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

{"title":"Matrix Metalloproteinase-9 Signaling Regulates Colon Barrier Integrity in Models of HIV Infection.","authors":"Michael Ohene-Nyako, Amanda L Persons, Christopher Forsyth, Ali Keshavarzian, T Celeste Napier","doi":"10.1007/s11481-024-10158-2","DOIUrl":"https://doi.org/10.1007/s11481-024-10158-2","url":null,"abstract":"<p><p>Infection with human immunodeficiency virus (HIV) increases risk for maladies of the gut barrier, which promotes sustained systemic inflammation even in virally controlled patients. We previously revealed morphological disorganization of colon epithelial barrier proteins in HIV-1 transgenic (Tg) rats. The current study evaluated mechanisms that may underlie gut barrier pathology induced by toxic HIV-1 proteins. Methamphetamine (meth) use is prevalent among HIV-infected individuals, and meth can exaggerate morbidity of HIV infection. Thus, we determined whether meth exposure worsened HIV-associated gut pathology using colon samples from HIV-1 Tg and non-Tg rats that self-administered meth 2 h/day for 21 days. Immunoblotting was conducted for occludin (a gut barrier protein) and matrix metalloproteinase-9 (MMP-9; a proteinase regulator of occludin). Colon levels of occludin were decreased, and MMP-9 levels and activity were increased in HIV-1 Tg rats. A Pearson correlation revealed an inverse relationship between occludin levels and MMP-9 activity. Doses of meth that were self-administered by Tg rats were lower than other rat models. Meth-induced trends in non-Tg rats were not significant, and meth did not exaggerate effects seen in Tg rats. Accordingly, only the HIV-effects on epithelial function were explored further. Transepithelial resistance (TER) across a monolayer of human colon epithelial cells (Caco-2) was used to examine treatments with the HIV-1 toxic protein, Tat, and the ability of pioglitazone, a PPARγ agonist that inhibits MMP-9, to mitigate Tat-induced changes. Exposure to Tat for 24 h decreased TER, which co-occurred with decreases in levels of barrier tight junction proteins (occludin, claudin-1, and zonula occludens-1) and with increases in the level and activity of MMP-9. Pretreatment or post-treatment with pioglitazone respectively prevented and restored Tat-induced impairments of Caco-2 barrier. Thus, while low doses of meth did not alter barrier proteins in the current study, exposure to HIV-1 proteins disrupted the gut barrier, and this action involved a dysregulation of MMP-9.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin K2 Ameliorates Diabetes-Associated Cognitive Decline by Reducing Oxidative Stress and Neuroinflammation.","authors":"Kaberi Chatterjee, Anubroto Pal, Dibya Sundar Padhy, Rajdeep Saha, Amrita Chatterjee, Monika Bharadwaj, Biswatrish Sarkar, Papiya Mitra Mazumder, Sugato Banerjee","doi":"10.1007/s11481-024-10156-4","DOIUrl":"https://doi.org/10.1007/s11481-024-10156-4","url":null,"abstract":"<p><p>Diabetes, a chronic metabolic disease, affects approximately 422 million people and leads to 1.5 million deaths every year, It is found that 45% of individuals with diabetes eventually develop cognitive impairment. Here we study effects of Vitamin K2 on diabetes-associated cognitive decline (DACD) and its underlying mechanism. Diabetes was induced in adult Swiss albino mice with high-fat diet and a low dose (35 mg/kg) of streptozotocin and measured by fasting glucose and HbA1c levels. After one week of development of diabetes, one group of animals received Vitamin K2 (100 µg/kg) via oral gavage for 21 days. Then different behavioural studies, including the elevated plus maze, Morris water maze, passive avoidance test and novel object recognition test were performed followed by biochemical tests including AchE, different oxidative stress parameters (SOD, GSH, MDA, catalase, SIRT1, NRF2), inflammatory markers (TNFα, IL1β, MCP1, NFκB), apoptosis marker (Caspase 3). Hippocampal neuronal density was measured using histopathology. Vitamin K2 treatment in diabetic animals led to reduced fasting glucose and HbA1c, It could partially reverse DACD as shown by behavioural studies. Vitamin K2 adminstration reduced corticohippocampal AchE level and neuroinflammation (TNFα, IL1β, MCP1, NFκB, SIRT1). It reduced oxidative stress by increasing antioxidant enzymes (SOD, GSH, catalase), transcription factor NRF2 while reducing caspase 3. This eventually increased CA1 and CA3 neuronal density in diabetic animals. Vitamin K2 partially reverses DACD by increasing ACh while reducing the oxidative stress via Nrf2/ARE pathway and neuroinflammation, thus protecting the hippocampal neurons from diabetes associated damage.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes Derived from DPA-treated UCMSCs Attenuated Depression-like Behaviors and Neuroinflammation in a Model of Depression Induced by Chronic Stress.","authors":"Peng Li, Fucheng Zhang, Chengyi Huang, Cai Zhang, Zhiyou Yang, Yongping Zhang, Cai Song","doi":"10.1007/s11481-024-10154-6","DOIUrl":"https://doi.org/10.1007/s11481-024-10154-6","url":null,"abstract":"<p><p>Depression is characterized by both neuroinflammation and neurodegeneration. Exosomes (Exo) have been shown to function as inhibitors of inflammation and promoters of neurogenesis. