J Neuroimmune Pharmacol [JOURNAL]
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200 papers
Intravenous zn-Aspartate Mitigates Neuroinflammation and Motor Dysfunction in an Lps-Induced Parkinson's Disease Rat Model.
Temnik M, Rudyk M, Balakin A … +6 more , Gurin S, Dovbynchuk T, Byshovets R, Dzubenko N, Tolstanova G, Skivka L
J Neuroimmune Pharmacol · 2025 Nov · PMID 41222752 · Full text
Emerging evidence links zinc dyshomeostasis to the pathogenesis of Parkinson's disease (PD), highlighting the need to explore zinc-based interventions. Zinc has five stable isotopes, with Zn and Zn being the most abundan...
Emerging evidence links zinc dyshomeostasis to the pathogenesis of Parkinson's disease (PD), highlighting the need to explore zinc-based interventions. Zinc has five stable isotopes, with Zn and Zn being the most abundant. Notably, healthy brain tissue is enriched in the lighter isotope Zn, while heavier isotopes are hypothesized to accumulate with age. This study examined the therapeutic potential of intravenously administered isotopically enriched Zn aspartate (Zn-asp) in a rat model of PD induced by a single stereotactic intranigral injection of lipopolysaccharide (LPS, 10 μg), which simulates acute neuroinflammation followed by progressive neurodegeneration. Treatment effects were evaluated using behavioral assessments, immunological profiling, biochemical and molecular analyses, and histopathology. Rats treated with Zn-asp showed a pronounced anti-inflammatory shift in microglial/macrophage metabolic profiles and reduced reactive astrogliosis. These changes were accompanied by improved motor performance and decreased anxiety-like behavior. Immunohistochemistry confirmed preservation of dopaminergic neurons. Overall, these findings suggest that Zn-asp attenuates neuroinflammation and supports neuronal survival, indicating its potential as a candidate for disease-modifying strategies in PD.
Gallic Acid Alleviates Cerebral Ischemia-reperfusion Injury in Mice by Mediating Microglial Polarization Through the NLRP3/mTOR Axis.
Hua W, Xu H, Chen R … +7 more , Zhang H, Zhang Y, Zhang X, Zhang Y, Liu J, Zhang L, Yang P
J Neuroimmune Pharmacol · 2025 Nov · PMID 41207987 · Publisher ↗
Cerebral ischemia-reperfusion (I/R) injury is a critical condition leading to severe neurological deficits. Inflammation, driven by microglial polarization, plays a significant role in the progression of I/R injury. Gall...
Cerebral ischemia-reperfusion (I/R) injury is a critical condition leading to severe neurological deficits. Inflammation, driven by microglial polarization, plays a significant role in the progression of I/R injury. Gallic acid (GA), a natural polyphenol, has been recognized for its anti-inflammatory and neuroprotective properties. Male mice subjected to middle cerebral artery occlusion (MCAO) were treated with GA. Neurological deficits, infarct size, and brain edema were assessed to evaluate the neuroprotective effects of GA. In vitro, oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to simulate I/R injury in microglial cells. The polarization of microglia was analyzed by flow cytometry, qPCR, and Western blot, focusing on M1 and M2 markers. Autophagy and inflammasome activation were investigated using Western blot, immunofluorescence, and flow cytometry, with the effects of GA modulated by autophagy and inflammasome inhibitors. GA treatment significantly improved neurological outcomes in MCAO mice by reducing infarct size, brain edema, and promoting the M2 polarization of microglia while inhibiting M1 polarization. GA enhanced autophagy and suppressed NLRP3 inflammasome activation via the mTOR pathway, reducing pro-inflammatory cytokine expression. Inhibition of autophagy reversed the protective effects of GA, leading to increased M1 polarization and exacerbated neuroinflammation. Additionally, activation of the NLRP3 inflammasome counteracted GA's effects, emphasizing the role of this pathway in microglial modulation. GA exerts neuroprotective effects in cerebral I/R injury by modulating microglial polarization through the NLRP3/mTOR axis. Its ability to promote autophagy and suppress inflammasome activation positions GA as a potential therapeutic agent for reducing neuroinflammation and improving outcomes in I/R injury.
Thrombomodulin-Induced Prevention of Peripheral Neuropathy in Oxaliplatin-Treated Mice Involves Complement C5a Inactivation and PAR1 Activation in Addition To HMGB1 Degradation.
Maruo K, Tsubota M, Tajima K … +7 more , Matsunaga H, Sekiguchi F, Minami T, Ito A, Tomono Y, Nishibori M, Kawabata A
J Neuroimmune Pharmacol · 2025 Nov · PMID 41186892 · Publisher ↗
High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, participates in the pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN). Thrombomodulin alfa (TMα), a recombin...
