JOURNAL OF NEUROCHEMISTRY
·
2015
·Vol. 134
·期 5
·904-914
·
IF 4.281
Zhuang Wu,Linlang Li,Long-Tai Zheng,Zhihong Xu,Lin Guo,Xuechu Zhen
Recent studies have shown that sigma-1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 agonist, has been recently identified as a potent allosteric modulator of sigma-1 receptor. Here, we investigated the anti-inflammatory effects of SKF83959 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma-1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c 17 to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma-1 receptors, and enhanced the inhibitory effects of DHEA on LPS-induced microglia activation in a synergic manner. Furthermore, in a microglia-conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Our results indicated that SKF83959 enhanced the activity of endogenous dehydroepiandrosterone (DHEA) in a synergic manner, and inhibited the activation of BV2 microglia and the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS).
研究领域:
神经科学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2021
·
IF 2.63
Qiburi Qiburi,Temuqile Temuqile,Huricha Baigude
The activated microglia contribute to stroke-induced neuroinflammation by upregulating the expression of a pleura of genes that are characterized as either proinflammatory or anti-inflammatory. The natural products alantolactone (Ala) and dehydrodiisoeugenol (Deh) found in Inula helenium L. and Myristica fragrans Houtt., respectively, are regularly used in traditional herb medicine, which play anti-inflammatory and antioxidant roles via regulation of canonical pathways such as nuclear factor kappa B (NF-κB) in microglia and microphages. To illustrate the full spectra of gene expression alteration in microglia treated with Ala, Deh, and the mixture of Ala and Deh (denoted as Mix), we performed RNA-seq analysis of total RNA extracted from lipopolysaccharide- (LPS-) treated microglia subsequently exposed to Ala, Deh, and Mix. While both chemicals regulated the gene expression that facilitates an anti-inflammatory polarization, the mixture exerted some distinctive synergic regulatory effect, which differed from either of the chemicals alone. Our data provide important evidence for further research on the therapeutic mechanism of traditional medicine including Eerdun Wurile (EW).
研究领域:
神经科学
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药理学
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分子生物学
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传统医学
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PubMed
高影响因子
Aging and Disease
·
2024
·
IF 7
Li Li,Paul R. Krafft,Na Zeng,Ranran Duan,Xiang Qi,Anwen Shao,Fushan Xue,John H. Zhang
Ischemic stroke can be a serious complication of selective carotid endarterectomy (CEA) in patients with carotid artery stenosis (CAS). The underlying risk factors and mechanisms of these postoperative strokes are not completely understood. Our previous study showed that TMEM166-induced neuronal autophagy is involved in the development of secondary brain injury following cerebral ischemia-reperfusion injury in rats. This current study aimed to investigate the role of TMEM166 in ischemic stroke following CEA. In the clinical part of this study, the quantitative analysis demonstrated circulating TMEM166, interleukin 6 (IL-6), and C-reactive protein (CRP) levels were significantly elevated in patients who suffered an ischemic stroke after CEA compared to those who did not. Furthermore, non-survivors exhibited higher levels of these proteins than survivors. In the preclinical part of this study, a middle cerebral artery occlusion (MCAO) model was implemented following CAS simulation in TMEM166 -/- mice. We found TMEM166 expression was positively correlated with the degree of ischemic brain injury. Ad5-TMEM166 transfection aggravated ischemic brain injury by inducing microglial autophagy activation and release of inflammatory cytokines. Accordingly, TMEM166 deficiency reduced brain inflammation and inhibited excessive microglial autophagy through the mammalian target of rapamycin (mTOR) pathway. These findings suggest that TMEM166 may play a key role in the development of ischemic injury after CEA and may serve as a biomarker for risk assessment of postoperative ischemic stroke.
