Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

Alzheimer's disease (AD) features Aβ-driven neuroinflammation and synaptic dysfunction that converge on cognitive decline, underscoring the potential value of multi-target interventions. Aurantio-obtusin (AO), a bioactive anthraquinone from Cassia obtusifolia L., exhibits reported anti-inflammatory and antioxidant activities; however, whether AO counteracts Aβ-associated behavioral impairment through coordinated modulation of inflammatory and synaptic alterations remains unclear. Here, we investigated whether AO alleviates Aβ₁₋₄₂-induced cognitive deficits and examined synapse- and inflammation-related molecular correlates. Male C57BL/6 mice received intracerebroventricular Aβ₁₋₄₂ to establish an acute AD-like model and were treated with AO (10 mg/kg/day, oral gavage) for consecutive weeks. The results showed that AO improved spatial learning and memory in the Morris water maze, recognition memory in the novel object recognition test, and working memory in the Y-maze, without affecting spontaneous locomotor activity. Furthermore, AO alleviated synaptic dysfunction by restoring synaptophysin expression and upregulating GAD65, and mitigated neuroinflammation by elevating anti-inflammatory factors (IL-4, IL-10, ARG1) and reducing TNF-α. In vitro experiments confirmed that AO was non-cytotoxic to N2A^APP cells across 0-80 μM, mildly downregulated BACE1 expression, and suppressed the Aβ-induced upregulation of pro-inflammatory mediators (IL-6, iNOS) in BV2 microglial cells. Overall, AO attenuated Aβ_1-42-driven behavioral impairment in parallel with improvements in synapse-associated markers and inflammatory readouts. These findings support further evaluation of AO as a natural compound associated with modulation of Aβ-related neuroinflammatory and synapse-associated alterations.

Gradual loss of the homeostatic balance owing to deregulation of endogenous antioxidant defense pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), contributes, at least in part, to the characteristic oxidative stress, neuronal loss, and cognitive decline associated with aging. Here, we adopted an integrated approach using behavioral, biochemical, histological, molecular, and in silico methods, exploring the neuroprotective efficacy of vitamin D against D-galactose-induced oxidative stress, neuroinflammation, and neurodegeneration. Chronic D-galactose administration (150 mg/kg, s.c) led to profound deficits in spatial learning, working memory, and recognition memory, besides increased oxidative stress, reduced antioxidant enzyme activity, suppression of Nrf2 and heme oxygenase-1 (HO-1) expression, and frank hippocampal neurodegeneration, as revealed by nissl staining. Vitamin D treatment (5 µg/kg i.p) significantly improved such deficits by restoring cognitive performance, reducing ROS and lipid peroxidation, enhancing endogenous antioxidant activities such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPx), and upregulating Nrf2 and HO-1 expression comparable to positive control, dimethyl fumarate (DMF). Co-administration of all-trans retinoic acid (ATRA), an antagonist for Nrf2, abrogated these protective effects, confirming the pathway specificity. Molecular docking studies have shown a strong binding affinity of Vitamin D to the regulatory domain of Nrf2, supporting a direct stabilizing interaction that may facilitate the activation of Nrf2. Nissl quantification has further demonstrated substantial preservation of neuronal integrity in hippocampal CA1, CA3, and DG regions following the treatment with vitamin D. Altogether, findings from this study show that vitamin D confers robust neuroprotection through Nrf2-dependent antioxidant mechanisms and mitigates aging-related neurodegeneration induced by D-galactose. The results highlighted vitamin D as a readily accessible therapeutic candidate for mitigating oxidative stress-driven cognitive decline.

Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.

Aging is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). Targeting cellular senescence has therefore emerged as a promising therapeutic strategy. Resveratrol (RV), a natural polyphenolic compound, exhibits anti-aging properties through the regulation of autophagy and oxidative stress; however, its mechanisms in AD remain incompletely understood. In this study, we investigated the effects and underlying mechanisms of RV in an Aβ1-42-induced AD model. In vivo, RV administration significantly reduced the expression of aging-related markers and activated autophagy-associated signaling pathways. In vitro, RV treatment markedly attenuated Aβ1-42-induced cell viability loss and excessive reactive oxygen species (ROS) production. Further mechanistic analyses demonstrated that RV-induced autophagy activation was closely associated with the AMP-activated protein kinase/UNC-51-like kinase 1 (AMPK/ULK1) and silent information regulator 1/nuclear factor-kappaB (SIRT1/NF-κB) pathways. Collectively, these findings suggest that RV alleviates AD-related pathological processes by promoting autophagy and delaying cellular senescence, highlighting its potential as a therapeutic agent for age-related neurodegenerative diseases.