High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, participates in the pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN). Thrombomodulin alfa (TMα), a recombinant soluble protein of endothelial thrombomodulin, prevents CIPN by promoting thrombin-dependent HMGB1 degradation and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI/plasma carboxypeptidase B/CPB2). We thus investigated the downstream molecules of activated protein C (APC) and TAFI (TAFIa), for prevention of oxaliplatin-induced peripheral neuropathy (OIPN) in mice. OIPN was prevented by TMα and by each of an anti-HMGB1-neutralizing antibody (HAb), APC and porcine pancreatic carboxypeptidase B (ppCPB, used as a stable surrogate of TAFIa), or their combination at subeffective doses. Intraplantar administration of HMGB1 induced mechanical allodynia, which was abolished by TMα, but not APC or ppCPB. The anti-OIPN effects of TMα and APC were reversed by an antagonist of proteinase-activated receptor 1 (PAR1), targetable by APC, and the effect of TMα was also reversed by a CPB inhibitor. Intraplantar administration of mouse C5a (mC5a), targetable by TAFIa, caused mechanical allodynia, an effect blocked by TMα, a mC5a receptor (mC5aR) antagonist or HAb. The mC5aR antagonist prevented OIPN development. Oxaliplatin significantly increased plasma C5a levels in the mice treated with argatroban, a thrombin inhibitor, capable of reducing the degradation of HMGB1 by the endogenous thrombin-thrombomodulin axis. Our data thus suggest that the anti-OIPN effect of TMα involves APC-induced PAR1 activation and TAFIa-induced degradation of C5a that induces HMGB1-dependent pain, in addition to HMGB1 degradation.
HMGB1-Induced Neurite Outgrowth in the Dorsal Root Ganglion Neurons and Regeneration Priming after their Axonal Injury by Sciatic Nerve Crush.
Sekiguchi F, Nakatake Y, Adachi A … +4 more , Tsubota M, Tomono Y, Nishibori M, Kawabata A
J Neuroimmune Pharmacol · 2025 Oct · PMID 41171540 · Publisher ↗
High mobility group box 1 (HMGB1), a nuclear protein, once released extracellularly, exists in two different active forms, i.e., all-thiol (at)- and disulfide (ds)-HMGB1. Given that HMGB1 promotes neuritogenesis, we exam...
High mobility group box 1 (HMGB1), a nuclear protein, once released extracellularly, exists in two different active forms, i.e., all-thiol (at)- and disulfide (ds)-HMGB1. Given that HMGB1 promotes neuritogenesis, we examined whether at/ds-HMGB1 would promote neuritogenesis in dorsal root ganglion (DRG) neurons, and participate in regeneration priming of DRG neurons by sciatic nerve crush (SNC). In cultured mouse DRG neurons, at-HMGB1, but not ds-HMGB1, accelerated neuritogenesis, an effect blocked by an antagonist of receptor for advanced glycation end-product (RAGE). A combination of thrombin and thrombomodulin alfa (TMα) capable of sequestering HMGB1 with its D1 domain and promoting HMGB1 degradation by thrombin tethered to its D2 domain synergistically suppressed the at-HMGB1-induced neuritogenesis, an effect abolished by angiopoietin-1 capable of inhibiting the binding of thrombin to TMα. The DRG neurons from the mice subjected to SNC exhibited accelerated neuritogenesis, even in the presence of an anti-HMGB1-neutralizing antibody (HMGB1-Ab). However, the neurite regeneration priming of DRG neurons by SNC in mice was prevented by daily treatment with HMGB1-Ab, minocycline, a macrophage/microglia inhibitor, ethyl pyruvate capable of inhibiting HMGB1 release from macrophages, and azeliragon, a RAGE antagonist. SNC caused macrophage accumulation in the sciatic nerves, but not DRG. Our data suggest that extracellular at-HMGB1 causes RAGE-dependent acceleration of neuritogenesis in cultured DRG neurons, which is suppressed synergistically by thrombin and TMα. Nonetheless, neurite regeneration priming of DRG neurons by SNC is considered to involve HMGB1 derived from macrophages recruited to the damaged axon, but is not mediated by HMGB1 released from cultured DRG cells.
Profiling the Cerebrospinal Fluid Proteome in Progressive Multiple Sclerosis: Treatment Effects and Associations with IgM Oligoclonal Bands.
El Mahdaoui S, Kosa P, Komori M … +9 more , Veiga González JL, Chow HH, Ratzer R, Madsen CG, Siebner HR, Bielekova B, Villar LM, Romme Christensen J, Sellebjerg F
J Neuroimmune Pharmacol · 2025 Oct · PMID 41165937 · Full text
Treatment options for progressive MS (PMS) are limited in numbers and efficacy, which is most pronounced in patients with inflammatory disease activity. Immunoglobulin M (IgM) oligoclonal bands (OCBs) may identify a subs...
Treatment options for progressive MS (PMS) are limited in numbers and efficacy, which is most pronounced in patients with inflammatory disease activity. Immunoglobulin M (IgM) oligoclonal bands (OCBs) may identify a subset of PMS with more active inflammatory disease. The effects of natalizumab and methylprednisolone on intrathecal inflammation and the association of IgM OCBs with other biomarkers in PMS is uncertain. In the current study, we investigated the cerebrospinal fluid (CSF) proteome of untreated patients with PMS, effects of natalizumab and methylprednisolone, and associations of IgM OCBs with disease activity and CSF biomarkers. We found a reduction of BCMA, SLAMF7, granzyme A, IgG, and desmoglein-2 with both therapies, as well as natalizumab-specific reductions of VCAM-1, CD48, MDC, MMP-9, sE-selectin, and CHIT1, and methylprednisolone-specific reductions of DR3, IgD, RTN4, and increases of sCD206, LYVE1, sCD163 and MMP-3. IgM OCBs were associated with reduced levels of PIGR, higher levels of NFL and VEGF, and more contrast-enhancing lesions. The study suggests T and B cell activity biomarkers as treatment-responsive CSF biomarkers in PMS. Additionally, we found natalizumab to reduce adhesion molecules and methylprednisolone to increase myeloid biomarkers. Lastly, we confirm that IgM OCBs are associated with a more inflammatory MRI and CSF profile.
