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

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.

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.

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.

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.

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.

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.

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^high 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.

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.

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.

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.