhibition in the dorsal horn, and sustaining maladaptive neuroimmune activity. Dysfunction of astrocytes, characterized by impaired glutamate clearance via excitatory amino acid transporter 2 and elevated C-X-C motif chemokine ligand 1 (CXCL1) and ATP release, drives neuronal sensitization, loss of neuroprotective metabolic support, and persistence of pain. In peripheral ganglia, connexin–43–mediated satellite glial cell coupling leads to hyperexcitability, resulting in neuropathic and orofacial pain and contributing to peripheral neuroinflammation. Presently, there is no unified framework for glial cell types, and the molecular mechanisms underlying microglial, astrocyte, and satellite glial cell contributions to the transition to chronic pain from acute pain are not completely elucidated. This review synthesizes current evidence on cellular and molecular mechanisms linking glial reactivity to pain chronification through sustained neuroinflammatory remodeling and impaired neuroprotection. It evaluates therapeutic strategies, including purinergic receptor P2X4 and toll-like receptor 4 antagonists, to metabolic reprogramming, exosome therapy, and neuromodulation, aimed at restoring homeostatic glial function and re-establishing neuroprotective glia–neuron interactions. A deeper understanding of the temporal and spatial dynamics of glial activation may enable personalized, non-opioid interventions that not only achieve durable analgesia but also prevent progressive neuroinflammatory damage and support long-term functional recovery. Full article

Alzheimer’s disease (AD) is considered one of the leading causes of death in the United States, and there is no effective cure for it. Understanding the neuropathological mechanisms underlying AD is essential for identifying early, reliable biomarkers and developing effective therapies. In this paper, we report on a comprehensive multimodal study of AD pathology using the 5xFAD mouse model. We employed light-scattering techniques, Partial Wave Spectroscopy (PWS) and Inverse Participation Ratio (IPR), to detect nanoscale structural alterations in brain tissues, nuclear components, and mitochondria. To support the light-scattering experiments, behavior, and histopathological studies were conducted. These analyses revealed significant increases in structural heterogeneity and mass density fluctuations in the brains of 5xFAD mice compared with Non-transgenic controls. Behavioral assessment performed using the Novel Object Recognition test demonstrated memory impairment in 5xFAD mice, reflected by a reduced recognition index. Histopathological analysis further revealed increased amyloid beta plaques and microglia activation in the hippocampus and cortex of 5xFAD mice compared with Non-transgenic controls. An increase in structural disorder within brain tissues can be attributed to higher mass density fluctuations, likely arising from macromolecular rearrangement driven by amyloid beta aggregation and neuroinflammatory responses as the disease progresses. Our findings suggest that PWS and IPR-derived metrics provide sensitive biophysical indicators of early cellular and subcellular disruption, offering potential as quantitative biomarkers for the detection of AD. Full article

The neuroendocrine and immune systems interact bidirectionally through shared ligands and receptors during inflammation, thereby regulating immune responses. Leptin, primarily known for its role in energy metabolism and appetite regulation, also modulates neuroinflammatory pathways. Its receptors are widely expressed on immune cells and contribute to immune mechanisms implicated in the pathogenesis of neuroinflammatory disorders such as multiple sclerosis (MS) and Alzheimer’s disease (AD). This review highlights recent advances in understanding leptin’s role in immune regulation, with a focus on its impact on MS and AD. A comprehensive literature review was conducted until October 2025, using PubMed, Google Scholar, and Scopus to identify studies investigating leptin in neuroinflammatory conditions, particularly MS and AD. Leptin exerts broad immunomodulatory effects by activating T cells, dendritic cells, and microglia, and promoting their proliferation and phagocytosis. Its elevation enhances Th1 and Th17 responses, drives pro-inflammatory macrophage phenotype polarization, and suppresses regulatory T cell and Th2 responses, immune pathways involved in MS. Peripheral leptin levels are increased in MS, especially during disease exacerbations. In contrast, in AD, they are typically reduced, particularly in patients with normal body mass index (BMI), where their decline contributes to amyloid-β and tau pathology. These divergent patterns position leptin as a bidirectional regulator at the intersection of immunity and neurodegeneration. Additionally, its protective or detrimental effects likely depend on whether it acts under physiological conditions or in the context of obesity-induced leptin resistance. Elevated leptin levels in obesity exacerbate inflammation and diminish its neuroprotective effects. In conclusion, leptin is elevated in MS patients but downregulated in AD, reflecting its bidirectional effects. In leptin resistance, peripheral proinflammatory signaling is maintained while central leptin signaling is restricted, thereby potentially promoting autoimmunity in MS and limiting neuroprotection in AD. Further mechanistic and longitudinal studies are needed to clarify the relationship between leptin dysregulation, leptin resistance, neuroinflammatory and neurodegenerative diseases. Full article

Background/Objectives: The molecular cascades involved in the induction and maintenance of neuroinflammation resulting from chronic compression of the cervical spinal cord in the setting of degenerative cervical myelopathy (DCM) have yet to be defined. Here, we determined the role of the fractalkine receptor, CX3CR1, during the neuroinflammatory response in a novel mouse model of DCM and demonstrated the relevance of this mechanism with human DCM tissue. Methods: Using our murine DCM model alongside the CX3CR1-knockout mice and a neutralizing antibody of CX3CR1 in wild-type mice, we examined protein, neurobehavioural and immunohistochemical readouts. The animal data were then complemented with immunohistochemical results from human post-mortem spinal cord tissue from individuals with DCM. Results: Humans and mice with DCM exhibited an up-regulation of CX3CR1 as well as markers of activated microglia/macrophages in the cervical spinal cord. Knockout and neutralization of CX3CR1 hindered microglia/macrophage activation and accumulation at the site of spinal cord compression. DCM mice exhibited decreased body speed and increased stance phase duration, which mirrors human DCM gait deficits. Strikingly, both CX3CR1 deficiency and CX3CR1 neutralization alleviated these gait deficits in DCM mice. Conclusions: Collectively, these data provide strong evidence that CX3CR1 plays a critical role in the secondary injury of neural structures in the setting of DCM. Further, targeting of CX3CR1 represents a promising therapeutic strategy to enhance neurological outcomes in DCM. Full article