Investigating the Potential of CDDO-Me as an HMGB1 Inhibitor in Mitigating Cerebral Ischemia-Reperfusion Injury.
Zhang L, Li G, Chen X … +3 more , Li T, Raj R, Shen P
J Neuroimmune Pharmacol · 2025 Oct · PMID 41144095 · Publisher ↗
HMGB1-mediated neuroinflammation assumes a pivotal position in the pathophysiological framework of a multitude of neurological disorders, including ischemic stroke, which still urgently need effective therapeutic agents....
HMGB1-mediated neuroinflammation assumes a pivotal position in the pathophysiological framework of a multitude of neurological disorders, including ischemic stroke, which still urgently need effective therapeutic agents. CDDO-Me, is a potentially useful therapeutic drug for diabetic nephropathy, whereas the neuroprotective properties and underlying mechanism in ischemic stroke have not been reported as yet. In the present study, CDDO-Me was found to alleviate OGD/R induced nerve cell injury and protect the cerebral ischemia of rats. In addition, the proinflammatory activity of HMGB1 was inhibited by CDDO-Me through directly binding to HMGB1 and then disrupting its interaction with receptor TLR4. The binding affinity of CDDO-Me to HMGB1 was 117 µM indicated by surface plasmon resonance (SPR) assay. On this basis, we observed that CDDO-Me could slightly change the secondary and steric conformation as well as the thermal stability of HMGB1. Subsequently, molecular dynamics (MD) simulation showed that CDDO-Me mainly binds to the A-box domain of HMGB1, which was maintained by weak interaction forces like van der Waals and hydrophobicity. Further virtual mutagenesis and binding free energy calculations identified F38 and F89 in the A-box as key residues involved in HMGB1-CDDO-Me interaction. These findings indicated that CDDO-Me can improve stroke-induced inflammatory damage through direct binding HMGB1 and negative regulation of HMGB1-TLR4 downstream cytokine signaling activity.
Inhibition of TRAF3IP2 Modulates NAMPT and NAD Metabolism in Glioblastoma.
Willingham K, Izadpanah A, Yasmine R … +6 more , Reilich A, Fatemeh D, Siva S, Braun S, Alt EU, Izadpanah R
J Neuroimmune Pharmacol · 2025 Oct · PMID 41123804 · Full text
Glioblastoma is a grade 4 diffuse astrocytic glioma that is the most aggressive brain malignancy, with poor treatment outcomes and median overall survival (OS) of 10-14 months. Glioblastoma is characterized by upregulati...
Glioblastoma is a grade 4 diffuse astrocytic glioma that is the most aggressive brain malignancy, with poor treatment outcomes and median overall survival (OS) of 10-14 months. Glioblastoma is characterized by upregulation of NAD metabolism, required to maintain rapid proliferation and DNA repair. Nicotinamide phosphoribosyltransferase (NAMPT), is the rate limiting enzyme in the NAD salvage pathway, and has emerged as a promising target in the treatment of glioblastoma. Previously, we reported the crucial role of adaptor protein TRAF3IP2 in glioblastoma tumorigenesis. In this study, we aim to investigate the role of TRAF3IP2 in modulating NAMPT expression and explore its downstream impact on promoting cellular energetics in glioblastoma cells. Our results reveal that inhibition of TRAF3IP2 in glioblastoma cells attenuates metabolic activity, as evidenced by decreased expression levels of NAMPT and the mTOR complex, leading to reduction in NAD synthesis and glycolytic function, decreased expression of NAD-dependent deacetylase SIRT1, and increased presence of cellular ROS and expression of tumor suppressor p53, cumulatively resulting in decreased cell viability in glioblastoma. These outcomes elucidate that inhibition of TRAF3IP2 exerts significant anti-tumor effects on glioblastoma by reducing NAD availability and cancer-cell metabolism, highlighting the therapeutic potential of TRAF3IP2 in glioblastoma.
Gut Microbiota Dysbiosis and Neuroimmune Alterations in a Postmenopausal-Stress Rat Model.
Chaudhary R, Lal R, Bansal N … +7 more , Garg N, Bishnoi M, Kondepudi KK, Saini RV, Gupta S, Chopra K, Bansal S
J Neuroimmune Pharmacol · 2025 Oct · PMID 41123747 · Publisher ↗
Estrogen deficiency in postmenopausal women disrupts reproductive, metabolic, brain, and gut health, partly by promoting inflammation, oxidative stress, and gut dysbiosis. Together, responsible for the development of gut...
