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

Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson's disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cord MSCs (hucMSCs) and the possible mechanisms involved. SH-SY5Y cells were induced with MPP⁺, and the impact of hucMSCs-EV on the damage to SH-SY5Y cells was examined. Mice were induced with PD-like symptoms by MPTP and the effects of hucMSCs-EV on neurological damage in mouse brain tissue were detected as well. HucMSCs-EV inhibited apoptosis and oxidative stress in MPP⁺-induced SH-SY5Y cells. HucMSCs-EV suppressed behavioral deficits and neuronal apoptosis in MPTP-induced mice, with an increased number of dopamine neurons in brain tissues and decreased p-alpha-syn expression in dopamine neurons. The expression of ribosomal protein S27A (RPS27A) in SH-SY5Y cells was elevated after co-culture of neurons and hucMSCs-EV, and RPS27A silencing abated the effect of hucMSCs-EV in vivo and in vitro. RPS27A bound to the MDM2 promoter, thus promoting P53 ubiquitination and degradation. MDM2 overexpression strengthened the therapeutic effect of hucMSCs-EV. We conclude that hucMSCs-EV promote the interaction between RPS27A and MDM2 by delivering RPS27A, which regulates the MDM2-P53 axis to promote degradation of P53 to ameliorate neurological damage in PD.

The high pain sensitivity in fibromyalgia (FM) is processed by the thalamus that presents as a key component in the pain pathway in FM patients. Noteworthy, Purinergic receptors, specifically P2X, are implicated in pain signaling and neuroinflammation via inflammasome signaling. However, there is no available data on the impact of pharmacological intervention on the P2X receptor in thalamic pain transmission in FM. To investigate this aspect, the clinically tested P2X inhibitor, Suramin (SURM), was utilized. FM was induced over three days using Reserpine (1 mg/kg/day, s.c.), followed by a single dose of SURM (100 mg/kg, i.p.). At the molecular level, SURM countered the overexpression of P2X7 and P2X4 receptors accompanied by reduced NLRP3 inflammasome complex and pyroptotic markers like gasdermin-D. This was associated with the suppression of the p38-MAPK and NF-κB pathways, along with a decrease in pro-inflammatory cytokines and tumor necrosis factor-α as observed by increased CD86 expression on M1 microglia phenotype, a neuroinflammatory marker. Concurrently, blocking the P2X receptor shifted microglia polarization towards the M2 phenotype, marked by elevated CD163 expression, as a neuroprotective mechanism. This was outlined by increased neurotrophic and anti-inflammatory IL-10 with normalization of disturbed neurotransmitters. Behaviorally, SURM ameliorated the heightened pain processing, as observed in mechanical and thermal pain tests. Furthermore, it lowered Reserpine-induced motor impairment in the rotarod and open-field tests. This improvement in the somatosensory experience was reflected in alleviating depressive-like behavior in the forced swimming test. These findings highlight the therapeutic potential of blocking thalamic P2X receptors in alleviating fibromyalgia symptoms.

This study aimed to determine the effects of the Mediterranean diet (MD) and lycopene on the development of EAE and on inflammatory markers. In the 43-day study, 72 female C57BL/6 mice were randomly divided into eight groups according to whether they were EAE or naive (control) mice, fed a Western diet or a MD, and whether they received lycopene. During the study, mice were fed ad libitum, and lycopene groups were given 10 mg/kg/day lycopene per mouse every other day for 28 days in oral gavage. The mice were scored for EAE, sacrificed and their spleen, lymph nodes, and spinal cords were removed. We observed slightly delayed EAE onset in the MD-Lyc group compared to the others, and the EAE clinical scores were also lower than in the other groups. T-cell counts in the spleen and lymph nodes of the MD-Lyc group were significantly lower than in other groups. The production of IFN-γ and IL-22 was higher than in the other groups. IL-17 A cytokine produced in the spleen was lower in the MD-Lyc group than in the other groups. In addition, the highest myelination score was seen in the MD-Lyc group. MD-Lyc group also had a unique microbiome profile compared with the remaining groups. In summary, MD and lycopene administration positively impacted EAE scores and myelination. However, more comprehensive studies at the in vitro and in vivo levels are needed to reveal the effect of this intervention on cell numbers in the CNS.