研究领域:
神经科学
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心血管疾病
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 9
·e71786
·
IF 4.3
Shan-Shan Feng,Sen-Yu Zhang,Yu-Can Li,Tao Zhang,Yu-Hang Yang
Neonatal hypoxic–ischemic encephalopathy (NHIE) is a leading cause of morbidity and mortality in term infants. The anesthetic dexmedetomidine (Dex) has been shown to reduce brain damage. In this study, hypoxia–ischemia (HI) in neonatal rats caused significant cerebral infarction, neurological deficits, learning and cognitive impairments, inflammatory responses, and microglia polarization. Dex treatment mitigated HI-induced brain injury in rats. Lipopolysaccharide (LPS) increased inflammation in BV2 cells, elevated M1 polarization markers, and raised the proportion of M1 cells. Dex reduced inflammation and M1 polarization in BV2 cells. Rbm47 was identified as a target of Dex, being downregulated in NHIE rat brain tissues and upregulated by Dex. Rbm47 co-localized with microglia and was decreased as the microglia marker Iba-1 increased. Adenovirus-mediated overexpression of Rbm47 alleviated brain injury in NHIE rats and reduced microglial inflammation and M1 activation, both in vitro and in vivo. Conversely, knockdown of Rbm47 hindered the protective effects of Dex against BV2 cell inflammation and M1 polarization. This study indicates that Rbm47 mediates the protective effects of Dex against NHIE brain injury. Graphical Dexmedetomidine upregulates Rbm47, suppressing M1 polarization and inflammation of microglia, thereby alleviating cerebral infarction, neurological deficits, and cognitive impairments in neonatal rats with hypoxic–ischemic encephalopathy.
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Bioactive Materials
·
2025
·
IF 20.3
Miaomiao Fei,Qidong Liu,Hui Zhang,Yawei Du,Liang Chen,Juan Wang,Wenguo Cui,Cheng Li
Abnormal mitochondrial division in microglia significantly impacts central nervous system (CNS) diseases. However, treating CNS diseases through microglial mitochondria presents several challenges: intracerebral delivery of drugs, microglial targeting, and mitochondrial regulation. Herein, a novel three-stage sequential targeted nasal drops delivery system that achieves precise drug delivery to the core of brain lesions through noninvasive nasal delivery, targeting microglia, and regulating mitochondria were developed. Firstly, dehydroepiandrosterone (DHEA), identified from clinical data and transcriptomic analyses as a key neurosteroid regulating mitochondrial fission, was selected. Secondly, surface-positively charged hydrogel microspheres were prepared to adhere to the nasal mucosa, thereby avoiding rapid clearance and achieving the first stage of nasal mucosa targeting. Subsequently, targeted liposomes carrying cytotoxic T lymphocyte-associated protein-4 were constructed and modified into microspheres, which released liposomes through the nasal cavity to enter the brain and bound to the activated microglial surface receptors CD80/86 accomplishing the second stage of cell targeting. In the third stage, the system released DHEA in response to the microenvironment, precisely regulating dynamin-related protein 1 involved in mitochondrial membrane remodeling, which inhibited abnormal mitochondrial division, stabilized mitochondrial morphology and function, inhibited microglial activation. This study demonstrated that three-stage sequential nasal drops efficiently traversed the nose-to-brain pathway via nasal mucosa in both murine (n = 200) and porcine (n = 16) models, while significantly ameliorating anesthesia/surgery-induced cognitive dysfunction in mice. Therefore, the three-stage sequential nasal drip is a promising method for the treatment of central nervous system diseases.