Estrogen deficiency in postmenopausal women disrupts reproductive, metabolic, brain, and gut health, partly by promoting inflammation, oxidative stress, and gut dysbiosis. Together, responsible for the development of gut-brain axis (GBA) dysfunction. Daily life stressors in women, particularly chronic stress, may further exacerbate this dysfunction; however, their synergistic effects with estrogen deficiency remain poorly understood. The current study aimed to develop an animal model of GBA dysfunction that mimics postmenopausal conditions. To induce GBA dysfunction, female Sprague Dawley rats were bilaterally ovariectomized (OVX) and exposed to chronic unpredictable mild stress (CUMS) for 28 days. To confirm GBA dysfunction, neurobehavioral, biochemical, molecular, and histopathological parameters were performed. We observed significant changes in physiological, & neurobehavioral parameters in OVX, CUMS, and OVX + CUMS group rats. We also observed marked enhancement in oxidative stress, neuroinflammation, and reduced acetylcholinesterase activity in the brain, and increased corticosterone levels in serum of OVX, CUMS, and OVX + CUMS group rats. Furthermore, we also observed a marked increase in pro-inflammatory cytokines, oxidative stress, reduction in MUC-2 and tight junction gene expression in the proximal colon, and changes in gut bacterial abundances in the feces of experimental groups. Histopathological examination revealed pronounced morphological damage in the proximal colon and brain of OVX, CUMS, and OVX + CUMS group rats. Thus, estrogen deficiency and chronic stress for one month synergistically induce GBA dysfunction. This developed animal model provides a robust platform for exploring novel therapeutic strategies to counteract GBA dysfunction arising from estrogen deficiency and chronic stress.
Pyrimidine Derivative, (E)-N-[4-(4-Chlorophenyl)-6-(4-Methylphenyl)Pyrimidin-2-yl]-1-(Furan-2-yl)Methanimine, Named BN5 Ameliorates Cognitive Dysfunction and Regulates esr1 and esr2b Expression in Female In Vivo Zebrafish Alzheimer Model.
Aswinanand B, Palani KN, Santhanam SD … +7 more , Ramamurthy K, Palaniappan S, Arasu MV, Guru A, Muthuramamoorthy M, Kumaradoss KM, Arockiaraj J
J Neuroimmune Pharmacol · 2025 Oct · PMID 41118046 · Publisher ↗
Alzheimer's disease (AD) is the most common form of dementia, characterized by a progressive decline in cognitive functions. It is more prevalent in women, especially after menopause, likely due to factors like longer li...
Alzheimer's disease (AD) is the most common form of dementia, characterized by a progressive decline in cognitive functions. It is more prevalent in women, especially after menopause, likely due to factors like longer life expectancy and hormonal changes. Current therapies focus on cholinesterase inhibitors, but recent studies suggest that pyrimidine derivatives hold promise as multi-target agents targeting complex mechanisms of AD. This study evaluated the potential of a pyrimidine derivative, (E)-N-[4-(4-chlorophenyl)-6-(4-methylphenyl)pyrimidin-2-yl]-1-(furan-2-yl)methanimine (named BN5), in a scopolamine (SCO)-induced female zebrafish model. SCO induces cognitive dysfunction mimicking AD conditions. BN5, particularly at a 60 µM concentration, significantly improved AD-related parameters, including anxiety, memory, shoaling, and social behaviour in vivo. Biochemical analyses supported these findings, as BN5 reversed SCO-induced changes in acetylcholinesterase (AChE) activity and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and γ-Aminobutyric acid (GABA) levels. Additionally, BN5 demonstrated positive regulation of neurotransmitter-related genes such as appb, bdnf, mbpa, and il-1β, essential for neural function and cognitive processes. It also upregulated estrogen receptor genes esr1 and esr2b, which have neuroprotective roles but are often downregulated in postmenopausal women due to hormonal changes. These results highlight the therapeutic potential of BN5, as it alleviates cognitive impairments through Aβ aggregation inhibition and addresses the decline in estrogen receptor activity, providing a targeted treatment option particularly beneficial for females, who are at greater risk of developing AD.
Differential Roles of Neuro-Inflammatory Regulator, MAPK11 in Cortex and Hippocampus Following Post-Stroke Cognitive Impairments in Rats.
Arora N, Rana AK, Singh D … +1 more , Acharya V
J Neuroimmune Pharmacol · 2025 Oct · PMID 41105199 · Publisher ↗
Ischaemic stroke is the leading cause of long-term cognitive impairments, affecting brain regions vulnerable to memory and learning, with complex and diverse mechanisms. The hippocampus along with cortex is crucial for s...
