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

The formation of Parkinson's disease is affected by various factors, among which neuroinflammation mediated by microglial activation plays a crucial role in the advancement of neurodegenerative diseases. Antimicrobial peptides temporin-1CEa and its analog LK2(6)A(L) exhibit excellent anti-inflammatory activity. To understand the anti-neuroinflammatory mechanisms of antimicrobial peptides in an immortalized mouse microglial cell line (BV2 cells), and assess neuroprotective effects in a PC12 cell line (rat adrenal pheochromocytoma cell) and Caenorhabditis elegans. Lipopolysaccharide (LPS, 500 ng/mL) was used to induce neuroinflammation in microglial BV2 cells. The effects of antimicrobial peptides on inflammatory cytokines and anti-inflammatory pathways activated by microglia were evaluated using cell counting kit-8 (CCK-8), enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR(RT-qPCR), and western blotting (WB). An apoptosis model was established by treating PC12 cells with the supernatant of LPS-stimulated BV2 cells, and the influence of antimicrobial peptides on apoptosis was analyzed via flow cytometry (FCM), Western blotting, and caspase-3 and caspase-9 activity assays. In the transgenic nematode BZ555, an LPS (200 μg/mL)-induced model of cephalic dopaminergic neurons (CEPs) injury was developed to explore the protective effects of antimicrobial peptides on dopaminergic neuron damage, food-sensing behavior, body bending, neurotoxicity, and lifespan. Furthermore, NL5901 was employed to evaluate the capacity of antimicrobial peptides to clear the accumulation of alpha-synuclein (α-synuclein) and their impact on body bending, neurotoxicity, and lifespan. Temporin-1CEa and LK2(6)A(L) inhibited the release of pro-inflammatory mediators by downregulating the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. At 3.125 μM, both temporin-1CEa and LK2(6)A(L) inhibited the apoptosis of PC12 cells induced by activated BV2 cells. In vivo experiments in nematodes demonstrated that temporin-1CEa and LK2(6)A(L) alleviated the damage to dopaminergic neurons induced by LPS and mitigated the capability to mitigate the accumulation of α-synuclein. In this study, antimicrobial peptides were shown to control inflammatory factors by downregulating the NF-κB and MAPK signaling pathways, thereby providing valuable insights for the agents in the neuroinflammation model of Parkinson's disease. Additionally, an unexpected finding revealed that these peptides could effectively reduce the accumulation of α-synuclein, which is a critical pathogenic factor, as its aggregated forms significantly contribute to Parkinson's disease progression. Notably, temporin-1CEa and LK2(6)A(L) exerted neuroprotective effects on dopaminergic neurons by inhibiting neuroinflammation and clearing the accumulation of α-synuclein.

Japanese encephalitis virus (JEV), which belongs to the virus family of Flaviviridae, is a threat to more than three billion people globally. There are no antiviral agents against JEV despite the availability of vaccines. This study considered the need for an effective drug against JEV by evaluating the antiviral and neuroprotective potentials of Chicoric Acid (CA) and Rutin in the in vitro and in vivo models of JE. In the in vitro study, CA and Rutin exhibited variable antiviral potency with IC₅₀ values ranging from 11.03 to 24.04 µM and 16.45 to 26.84 µM in different treatment approaches. These agents demonstrated significant antiviral effects via viricidal activity and inhibiting the virus's entry into the host cells. In addition, treatment of JEV-infected SH-SY5Y cells with these compounds significantly reduced the intracellular viral load, the proportion of apoptotic cells, and the ROS level in a dose-dependent manner. In the in vivo studies, Rutin (50 mg/kg) significantly increased the survival rate and attenuated the encephalitis symptoms in the JEV-infected mice compared to other doses. Rutin (25 and 50 mg/kg) significantly reduced infectious viral particles, viral RNA, and viral NS3 protein expression in the mice's brains. Additionally, Rutin significantly mitigated JEV-induced neuroinflammation by decreasing microglial activation, inflammasome formation, proinflammatory cytokine, and ROS levels. In conclusion, Rutin exhibits non-specific viricidal activity, reduced viral load, and inflammatory cytokines; thus, it could be a potential therapeutic option in managing JE, subject to future investigations.