研究领域:
神经生物学
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免疫学
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药理学
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生物材料科学
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Yuxin Zhang,Lixuan Yang,Yonghui Gan,Chenchen Zhao,Chao Zhou,Jian Chen,Yanping Yin,Shengnan Xia,Haiyan Yang,Xinyu Bao,Meijuan Zhang,Yun Xu,Jingwei Li
Microglia, the primary immune cells of the central nervous system, play a crucial role in the neuroinflammatory processes following ischemic stroke. Targeting neuroinflammation is a promising strategy to enhance the outcomes of ischemic stroke. Benzydamine (BA), a well-known non-steroidal anti-inflammatory drug, has demonstrated potential in inhibiting pro-inflammatory cytokines across various disease models. However, the potential role of BA in microglial activation and post-stroke neuroinflammation remains unclear. Our study reveals that BA effectively suppresses the lipopolysaccharide (LPS)-stimulated pro-inflammatory responses of primary microglia, with high-dose BA (10 μM) suppressing LPS-induced inflammatory markers by up to 59.1 % in the mRNA levels of IL-1β. Furthermore, BA mitigated ischemic brain injury in experimental stroke mice. BA treatment also significantly attenuated neuroinflammatory responses and attenuates ischemic brain injury in experimental stroke mice. Further investigation revealed that BA reduces the release of the LPS-stimulated pro-inflammatory factors and activation of primary microglia by directly binding to and inhibiting the activity of cathepsin S (CTSS). In conclusion, our study identifies BA as a promising CTSS inhibitor with potential to suppress neuroinflammation following ischemic stroke. Our findings provide a theoretical basis for developing new neuroprotective strategies.
研究领域:
神经科学
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药理学
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免疫学
·
神经病学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Li Li,Ru Liu,Jing He,Jing Li,Juan Guo,Yun Chen,Ke Ji
Objective. Microglial BV-2 cells are activated in the brain following insomnia. Naringin (NAR) is a polymethoxylated flavonoid that is also commonly found in citrus fruits and is known for its antioxidant potential. However, the effect of NAR on microglial cells has rarely been studied in the brain of an organism after insomnia. This study aimed to investigate the effects and potential mechanisms of action of NAR on microglial cell activation and inflammation. Methods. BV-2 cells were obtained from the China Center for Type Culture Collection and randomly divided into five treatment groups: control, model, NAR (10 μM), WP1066 (5 μM), and NAR + WP1066. With the exception of the control group, all groups were stimulated with LPS (1 μg/mL) for 6 h. CCK8 was used to quantify cell viability and a scratch test was performed to detect cell migration. The expression levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), nterleukin 10 (IL-10), and insulin like growth factor (1IGF-1) were measured by ELISA. Western blotting was performed to determine the levels of p-STAT3 and p-JAK. The Focalcheck™ Thin-Ring Fluorescent Microspheres kit was used to detect cell phagocytosis. Immunofluorescence was used to observe the expression of iNOS and arginase1 in BV-2 cells. Results. Compared with the control group, cell migration, cell viability, and the expression of IL-1β, IL-6, TNF-α, and iNOS were significantly increased in the model group, whereas the expression levels of IL-10, IGF-1, and arginase 1, as well as cell phagocytosis were reduced. With the increase in NAR concentration, cell migration, cell viability, the expression levels of IL-1β, IL-6, TNF-α, and iNOS decreased, while the expression of IL-10, IGF-1, and arginase 1 increased. Compared with the control group, p-STAT3, and p-JAK expression in the model group were significantly increased (P<0.05). Compared with the model group, the expression of p-STAT3 and p-JAK in the NAR, NAR + WP1066, and WP1066 groups was significantly decreased (). Conclusion. NAR treatment inhibited the proliferation, migration, and inflammation of BV-2 cells as well as the activation of microglia to the M1 phenotype. Conversely, NAR treatment promoted the activation of microglia to the M2 phenotype and enhanced the phagocytic function of BV-2 cells by regulating the activity of the JAK/STAT3 pathway.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2021
·
IF 2.63
Xubin Bao,Cai Chen,Liyong Yuan
Triptolide (T10) is a common anti-inflammatory and analgesic drug. However, the activation of microglia and elimination of the corresponding inflammatory response are new targets for the treatment of neuropathic pain. Chemokine CCL (CCL2) is a key mediator for activating microglia. In this study, the effects of triptolide on the activation and polarization of microglia cells and CCL2 and its corresponding receptor, chemokine receptor 2 (CCR2), were mainly discussed. Microglia were stimulated with 1 μg/mL lipopolysaccharide (LPS) and pretreated with 10, 20, and 40 nM T10 and CCR2 antagonist (RS102895), respectively. The quantitative polymerase chain reaction (QPCR) and western blot results showed that T10 could obviously inhibit the upregulation of CCL2 and CCR2 induced by LPS stimulation in microglia cells, inhibit the fluorescence intensity of glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) antibody immunostaining in cells, and upregulate the fluorescence intensity of arginase 1 antibody in cells. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) was inhibited in a dose-dependent manner. RS102895 can significantly reverse the activation and M2 polarization of microglia pretreated with 40 nM T10 and weaken the anti-inflammatory effect of T10. The addition of CCL2 did not extremely affect the function of RS102895. T10 may inhibit microglia activation and M1 polarization by inhibiting the expression of CCL2 and CCR2, promoting M2 polarization, reducing the level of inflammatory factors in cells, and exerting its analgesic effect, which is worthy of clinical promotion as a drug for neuropathic pain.