Ischaemic stroke is the leading cause of long-term cognitive impairments, affecting brain regions vulnerable to memory and learning, with complex and diverse mechanisms. The hippocampus along with cortex is crucial for shaping essential cognitive functions in post-stroke cognitive impairments. However, the region-specific neural, molecular and cellular mechanistic response to ischaemic-damage, particularly the role of inflammation is rarely explored. In this context, we carried out post-stroke region-specific research, including the development of BCCAo model and the neurobehavioral assessment targeting memory and learning deficits. Here, we performed NGS and depth-in-network analysis of the isolated cortical and hippocampal regions of the post-stroke BCCAo model, revealing 13 significant neurodegenerative hub genes including Map2k6 and Mapk11, which play crucial roles in inflammation-mediated post-stroke neurodegenerative cascades. Significant upregulation of MAP2K6/MAPK11 in the cortex of ischaemia-treated rats was observed, whereas its comparatively diminished expression in the hippocampus demand exploration of region-specific study in chronic ischaemic conditions. Furthermore, we demonstrated the role of MAPK11 as neuroinflammatory regulator and alleviating the cognitive impairments by including the upstream Akt/GSK3β pathway components. Our findings not only highlighted the potential roles of MAP2K6/MAPK11 driving neuroinflammatory processes regulating ischaemic cascades but also pinpointed the hippocampus's relative resilience preserving cognitive function. Targeting MAPK11 and its associated neuroinflammatory pathways in the cortex to mitigate PSCI holds promise as a therapeutic strategy in chronic ischaemia.
Lipid-Metabolically Active TREM2 Microglia‑Derived Macrophages Predict Poor Prognosis and Represent an Immunotherapeutic Target in Glioma.
Li J, Yu X, Yang D … +7 more , Chen S, Xu J, Ma X, Huang C, Xu B, Xue L, Wang Y
J Neuroimmune Pharmacol · 2025 Oct · PMID 41085811 · Publisher ↗
Gliomas are the most common primary brain tumors and characterized by poor prognosis and heavy infiltration of tumor-associated macrophages. Triggering receptor expressed on myeloid cells-2 (TREM2), known to modulate mac...
Gliomas are the most common primary brain tumors and characterized by poor prognosis and heavy infiltration of tumor-associated macrophages. Triggering receptor expressed on myeloid cells-2 (TREM2), known to modulate macrophage function, has shown conflicting roles in glioma pathology. In this study, we comprehensively investigated the expression, function, and clinical relevance of TREM2 in gliomas using public datasets, single-cell RNA sequencing (scRNA-seq) analysis, and multiplex immunofluorescence. scRNA-seq identified a distinct subset of microglia-derived macrophages with high TREM2 expression that exhibit a dual phenotype of immunosuppression and enhanced lipid metabolism. These cells show enrichment of genes involved in fatty acid metabolism and lipoprotein clearance, including significant upregulation of apolipoprotein E (APOE), a known TREM2 ligand. Clinically, high TREM2 expression in microglia-derived macrophages correlates with increased tumor grade, recurrence, and shorter overall and disease-free survival. In contrast, APOE expression was correlated with better survival in public datasets, though not significantly in our patient cohort. Our findings suggest that TREM2 microglia-derived macrophages constitute a pro-tumorigenic subpopulation within the glioma microenvironment and may serve as a robust prognostic marker. The interplay between TREM2 and APOE further underscores the immunometabolic complexity of gliomas and points to TREM2 as a promising target for therapeutic intervention.
The Identification and Synthesis of New Sea Cucumber Peptides Leveraging Peptidomics Technology, along with their Anti-Parkinson's Disease Efficacy.
Liu J, Shi Y, Jin L … +8 more , Sun B, Wang R, Ge G, Zhu G, Cui X, Zhao J, Zhang Y, Li S
J Neuroimmune Pharmacol · 2025 Oct · PMID 41082072 · Publisher ↗
Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, remains without a curative pharmacological intervention. Sea Cucumber Peptides (SCP) are recognized for their antioxidant properties and neu...
Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, remains without a curative pharmacological intervention. Sea Cucumber Peptides (SCP) are recognized for their antioxidant properties and neuroprotective potential, while no specific SCP have been documented for PD treatment. Moreover, sea cucumbers have long been consumed as a traditional food; viewed through the lens of "food-medicine homology", their peptides possess clear pharmaceutical potential. This study sets out to pinpoint particular peptide sequences from sea cucumbers could combat PD, exploring their therapeutic efficacy and the underlying mechanisms. We treated Rotenone (Rot)-induced C57BL/6 J mice and SH-SY5Y cells with the SCP which were extracted from the sea cucumbers, to assess the impact on behavioral metrics in mice, histopathological outcomes, cellular viability, and in vitro bioactivity. Employing a combination of peptide profiling and silico analysis, we established a SCP spectrum to identify novel SCP with potential anti-PD activity. The therapeutic effects and mechanisms of the peptides were further investigated in 7-day-old zebrafish larvae and SH-SY5Y cells exposed in Rot, respectively. Our findings indicate that the SCP significantly improved behavioral deficits in mice, reduced the degeneration of dopaminergic neurons in the substantia nigra, and increased the survival of Rot-exposed SH-SY5Y cells. Notably, a novel peptide, Gln-Trp-Phe-Asp-Trp (QWFDW), emerged from our peptide profiling and in silico analysis, showing significant anti-PD activity. QWFDW was demonstrated to enhance the behavioral performance of Rot-induced zebrafish larvae, and ameliorate the pathological features of PD by attenuating endogenous reactive oxygen species (ROS) and maintaining mitochondrial membrane potential in SH-SY5Y cells. At the cellular level, QWFDW activates the Nrf2/HO-1/GPX4 pathway to alleviate ferroptosis and exert therapeutic effects on PD. Collectively, our results point out that SCP, particularly QWFDW, was a prospective therapeutic agent for PD.