CD16⁺ monocytes are a minor subset of the total monocyte population that play a disproportionate role in contributing to neuroinflammation in human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND). This has been evidenced by the enhanced transmigration of CD16⁺ monocytes into the brain compared to their CD16^- counterpart. CD16⁺ monocytes can be activated by HIV ssRNAs through toll-like receptors (TLR) 7 and TLR8, and subsequently interact with brain-resident cells, including astrocytes. Previous studies from our laboratory identified monocyte-derived IL-1ß as an inducing cytokine for astrocyte-derived neuroinflammatory factors. Despite cannabis use among the HIV community, the mechanisms by which immune-modulating cannabinoids, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), alter human immune responses in the context of HAND-associated neuroinflammation remain elusive. We hypothesized that THC and CBD suppress CD16⁺ monocyte-induced astrocyte secretion of inflammatory mediators and monocyte recruitment via chemotaxis in the context of HIV. Results from this study show that THC and CBD impair CD16⁺ monocyte IL-1ß-mediated astrocyte production of IL-6, IL-8, and MCP-1 when these two cell types are cocultured in the presence of TLR7 or TLR8 stimulation. Additionally, monocytes from HIV+ subjects exhibited enhanced migration compared to monocytes from HIV- subjects, which was suppressed by THC treatment but not by CBD. The effects on migration were associated with reduced cellular expression of polymerized actin and high-affinity conformation integrin receptors. Collectively, these findings suggest that THC, and to a lesser extent CBD, may have therapeutic potential for mitigating CD16⁺ monocyte-mediated neuroinflammation associated with HAND.

People with HIV (PWH) exhibit persistent immune activation despite suppressive antiretroviral therapy, contributing to neurocognitive vulnerability. Marijuana use is common among PWH and may influence inflammatory pathways, but its in vivo immunologic effects in treated HIV remain unclear. In this cross-sectional study (Durham, NC; 2021-2023), 238 adults with and without HIV were grouped by chronic marijuana use. Soluble immune biomarkers were measured in plasma/serum, and log-transformed outcomes were analyzed using hierarchical multivariable regression. Seven biomarkers showed significant model fit: sCD163, IFN-γ, TNF-α, TNF-RII, CXCL10, CCL4, and VCAM-1. Among HIV-negative participants, marijuana use was linked to reduced CXCL10, suggesting disruption of IFN-γ-dependent chemotactic signaling. In contrast, HIV infection in the absence of marijuana use was associated with a broad, multi-pathway inflammatory profile, including TNF signaling, interferon activation, monocyte/macrophage activation, and endothelial recruitment. Among PWH, marijuana use did not modulate these effects, although CCL4 and VCAM-1 were not significantly elevated in this group compared to controls. However, these markers did not differ between marijuana-using and non-using PWH, suggesting a potential divergence from the broader inflammatory profile rather than a clear marijuana-associated attenuation. Cognitive analyses demonstrated a modest inverse association between memory performance and TNF-related markers, indicating that HIV-associated inflammatory signaling may relate to memory function, whereas marijuana-related cognitive effects require further study.

The purpose of this study is to investigate the mechanism of Zhilong Huoxue Tongyu (ZL) capsule on the treatment of intracerebral hemorrhage (ICH). In this study, ICH model was established to assess the neuroprotective efficacy of ZL capsule. The ICH-induced neurological deficits were analyzed by behavioral studies including Zea-Longa score, Neurological Severity Score, Open filed test, Y-maze test, Morris water maze, Rotarod test and pathological staining such as HE staining and Nissl staining. Perls staining was used to measure iron deposition after ICH. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) assay kits were performed to measure the level of lipid peroxide after ICH. The levels of oxidative stress-related targets were verified by quantitative real-time PCR and western blot. This study demonstrated that ZL capsule treatment significantly reduced ICH-induced neurological deficits after ICH, improved the memory learning functions of rats and attenuated ICH‑Induced neuron damage in rats. After ICH, oxidative stress in brain tissue increased and ZL capsule could alleviate the pathological state of oxidative stress. The SOD and GSH activities were dramatically increased after the treatment of ZL capsule compared with the Ns group, while the content of MDA was markedly decreased after treatment with ZL capsule compared with Ns group. After ICH, the SLC40A1, SLC7A11, SESN2 and GPX4 mRNA in brain tissue increased, and the NOX4 and TFR1 mRNA in brain tissue decreased after the treatment of ZL capsule. Proteomics analysis also confirmed these results. Our data suggested that ZL capsule showed a neuroprotective function after ICH and alleviated ICH induced neurological deficits in rats. The possible mechanism may be that ZL capsule inhibits iron deposition and lipid peroxidation, lessening oxidative stress in brain tissue. This study offers new insights into how the ZL capsule affects ICH at the molecular level and could be conducive to developing therapeutic drugs for ICH and traditional Chinese medicine.