Current medications for seizure symptoms can reduce seizure severity but do not stop or slow their progression. These drugs often have unpleasant side effects and may not work for all patients. The search for new therapeutic targets for seizure progression can be expedited through drug repurposing, which leverages existing approved medications, ultimately reducing clinical trial costs. This study investigates the neuroprotective properties of pomalidomide, an immunomodulatory drug, in a male rat model of pentylenetetrazol-induced seizures. Pomalidomide pretreatment significantly decreased the frequency and severity of seizures and delayed their onset. It elevated glutathione peroxidase (GPX) and superoxide dismutase (SOD) levels while lowering malondialdehyde (MDA), showcasing its antioxidant effects. Furthermore, it activated the Nrf2/HO-1 signaling pathway by increasing gene expression in the hippocampus, providing neuroprotection in the CA1 and CA3 regions. These findings suggest that pomalidomide may enhance the antioxidant defense system, support the Nrf2/HO-1 pathway, and protect the hippocampus, indicating its potential for treating patients with seizures, particularly intractable ones.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with growing evidence highlighting the dual role of immunomodulation in its pathogenesis and potential therapeutic strategies. Disturbance in the immune system increases the inflammatory cytokines that cause tau hyperphosphorylation and neuroinflammation. Also, immune checkpoint inhibition further increases the amyloid-beta deposition. Therefore, this review examines the intricate interplay between the immune system and AD, focusing on how immunomodulatory mechanisms influence key pathological hallmarks, including amyloid-beta aggregation, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. We analyse critical signaling pathways involved in immune regulation, such as Toll-like receptor (TLR), Janus kinase/signal transducer and activator of transcription (JAK/STAT), phosphoinositide 3-kinase/Akt (PI3K/Akt), Wnt/β-catenin, tumor necrosis factor (TNF), and triggering receptor expressed on myeloid cells (TREM), along with immune checkpoints like programmed cell death protein 1 (PD-1). Preclinical studies of immunomodulatory agents, including salidroside, festidinol, astragalin, sulforaphane, BM-MSC, simvastatin, Ab-T1, hTREM2, and XENP345, demonstrate promising effects. Additionally, clinical investigations of drugs such as simufilam, AL002, TB006, VGL101, DNL919, XPro1595, astragalus, and IBC-Ab002 underscore the therapeutic potential of targeting immune pathways in AD. This review emphasizes how neuroinflammation, microglial activation, and peripheral immune responses contribute to disease progression. By exploring immunomodulatory mechanisms, the article sheds light on potential therapeutic targets that could help mitigate AD pathology which may pave the way for novel interventions preventing neurodegeneration in AD.

Glioblastoma is the most common and aggressive brain tumor with a low survival rate. Due to its heterogeneous composition, high invasiveness, and frequent recurrence after surgery, treatment success has been limited. In addition, due to the brain's unique immune status and the suppressor tumor microenvironment (TME), glioblastoma treatment has faced more challenges. Exosomes play a critical role in cancer metastasis by regulating cell-cell interactions that promote tumor growth, angiogenesis, metastasis, treatment resistance, and immunological regulation in the tumor microenvironment. This review explores the pivotal role of exosomes in the development of glioblastoma, with a focus on their potential as non-invasive biomarkers for prognosis, early detection and real-time monitoring of disease progression. Notably, exosome-based drug delivery methods hold promise for overcoming the blood-brain barrier (BBB) and developing targeted therapies for glioblastoma. Despite challenges in clinical translation, the potential for personalized exosome = -054321`therapies and the capacity to enhance therapeutic responses in glioblastoma, present intriguing opportunities for improving patient outcomes. It seems that getting a good and current grasp of the role of exosomes in the fight against glioblastoma would properly serve the scientific community to further their understanding of the related potentials of these biological moieties.

Alzheimer's disease (AD) represents the most prevalent form of dementia, characterized by progressive cognitive impairment and chronic neuroinflammation. Immune checkpoint inhibitors (ICIs), including anti-programmed cell death (PD)-1 and anti-PD-L1, signify a revolutionary advancement in cancer treatment by preventing T-cell exhaustion; however, their therapeutic application in AD presents a conundrum. Hypothesis: Recent preclinical studies indicate that PD-1 inhibition in AD mouse models induces an interferon-gamma (IFN-γ)-mediated response, leading to increased recruitment of monocyte-derived macrophages into the brain, enhanced clearance of amyloid-beta (Aβ) plaques, and improved cognitive performance. Nonetheless, this therapeutic effect is counterbalanced by the potential for exacerbated neuroinflammation, as PD-1/PD-L1 blockade may potentiate pro-inflammatory T helper (Th)1 and Th17 responses. In this review, we critically discuss the pertinent pro-inflammatory and neuroprotective facets of T cell biology in the pathogenesis of AD, emphasizing the potential for modulation of the PD-1/PD-L1 axis to influence both Aβ clearance and the dynamics of neuroinflammatory processes. In summary, we determine that ICIs are promising tools for reducing AD pathology and improving cognition. However, it is essential to refine treatment protocols and carefully select patients to optimize neuroprotective effects while adequately considering inflammatory risks.