S-Ketamine Alleviates Anxiety-Induced Chronic Postoperative Pain by Affecting Glucose Metabolism of Striatal Microglia in a Rat Model.
Xu R, Zhu W, Xu X … +5 more , Yao Y, Liu Q, Yang Y, Huang Y, Ma Z
J Neuroimmune Pharmacol · 2025 Oct · PMID 41082017 · Publisher ↗
Patients admitted for surgery commonly experience preoperative anxiety. Previous studies have shown that preoperative anxiety often delays recovery from postoperative pain or even aggravates pain. Therefore, it is necess...
Patients admitted for surgery commonly experience preoperative anxiety. Previous studies have shown that preoperative anxiety often delays recovery from postoperative pain or even aggravates pain. Therefore, it is necessary to explore the mechanisms by which anxiety prolongs chronic postoperative pain. A single prolonged stress (SPS) rat model was constructed to investigate the effects of anxiety and depression using behavioral tests. Changes in the levels of tight junction proteins in the cerebral striatum (CPu) of the rats were assessed by western blotting 1 to 21 days after the operation. The level of inflammation was detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Glucose metabolism levels and changes in related signaling pathways in microglia were assessed using western blotting, immunofluorescence, ELISA, and flow cytometry. The effects of S-ketamine treatment on the rats were also determined using the above methods. Preoperative SPS aggravated acute pain after plantar incision in rats and significantly prolonged the postoperative pain recovery time. The incised SPS rats began to show significant blood-brain-barrier (BBB) damage on the third day after surgery. Simultaneously, SPS caused neuroinflammation and microglial activation in the CPu after plantar incision. CPu microglia participated in neuroinflammation by undergoing glucose metabolic reprogramming mediated by the mTOR-p70S6K-4EBP1 pathway. Preoperative administration of a single dose of S-ketamine was an effective analgesic, as it inhibited SPS-induced postoperative inflammation. S-ketamine partially corrected SPS-induced abnormal glycolysis in striatal microglia through the mTOR-p70S6K-4EBP1 pathway. S-ketamine effectively relieved postoperative chronic pain caused by preoperative anxiety by correcting glucose metabolic reprogramming in CPu microglia.
Neurological Adverse Events from COVID-19 Vaccination and It's Associated Factors in Burkina Faso: Analysis of Spontaneous Reports from the National Database of Pharmacovigilance from 2021 to 2023.
Dabilgou AA, Ouedraogo EW, Kyelem JMAW … +4 more , Dravé A, Wanré O, Napon C, Millogo A
J Neuroimmune Pharmacol · 2025 Oct · PMID 41082015 · Publisher ↗
INTRODUCTION: Neurological adverse effects are frequent, primarily non-serious, due to the tropism of COVID 19 adverse effects for neuronal structures and tissues. To our knowledge, there are no studies on neurological a...
INTRODUCTION: Neurological adverse effects are frequent, primarily non-serious, due to the tropism of COVID 19 adverse effects for neuronal structures and tissues. To our knowledge, there are no studies on neurological adverse effects of COVID-19 vaccines in Burkina Faso. The purpose of this study was to determine the prevalence of neurological side effects of COVID-19 vaccines, to catalogue neurological adverse effects, to describe these manifestations, and to identify factors associated. MATERIALS AND METHODS: This was a cross-sectional study of people who had experienced adverse events of COVID-19 vaccines during the period from 1 December 2021 to 31 December 2023. Individuals who had experienced at least one adverse event after immunisation (AEFI) of the COVID-19 vaccine registered in the Vigibase Burkina database were included. The data was gathered through a questionnaire. RESULTS: The study included 1,060 people who experienced adverse events. Of them, 614 (57.9%) had neurological adverse effects. Their mean age was 44.08 ± 18 years. Most of the participants were men (56.8%) and healthcare workers (61.2%). Most of the participants (65.8%) had their side effects occur within 24 h. The AstraZeneca vaccine was reported in 51.8% of participants. The prevalence of side effects after the first dose was 83%.The most common symptoms were headaches (49.7%), myalgia (21.7%) and radiculopathies (9%). There was a significant association between the AstraZeneca vaccine and adverse neurological events (p = 0.000000). Factors associated with the appearance of serious neurological symptoms were age ≥ 60 years (p = 0.02744) and comorbidities (p = 0.000002). CONCLUSION: Neurological adverse events after COVID-19 immunisation were frequent and benign among spontaneous notifications. Headache was the most common neurological adverse effect of COVID-19 vaccines. Serious side effects were more frequent in the elderly and people with comorbidities.
Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia.
Starr A, Rathore S, Daniali M … +3 more , Gaskill PJ, Akay-Espinoza C, Jordan-Sciutto KL
J Neuroimmune Pharmacol · 2025 Oct · PMID 41075102 · Full text
Emerging evidence suggests brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a...
Emerging evidence suggests brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a proposed pathogenic mechanism in HIV-associated neurocognitive disorders (HAND). We investigated whether cannabinoid receptor 2 (CB), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB-specific agonist JWH-133, we found that CB activation reduced HIV replication in primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg) at differing doses, corresponding to the basal expression of CNR2, which encodes CB, and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced release of cytokines from HIV-infected MDMs but not iMg. RNA-seq revealed that CB agonism primarily altered interferon and integrated stress response pathways in MDMs while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB response between myeloid lineage cell types and implicates CB-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.