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by hallmark pathologies such as amyloid-beta (Aβ) plaque accumulation, tau hyperphosphorylation, and progressive neuronal dysfunction. While much attention has focused on neurons and microglia, recent studies underscore the significant yet understudied roles of oligodendrocytes (OL) and oligodendrocyte precursor cells (OPC) in AD pathology. OL, responsible for myelin production and maintenance, are impaired early in AD, contributing to demyelination, synaptic dysfunction, and cognitive decline. Emerging evidence reveals that Aβ and tau pathology disrupt OPC differentiation and induce senescence, exacerbating neuroinflammation and reducing remyelination potential. Demyelination precedes overt AD symptoms, positioning it as a potential early biomarker. Furthermore, animal models reveal that OPC density and function deteriorate with age, particularly in the presence of Aβ plaques, highlighting their vulnerability in the AD environment. Transcriptomic studies also link cholesterol biosynthesis and lipid metabolism dysregulation in OPC to AD progression, emphasizing the intricate relationship between OL, metabolic processes, and amyloid toxicity. Additionally, the identification of disease-associated oligodendrocytes (DAO), characterized by altered gene expression and proximity to Aβ plaques, highlights their involvement in neuroinflammation and APP processing. This review synthesizes recent insights into OL and OPC dysfunction in AD, focusing on their roles in neuroinflammation, Aβ clearance, and myelin integrity. It discusses the potential of targeting OL and OPC pathways, such as enhancing remyelination and mitigating senescence, as novel therapeutic strategies. By addressing gaps in our understanding of OL dynamics, this work sheds light on their critical contributions to AD pathology and sets the stage for future research and intervention.

Telitacicept, a novel recombinant fusion protein comprising the ligand-binding domain of the TACI receptor and the Fc component of human IgG, has rarely been studied for the treatment of neuromyelitis optica spectrum disorders (NMOSD). This study aimed to explore the effects of telitacicept in NMOSD mice. An NMOSD mouse model was constructed. Fifty microliters of 0.8 mg/mL telitacicept was injected intravenously on Days 4, 8, 12 and 16 postimmunization (p.i.). Behavioral scoring, magnetic resonance imaging and histopathological evaluation were conducted on Day 19. B lymphocytes and their subgroups were analyzed by flow cytometry. Concentration of serum IgM was measured using an ELISA kit. Concentrations of B lymphocyte stimulator (BLyS) and IL-6 were measured via LEGENDplex. Differentially expressed genes of B lymphocytes were screened via mRNA sequencing and verified by qPCR. Behavioral score of telitacicept-treated NMOSD mice significantly decreased (p < 0.0001). Inflammation, demyelination, loss of AQP4 and GFAP in the spinal cord were markedly alleviated (p < 0.05). B lymphocytes and their subsets were reduced to varying degrees (p < 0.05). Telitacicept treatment significantly reduced serum IgM levels (p < 0.01), as well as BLyS and IL-6 concentrations (p < 0.05). Telitacicept induced differential gene expression in B lymphocytes, inhibiting the expression of transcription factors related to B lymphocyte maturation, such as IRF8, BLIMP1, and Pou2af1, as well as cell surface receptors such as CD19 and CD21. Telitacicept has a therapeutic effect on NMOSD mice by regulating the differentiation of B lymphocyte subsets and inhibiting the production of pathogenic antibodies.

Endoplasmic reticulum (ER) stress and misfolded proteins accumulation are recognized as central factors in the development of psychiatric disorders. This study evaluated the potential therapeutic effect of fluvoxamine, a potent sigma-1 receptor agonist in alleviating protein misfolding and the subsequent ER stress in ketamine-induced model of schizophrenia. NE100 hydrochloride, a sigma-1 receptor blocker, was used to investigate the role of this receptor in fluvoxamine-mediated effects. Rat model of schizophrenia was induced by intraperitoneal administration of ketamine (30 mg/kg/day) for 5 consecutive days. Then, rats were treated with fluvoxamine (30 mg/kg/day, p.o), with or without NE100 (1 mg/kg/day, i.p), for 14 days. Fluvoxamine improved the learning abilities, cognitive flexibility, and sociability functions of ketamine-subjected rats as evidenced in Morris water maze and three-chamber social interaction tests. It mitigated ketamine-induced inhibition of nNOS/PSD-95/NMDAR signaling pathway, thus augmented the function of parvalbumin-GABAergic neurons as indicated by increasing the prefrontal cortical levels of parvalbumin and GAD67. Fluvoxamine also attenuated the prefrontal cortical production of unfolded protein response markers, namely, IRE-1, PERK, and ATF-6, highlighting its ability to alleviate ER stress. Further, it exerted anti-apoptotic and anti-inflammatory effects as shown by lowering Iba-1, tumor necrosis factor-α (TNF-α), Bax, and caspase-12 levels contrary to elevating Bcl-2. Additionally, it attenuated the histopathological alterations in prefrontal cortical neurons. Noteworthy, the co-administration of NE100 reduced the advantageous effects of fluvoxamine, indicating the involvement of sigma-1 receptor in mediating the observed antipsychotic effects. Thus, sigma-1-mediated signaling pathways could be therapeutic targets for preventing or slowing schizophrenia progression.