研究领域:
药理学
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神经科学
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免疫学
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·44
·
IF 4.3
Xie Min,Cheng Yu,Yang Lizhen,Lin Zijin,Shen Hao,Zhou Xinhua,Liu Zheng,Xing Jieyu,Zhou Sigui,Chen Haiyun
Parkinson’s disease (PD) is the second most prevalent neurological disorder without a clear etiology and specific cure. Microglia-mediated neuroinflammation plays a pivotal role in the pathogenesis and progression of PD, which is influenced by various factors and involves multiple signaling pathways. CT-011, synthesized by combining nitrone-tetramethyl pyrazine (TMP) and caffeic acid through an ester bond, has shown neuroprotection against ischemic stroke and glutamate-induced neuronal damage in animal models. The purpose of this study is to explore the impact of CT-011 on PD-related neuroinflammation and its potential in treating PD. Results showed that CT-011 significantly inhibited lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines and mediators in BV2 microglial cells. CT-011 also effectively mitigated LPS-induced mitochondrial membrane potential (MMP) reduction, mitochondrial and intracellular reactive oxygen species (ROS) production. Meanwhile, CT-011's anti-inflammatory effect was related to its inhibition of the TLR4-mediated MyD88/NF-B and PI3K-mediated AKT/GSK3β pathways. More significantly, CT-011 repressed the NLRP3 inflammasome activation. Additionally, CT-011 protected primary neurons against microglial-mediated neurotoxicity in vitro , and ameliorated dopaminergic neuronal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice with a consistent anti-neuroinflammatory effect in vivo. These results demonstrate that CT-011 effectively inhibits microglia-mediated neuroinflammation and exerts neuroprotective effects on dopamine neurons, thus making it a promising therapeutic candidate for PD.
研究领域:
神经药理学
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神经退行性疾病
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分子神经科学
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炎症研究
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PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2023
·
IF 2.4
Yanqiang CHEN,Cong ZHANG,Liming ZHAO,Rong CHEN,Peipei ZHANG,Junxia LI,Xueping ZHANG,Xiangjian ZHANG
Excessive neuroinflammation mediated by microglia has a detrimental effect on the progression of ischemic stroke. Eriocalyxin B (EriB) was found with a neuroprotective effect in mice with Parkinson’s disease by suppressing the microglial overactivation. This study aims to investigate the roles of EriB in permanent middle cerebral artery occlusion (pMCAO) mice. The pMCAO was induced by intraluminal filament method in internal carotidartery of mice, which underwent an immediately intraperitoneal injection of EriB (10 mg/kg) post surgery. The behavior score, 2,3,5-triphenyltetrazole chloride staining, Nissl staining, TUNEL, immunohistochemistry, immunofluorescence, PCR, ELISA and immunoblotting revealed that EriB administration reduced brain infarct and neuron death, ameliorated neuroinflammation and microglia overactivation in pMCAO mice, manifested by alterations of TUNEL-positive cell numbers, ionized calcium binding adaptor molecule 1 (Iba-1)-positive cell numbers, expression of tumor necrosis factor-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase and arginase 1. In addition, EriB suppressed ischemia-induced activation of nuclear factor kappa B (NF-κB) signaling in brain penumbra, suggesting the involvement of NF-κB in EriB function. In conclusions, EriB exerted anti-inflammatory effects in ischemia stroke through regulating NF-κB signaling pathway, which may provide insights into the neuroprotective effect of EriB on the treatment of ischemic stroke.
