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

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.

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 (CB₂), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB₂-specific agonist JWH-133, we found that CB₂ 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 CB₂, 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 CB₂ 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 CB₂ activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB₂ response between myeloid lineage cell types and implicates CB₂-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.

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.

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.

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.

In this study, we aimed to evaluate the AD structural hallmarks along with brain biomarkers and neurobehavioral alterations in a repeated intranasal Aβ_1-42 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_1-42 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.