TNF-α Inhibition Modulates CX3CR1, Pyroptosis-related Genes, and BDNF to Alleviate Anxiety-like Behavior in Type 2 Diabetic Rats.
Septyaningtrias DE, Sholikah TA, Suhda S … +2 more , Sumiwi YAA, Susilowati R
J Neuroimmune Pharmacol · 2025 Oct · PMID 41075047 · Publisher ↗
BACKGROUND: Type 2 diabetes is strongly associated with neuroinflammation and neurodegeneration in the hippocampus, yet the underlying mechanisms are not fully understood. This study seeks to address this gap by explorin...
BACKGROUND: Type 2 diabetes is strongly associated with neuroinflammation and neurodegeneration in the hippocampus, yet the underlying mechanisms are not fully understood. This study seeks to address this gap by exploring the role of TNF-α in modulating behavior, fractalkine (CX3CL1) signaling, and pyroptosis-related pathways in the hippocampus of streptozotocin (STZ)-nicotinamide (NA)-induced diabetic rats, thereby providing insights into potential therapeutic targets for diabetes-induced neuroinflammation. METHODS: Male Sprague–Dawley rats (10–12 weeks old) were assigned to three groups: the etanercept-treated diabetic (DE) group, diabetic control (DC) group, and normal control (NC) group. Type 2 diabetes was induced via intraperitoneal injections of STZ and NA, with fasting blood glucose levels > 200 mg/dL confirming the condition. Etanercept was administered biweekly. Anxiety-like behavior and locomotor activity were evaluated using the open field test. After ten weeks, the rats were sacrificed, and the hippocampal tissues were dissected for immunohistochemical analysis of GFAP, CX3CR1, CX3CL1, BDNF expression, as well as qPCR, to quantify pyroptosis-related gene expression. RESULTS: TNF-α inhibition through etanercept treatment attenuated anxiety-like behavior, reduced GFAP and CX3CR1 expression, and lowered the levels of pyroptosis-related genes (Il-1b, Il-18, Nlrp3) in the hippocampus of diabetic rats, whereas CX3CL1 expression remained unaffected. Additionally, etanercept treatment increased BDNF expression in the hippocampus, suggesting a potential neuroprotective effect. CONCLUSION: This study suggests that TNF-α inhibition decreases hippocampal GFAP, CX3CR1, and pyroptosis-related gene expression, while enhancing BDNF. These changes may contribute to reduced anxiety-like behavior, highlighting a potential neuroprotective role of TNF-α inhibition in type 2 diabetes.
Cytokine Blockade Attenuates Inflammation and Improves Depressive Psychopathology After COVID-19: A Naturalistic Observational Study.
Palladini M, Azzalin AA, Bessi M … +4 more , De Lorenzo R, Rovere-Querini P, Benedetti F, Mazza MG
J Neuroimmune Pharmacol · 2025 Oct · PMID 41071398 · Publisher ↗
Current insight on inflammation in psychiatry suggests that perturbation of inflammatory set points could foster psychopathology and recent evidence support immune-inflammatory mechanisms as targets for antidepressant ph...
Current insight on inflammation in psychiatry suggests that perturbation of inflammatory set points could foster psychopathology and recent evidence support immune-inflammatory mechanisms as targets for antidepressant pharmacology. In the present naturalistic observational study we evaluated the possible effect of the cytokine-blocking agents in preventing the development of post-COVID depression in a large sample of survivors also exploring the relationship between post-COVID depressive risk, treatment with cytokine-blocking agents, and innate immune response markers. 588 COVID-19 survivors were included, of them 374 received the best available treatment at the time and 131 received standard treatment combined with cytokine-blocking agents (anakinra, tocilizumab, sarilumab, reparixin and mavrilimumab). Post-COVID depressive psychopathology was evaluated at short (34.6 ± 17.39 days) and long term (126.76 ± 61.4 days) follow-ups. The systemic inflammation index as (neutrophils*platelets)/lymphocytes was computed in a subgroup of 274 patients. COVID-19 survivors who were treated with cytokine-blocking agents experienced less severe depressive symptomatology and, simultaneously, less susceptibility to develop clinically relevant depression. Moreover, the longitudinal investigations, revealed that patients treated with cytokine-blocking agents underwent a spontaneous symptoms relief over time. Systemic inflammation index decrease over hospitalization was found to affect the susceptibility to long-term depression. Finally, we observed that cytokine-blocking agents' impact on depression was mediated by lowering of systemic inflammation. Our findings indicate potential efficacy of cytokine-blocking agent treatment during the early stages of COVID-19, mitigating post-COVID depressive symptoms by attenuating systemic inflammation. Further investigation through preclinical and clinical studies is warranted to elucidate immune-inflammatory pathways as viable targets for antidepressant psychopharmacology.
Sinomenine Hydrochloride Impedes Memory Impairments via Nrf2/HO-1-Mediated Inhibition of Oxidative Stress, Neuroinflammation and Apoptosis in Mice Brain.