Inflammation, neurotransmitters, and apoptotic neurons are crucial elements in the progression of Major Depressive Disorder (MDD). Previous studies have demonstrated that mesenchymal stem cells (MSCs) had a positive impact on neuroinflammation and neuroprotection. In this context, human umbilical cord mesenchymal stem cells (hUC-MSCs) were administered into chronic unpredictable mild stress model (CUMS) mice to evaluate their effects on inflammation, neurotransmitters, microglia, neurons activation, and neuronal apoptosis. The distribution of hUC-MSCs within the brain was detected by CM-Dil-labelled hUC-MSCs. Our results indicated that hUC-MSCs infiltrated the brains of CUMS mice to protect the integrity of the blood-brain barrier (BBB). Furthermore, hUC-MSCs inhibited microglia activation to result in decreased inflammation levels and increased neurotransmitters, ultimately alleviating neuronal damage and regulating neuronal activity. These findings suggest that hUC-MSCs can maintain the BBB integrity and reduce neuroinflammation and neuronal damage, thereby effectively alleviating depression-like and anxiety-like behavior.

The pathophysiology of diabetes-induced brain injury involves pyroptosis, an inflammatory programmed cell death. This study aimed to investigate the potential protective effect of cranberry extract (CE) against diabetes-induced brain injury. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin in rats. Brain tissue samples were investigated for biochemical determination of the reduced glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), and the quantitative RT-PCR for the gene expression of glial cell-derived neurotrophic factor (GDNF), lncRNA GAS-5, and pyroptosis markers. ELISA was used to determine the caspase-1 level and immunohistochemical staining for assessing IL-1β. Prophylactic dosing of the CE in diabetic rats improved cognitive behavior and significantly suppressed MDA concentration, pyroptosis genes expression (gasdermin D and caspase 1), and lncRNA GAS-5. In addition, CE significantly elevated GSH concentration, SOD activity, and gene expression of GDNF and markedly reduced IL-1β positive stained cells score in the brain. Phytochemical characterization of the CE by FT-IR and UPLC-PDA-MS/MS revealed cyanidin arabinoside, procyanidins, quercetin, and isorhamnetin as key components. CE protects against diabetes-induced cognitive dysfunction in rats by targeting redox-related signaling pathways and inducing an anti-inflammatory effect. LncRNA GAS-5 downregulation and pyroptosis pathway inhibition may contribute to its beneficial effects, suggesting its therapeutic potential.

Fibromyalgia (FM) is a pain disorder characterized by pervasive musculoskeletal pain associated with exhaustion, depression, and irregular sleep patterns. Semaglutide, an innovative glucagon-like peptide-1 (GLP-1) agonist, has shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory pain. The objective of this study is to ascertain semaglutide's therapeutic potential against FM-like symptoms caused by reserpine. Reserpine (1 mg/kg/day; SC) was administered into rats for 3 consecutive days, then they were treated daily with semaglutide intraperitoneally in low (5 nmol/kg), intermediate (10 nmol/kg), or high doses (20 nmol/kg), respectively, for 14 consecutive days. Semaglutide alleviated reserpine induced histopathological and immunohistopathological changes in spinal cord of rats evidenced by a remarkable rise in immuno-expression of cluster of differentiation 163 (CD163) contrary to a significant diminution in CD86 level as compared with reserpine group. Semaglutide also had an analgesic effect and improved motor incoordination, and depression brought on by reserpine. Furthermore, it had an anti-inflammatory impact via stimulating cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA)/ cAMP response element (CRE)-binding protein (CREB) signaling pathway and shifting M1/M2 macrophage polarization towards the M2. Semaglutide's anti-inflammatory actions were manifested through inhibition of inducible nitric oxide synthase and reduction in dorsal root ganglia concentrations of tumor necrosis factor-α together with elevation in the levels of arginase-1 and interleukin-4.