The underlying pathological mechanism of ischemic stroke is complex, with oxidative stress and inflammation being two key factors that are intertwined and mutually influential. They also serve as important potential targets for the intervention of cerebral ischemia. Pyrroloquinoline quinone (PQQ) is known for its neuroprotective properties and the ability to modulate immune system function. Previous studies have demonstrated that PQQ mitigates brain infarction in rodent models of cerebral ischemia; however, the neuroprotective mechanisms underlying PQQ's effects against ischemic brain injury are not yet fully understood. This study used an MCAO rat model, an OGD model with SH-SY5Y cells, and an LPS-activated BV2 microglia model to investigate the neuroprotective functions of PQQ on brain ischemia. Using various experimental methods, including cell viability assays, oxidative stress damage assessments, inflammatory factor expression analysis, behavioral tests in animal models, and histological evaluations, we discovered that PQQ activates the nuclear translocation of Nrf2 in neurons, thereby enhancing downstream antioxidant responses. Additionally, PQQ inhibits NF-kB activation in microglia and suppresses their M1-type polarization, leading to decreased pro-inflammatory mediators' expression levels and reduced neural inflammatory damage. These results provide further insights into the neuroprotective mechanisms involved in PQQ's effects against cerebral ischemia and may offer evidence for its translational application in treating brain ischemia.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with memory loss and difficulties in performing daily activities, particularly in the aging brain.

Purpose of the study: This study aimed to evaluate the neuroprotective effects of macroalgae-derived polysaccharides from seaweed against scopolamine-induced amnesia, oxidative stress, and amyloid plaque (Aβ) production in rodents, following standard experimental protocols.

Methods: Three novel polysaccharides were extracted from Chara vulgaris, Cladophora glomerata, and Spirogyra crassa, namely: methylated pectin-type polysaccharides (PS1), methylated pectin-type polysaccharides (homo galacturonan and rhamno galacturonan, PS2), Ulvan-type polysaccharide, and xyloglucan polysaccharides (PS3). These polysaccharides were characterized using a variety of analytical techniques, including SEM, FTIR, XRD, ¹H-NMR, and ¹³C-NMR. The polysaccharides were administered at a dose of 30 mg/kg to male albino mice exposed to scopolamine (1 mg/kg) for three weeks. To assess their neuroprotective effects, Morris Water Maze (MWM) and Y-maze tests, antioxidant enzyme assays (Catalase, GSH, LPO), and western blotting were performed.

Results: The results showed that all three polysaccharides significantly (p ≤ 0.001) mitigated redox imbalance and reduced (p ≤ 0.001) microglial activation, thereby decreasing scopolamine-induced neuroinflammation and amyloid beta (Aβ) accumulation. Additionally, these polysaccharides improved neuronal synapses and cognitive function by modulating the NRf-2/TLR4/NF-kB signaling pathway.

Data analysis: The data analysis and graph generation were performed using GraphPad Prism software, version 5.0, with a significance level set at a p-value of < 0.05.

Conclusion: The findings highlighted the potential of these three novel natural polysaccharides as promising candidates for the treatment of scopolamine-induced oxidative stress-mediated neurodegenerative disorders, such as Alzheimer's disease.

Mitochondrial dysfunction is a hallmark of many psychiatric disorders, and SIRT1 signaling plays a critical role in regulating mitochondrial dynamics, function, and autophagy. This study investigated the interplays between erythropoietin (EPO), mitochondrial protection, and SIRT1 signaling in depression. Chronic restraint stress (CRS)- induced depression mouse model and CORT-treated HT22 cells were employed, which were subsequently treated with EPO. CRS mice exhibited depressive-like behaviors, which were alleviated by EPO treatment, as evidenced by decreased immobility and increased sucrose preference. EPO also enhanced mitochondrial function by stimulating mitophagy and improving mitochondrial homeostasis, as indicated by elevated ATP levels, reduced nitric oxide, and restored expression of mitochondrial-related genes in both the hippocampus of CRS mice and CORT-treated HT22 cells. Additionally, EPO restored suppressed SIRT1 expression, promoted dendritic spine density and synaptic gene expression in the hippocampus, increased p-STAT5 phosphorylation, and increased NAMPT expression and NAD + levels. Notably, pharmacological inhibition of SIRT1 via EX-527 counteracted EPO effects, exacerbating depressive symptoms and mitochondrial homeostasis. Furthermore, EX-527 treatment decreased ATP levels and mitochondrial DNA copy numbers in CRS + EPO-treated mice and reduced ATG5 expression. However, EX-527 did not significantly impact BNIP3, Parkin, PINK1, LC3B-II, Ace-FOXO1, or FOXO1 expression. EX-527 exposure significantly increased Ac-LC3B precipitation in the hippocampus of CRS + EPO-treated mice and the COXIV/LAMP1 ratio in the HT22 cells. In summary, these results suggested that EPO antidepressant effects were mediated through SIRT1 regulation, which influenced LC3B deacetylation, improving CRS-induced mitochondrial dysfunction and autophagy impairment.