Ali W, Choe K, Rehman IU … +5 more , Park HY, Jang S, Ullah S, Park TJ, Kim MO
J Neuroimmune Pharmacol · 2025 Oct · PMID 41071391 · Full text
Oxidative stress is a key factor in the progression of Alzheimer's disease (AD) and other neurodegenerative disorders. We evaluated whether sinomenine hydrochloride (SH) exhibits antioxidant and anti-inflammatory effects...
Oxidative stress is a key factor in the progression of Alzheimer's disease (AD) and other neurodegenerative disorders. We evaluated whether sinomenine hydrochloride (SH) exhibits antioxidant and anti-inflammatory effects against cadmium chloride (CdCl2)-induced neurodegeneration and synaptic impairment in mouse brains. The mice were allowed to undergo Cd injection for two weeks. SH was administered orally for eight consecutive weeks (100 mg/kg/bw/mouse, p.o.). The heavy metal cadmium (Cd) disrupts cellular metabolism in the brain, increasing levels of reactive oxygen species (ROS) and lipid peroxidation (LPO), which affects glutathione (GSH) and the production of regulatory enzymes, such as glutathione reductase (GSH-R). An imbalance in this homeostatic system may lead to the downregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the enzyme heme oxygenase 1 (HO-1) expression in the Cd-injected mouse brain. Interestingly, the levels of both Nrf2 and HO-1 increased in the Cd + SH-treated mice. Additionally, toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (p-NF-kB), and phospho-c-Jun N-terminal kinase (p-JNK) expressions were elevated in the Cd-treated group, but significantly downregulated in the Cd + SH-treated mice brains. Similarly, SH inhibits Cd-induced apoptotic markers in mouse hippocampal tissues. These results suggest that SH may mitigate Cd-induced mitochondrial oxidative stress and inflammatory responses in wild-type mice brain hippocampus by regulating the NRF-2/HO-1 signaling pathways.
Comparative Study on the Neuroprotective Effects of Perindopril and Benazepril in Experimentally-induced Chronic Mild Stress in Rats.
Badawy AM, Gad AM, Abdel-Maged AE … +3 more , Michel HE, El-Naga RN, Azab SS
J Neuroimmune Pharmacol · 2025 Oct · PMID 41065910 · Full text
Depression remains a major global health issue, characterized by inadequate response rates to conventional antidepressant therapies. This highlights a critical need for novel treatment strategies. Our study investigated...
Depression remains a major global health issue, characterized by inadequate response rates to conventional antidepressant therapies. This highlights a critical need for novel treatment strategies. Our study investigated the antidepressant effects of benazepril, a non-centrally acting angiotensin-converting enzyme (ACE) inhibitor, and compared it with perindopril, a centrally acting ACE inhibitor. We utilized a rat model of depression induced by chronic unpredictable mild stress (CUMS) to evaluate their efficacy. The CUMS protocol effectively caused several depression-like behaviors and impaired neurobehavioral functions in the rats. Analysis of brain tissues from these animals revealed several key pathological hallmarks: diminished monoamine neurotransmitter levels, heightened oxidative stress, robust inflammatory responses, and increased apoptotic processes. Our findings demonstrated that both perindopril and benazepril significantly reversed these CUMS-induced deficits. Specifically, both ACE inhibitors exhibited potent antioxidant, anti-inflammatory, and anti-apoptotic properties. This was coupled with their effective inhibition of the renin-angiotensin-aldosterone system (RAAS) signaling pathway, a mechanism known to be implicated in stress responses and mood disorders. Notably, while many ACE inhibitors have been extensively studied for their central effects, research on benazepril's direct effects within the brain or central nervous system in rats is notably limited. This study is among the first to highlight the antidepressant potential of benazepril, a non-centrally acting ACE inhibitor, and provides novel insights into its comparative efficacy against perindopril. These results collectively emphasize the broader therapeutic potential of ACE inhibitors in treating depression and underscore the need for further research to fully explore their underlying mechanisms and diverse applications in psychiatric disorders.
Intranasal Aβ Exposure Led To Neurobehavioral Alteration, Neuroinflammatory and Neurodegenerative Molecular Biomarkers in Mice Brain.
Gautam AS, Akhtar MZ, Uttamrao LV … +4 more , Kumari N, Pandey SK, Dey M, Singh RK
J Neuroimmune Pharmacol · 2025 Oct · PMID 41055851 · Publisher ↗
In this study, we aimed to evaluate the AD structural hallmarks along with brain biomarkers and neurobehavioral alterations in a repeated intranasal Aβ exposure mouse model. This model is a simple, non-invasive, and less...
In this study, we aimed to evaluate the AD structural hallmarks along with brain biomarkers and neurobehavioral alterations in a repeated intranasal Aβ exposure mouse model. This model is a simple, non-invasive, and less stressful method and may allow direct access of Aβ to the brain. The results of this study showed a dose-dependent increase in the level of Aβ deposition, tau phosphorylation, neuroinflammatory and oxidative stress biomarkers in brain tissue, along with learning and memory deficits in mice. This model may be suitable for evaluating the biochemical, structural, functional histological alterations, along with the neurobehavioral deficits mimicking AD.
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