研究领域:
神经科学
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药理学
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炎症
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中风
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
·
IF 6.2
Jia-Gen Cui,Hao Zhang,Ming-Shan Chen,Jia-Xin Wang,Xue-Nan Li,Jin-Long Li
Lycopene (LYC), a natural antioxidant compound abundant in tomatoes, has established neuroprotective roles due to its antioxidant and anti-inflammatory properties. Di (2-ethylhexyl) phthalate (DEHP), a common plasticizer, is known to exert neurotoxic effects. However, the mechanisms of DEHP-induced neurotoxicity remain unclear. Furthermore, effective preventive strategies against this neurotoxicity are still lacking. This study, employing in vitro (BV2 cells) and in vivo (ICR mouse) models, demonstrates that LYC prevents DEHP-induced cerebellar damage by suppressing the triggering of dose-dependent microglial ferroptosis and neuroinflammation. Mechanistically, LYC inhibited the phosphatidylethanolamine-binding protein 1 (PEBP1)/arachidonate 15-lipoxygenase (ALOX15) axis (supported by immunofluorescence and Western blot assays), leading to reduced reactive oxygen species by approximately 48% in the cerebellum, which ultimately prevented neuroinflammation. Our findings reveal that LYC prevents DEHP-induced neurotoxicity by inhibiting microglial ferroptosis via the PEBP1/ALOX15 axis. Furthermore, our findings highlight the clinical promise of LYC as a novel neuroprotective treatment against environmental toxicant-induced damage.
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高影响因子
NEUROCHEMICAL RESEARCH
·
2026
·Vol. 51
·期 4
·226
·
IF 4.5
Qin Dani,Lei Yong,Le Meini,Cheng Mengke,Zhao Yingmin,Xia Lingyun,Li Xinyuan,Dong Xiaohua
Hypoxic-ischemic encephalopathy (HIE) is a severe perinatal brain injury that often leads to neurological impairments in survivors. Currently, effective therapeutic strategies for HIE remain limited and require further exploration. Emerging evidence indicates that microglia-mediated neuroinflammation plays a pivotal role in the pathophysiology of HIE. Nevertheless, clinically effective anti-inflammatory agents specifically targeting HIE are still lacking. Glycerol-3-phosphate (G3P) is a biologically significant metabolite involved in various cellular metabolic pathways. In this study, we investigated the neuroprotective effects of G3P against hypoxic-ischemic (HI)-induced brain injury by modulating microglial activation. In LPS-treated microglia, G3P suppressed the release of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential (MMP), and promoted a shift toward an anti-inflammatory microglial phenotype. In addition, G3P treatment in zebrafish showed no toxicity and significantly mitigated HI-induced oxidative stress, while suppressing both the recruitment and pro-inflammatory activation of mpeg1⁺ macrophages and lyzc⁺ neutrophils. Moreover, administration of G3P dramatically reduced infarct volume and alleviated neuronal loss in rats with hypoxic-ischemic brain damage (HIBD). Y-maze and Morris water maze tests demonstrated that G3P treatment significantly enhanced spatial learning and memory in HIBD rats. Furthermore, G3P markedly reduced the hyperactivation of microglia and astrocytes in both cortical and hippocampal regions. Mechanistically, Immunofluorescence and Western blot analyses revealed that G3P exerted anti-inflammatory effects by inhibiting cyclic GMP-AMP synthase -stimulator of interferon genes (cGAS-STING) signalling pathway and its downstream TBK1/the nuclear factor kappa B (NF-κB) signaling pathway. These findings highlight G3P as a promising therapeutic candidate for HIE.
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高影响因子
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