Neuropeptide Y (NPY) is a highly conserved 36-amino acid neuropeptide broadly distributed throughout the central and peripheral nervous systems, where it classically regulates appetite, stress responses, and circadian rhythms. Increasing evidence now positions NPY as a critical mediator at the interface of neural and immune signaling within the tumor microenvironment (TME). In cancer, NPY is released not only from tumor-innervating sympathetic fibers but also, in some contexts, directly from tumor cells, thereby establishing autocrine and paracrine signaling circuits that support tumor progression. Acting through its G protein-coupled receptors (Y1, Y2, Y4, Y5, and Y6), NPY exerts pleiotropic effects on both malignant and immune cell populations. Activation of Y1R and Y2R has been associated with enhanced tumor cell proliferation, angiogenesis, and vascular remodeling, whereas Y5R links stress-associated neuroendocrine signaling to accelerated tumor growth. Importantly, within the immune compartment, NPY promotes macrophage polarization toward an M2-like immunosuppressive phenotype, suppresses natural killer cell cytotoxicity, and dampens T cell activation, collectively fostering a tolerogenic and immune-evasive TME. These convergent neural and immunological effects highlight NPY as a dual-function neuromodulator and immunoregulator in cancer. In this review, we propose that NPY signaling represents a previously underappreciated neuro-immune checkpoint that integrates stress signals with tumor immune suppression. Targeting the NPY-receptor axis may therefore offer novel opportunities to reprogram the neuro-immune landscape of tumors and enhance the efficacy of cancer immunotherapy, particularly in stress-responsive malignancies.

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Natural killer cells participate in MS through context-dependent regulatory and cytotoxic functions, yet their precise contribution to disease remains incompletely defined. This review summarizes current knowledge on NK cell development, receptor-mediated activation and inhibition, and mechanisms shaping NK cell responses in the inflamed central nervous system. We examine evidence from experimental autoimmune encephalomyelitis and clinical studies describing how distinct NK subsets may exert protective or pathogenic effects depending on disease stage and microenvironment. Emerging strategies to modulate NK cell function, including cytokine-based stimulation, metabolic and epigenetic regulation, and engineered NK platforms, are also discussed. These approaches have been primarily developed in oncology, and their relevance to MS currently remains preclinical, with only early exploratory efforts reported in autoimmune contexts. Overall, we aim to provide a clear and updated assessment of NK cell biology in MS and to outline the opportunities and limitations of NK-targeted interventions. Further mechanistic and translational studies are required before NK-focused strategies can be reliably considered for therapeutic development in MS.

This study was designed to investigate the impact of Lamotrigine (LTG) on astrocyte activation in epilepsy during pregnancy and to elucidate its potential underlying mechanisms. A rat model of epilepsy during pregnancy was established using pentylenetetrazole (PTZ) injection. CTX-TNA2 cells were treated with IL-1β to activate astrocytes. NLRP3 expression was modulated using NLRP3 inhibitor and pcDNA 3.1-NLRP3 overexpression. Neuronal damage, apoptosis, and astrocyte activation were evaluated by HE staining, TUNEL staining, and immunofluorescence, respectively. Levels of inflammatory cytokines were determined by ELISA. Protein and mRNA expression levels associated with inflammation and astrocyte activation were analyzed by Western blot and RT-qPCR. LTG significantly reduced the expression of NLRP3, TXNIP, and suppressed inflammatory responses. In vivo, LTG attenuated neuronal damage and apoptosis in the cerebral cortex and hippocampal CA1 region, accompanied by decreased levels of TNF-α, IL-1β, and IL-6, as well as reduced expression of GFAP, GLAST, and phosphorylated p65. Co-treatment with the NLRP3 inhibitor MCC950 further enhanced these effects. In vitro, LTG inhibited astrocyte proliferation and activation, whereas NLRP3 overexpression partially reversed these effects. LTG alleviates astrocyte activation and neuroinflammation in pregnancy-associated epilepsy, potentially through modulation of the NLRP3/TXNIP axis. These findings provide novel insights into the pathogenesis of epilepsy during pregnancy and suggest potential therapeutic strategies.