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid, can combat depression by increasing levels of docosapentaenoic acid (DPA). This study explored the effects of DPA on the therapeutic potential of Exo derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in glia-induced neuroinflammation associated with depression. Exposure to chronic unpredictable mild stress (CUMS) over six weeks induced depression- and anxiety-like behaviors, while decreasing the levels of serotonin and dopamine. Molecularly, CUMS increased the concentrations of the microglial M1 markers Iba1, iNOS, and IL-1β, while reducing the M2 markers Arg1, CD206, and IL-10 in the prefrontal cortex and hippocampus. However, Exo therapy reversed these effects. Moreover, DPA treatment of Exo demonstrated superior efficacy in alleviating depressive behaviors, neurotransmitter deficiencies, and M1 microglial activation. In vitro, Exo suppressed LPS-stimulated BV2 cell viability and M1 microglial activation, while mitigating the SH-SY5Y cell apoptosis triggered by treatment with the conditioned medium from LPS-activated BV2 cells. Furthermore, administration of DPA enhanced this effect. Mechanically, DPA enhanced Exo function by upregulating miR125b-5p expression, thereby targeting the MyD88/TRAF6/NF-κB signaling pathway. In summary, Exo exhibited antidepressant effects by suppressing M1 microglial neuroinflammation, while DPA treatment provided a more potent therapeutic effect on depression-like changes through the upregulation of miR125b-5p targeting the MyD88/TRAF6/NF-κB pathway.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble Epoxide Hydrolase Inhibitor Ameliorates Olfactory Dysfunction, Modulates Microglia Polarization, and Attenuates Neuroinflammation after Ischemic Brain Injury.","authors":"Chien-Fu Yeh, Tung-Yueh Chuang, Ming-Ying Lan, Yung-Yang Lin, Wei-Hao Huang, Yu-Wen Hung","doi":"10.1007/s11481-024-10155-5","DOIUrl":"https://doi.org/10.1007/s11481-024-10155-5","url":null,"abstract":"<p><p>Olfactory bulb (OB) microglia activation and inflammation can lead to olfactory dysfunction, which often occurs after an ischemic stroke. Inhibition of soluble epoxide hydrolase (sEH) attenuates neuroinflammation in brain injuries by reducing the degradation of anti-inflammatory epoxyeicosatrienoic acids. However, whether sEH inhibitors can ameliorate olfactory dysfunction after an ischemic stroke remains unknown. Ischemic brain injury and olfactory dysfunction were induced by middle cerebral artery occlusion (MCAO) in Wistar Kyoto rats. The rats were administered 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a selective sEH inhibitor. Olfactory function, cerebral infarct volume, and the degree of degeneration, microglial polarization and neuroinflammation in OB were evaluated. Following treatment with AUDA, rats subjected to MCAO displayed mild cerebral infarction and OB degeneration, as well as better olfactory performance. In OB, AUDA triggered a modulation of microglial polarization toward the M2 anti-inflammatory type, reduction in proinflammatory mediators, and enhancement of the antioxidant process. The effectiveness of AUDA in terms of anti-inflammatory, neuroprotection and anti-oxidative properties suggests that it may have clinical therapeutic implication for ischemic stroke related olfactory dysfunction.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trifluoro-Icaritin Ameliorates Neuroinflammation Against Complete Freund's Adjuvant-Induced Microglial Activation by Improving CB2 Receptor-Mediated IL-10/β-endorphin Signaling in the Spinal Cord of Rats.","authors":"Guangsen Liu, Dandan Jia, Weiwei Li, Zhihua Huang, Reai Shan, Cheng Huang","doi":"10.1007/s11481-024-10152-8","DOIUrl":"https://doi.org/10.1007/s11481-024-10152-8","url":null,"abstract":"<p><p>The underlying pathogenesis of chronic inflammatory pain is greatly complex, but the relevant therapies are still unavailable. Development of effective candidates for chronic inflammatory pain is highly urgent. We previously identified that trifluoro-icaritin (ICTF) exhibited a significant therapeutic activity against complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, however, the precise mechanisms remain elusive. Here, the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis were used to determine the pain-related behaviors. The expression and co-localization of pain-related signaling molecules were detected by Western blot and immunofluorescence staining. Our results demonstrated that ICTF (3.0 mg/kg, i.p.) effectively attenuated mechanical allodynia, thermal hyperalgesia and improved motor dysfunction induced by CFA, and the molecular docking displayed that CB2 receptor may be the therapeutic target of ICTF. Furthermore, ICTF not only up-regulated the levels of CB2 receptor, IL-10, β-endorphin and CD206, but also reduced the expression of P2Y12 receptor, NLRP3, ASC, Caspase-1, IL-1β, CD11b, and iNOS in the spinal cord of CFA rats. Additionally, the immunofluorescence staining from the spinal cord showed that ICTF significantly increased the co-expression between the microglial marker Iba-1 and CB2 receptor, IL-10, β-endorphin, respectively, but markedly decreased the co-localization between Iba-1 and P2Y12 receptor. Conversely, intrathecal administration of CB2 receptor antagonist AM630 dramatically reversed the inhibitory effects of ICTF on CFA-induced chronic inflammatory pain, leading to a promotion of pain hypersensitivity, abnormal gait parameters, microglial activation, and up-regulation of P2Y12 receptor and NLRP3 inflammasome, as well as the inhibition of CB2 receptor and IL-10/β-endorphin cascade. Taken together, these findings highlighted that ICTF alleviated CFA-induced neuroinflammation by enhancing CB2 receptor-mediated IL-10/β-endorphin signaling and suppressing microglial activation in the spinal cord, and uncovered that CB2 receptor may be exploited as a novel and promising target for ICTF treatment of chronic inflammatory pain.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.","authors":"Paula Izquierdo-Altarejos, Mar Martínez-García, Iván Atienza-Pérez, Alberto Hernández, Victoria Moreno-Manzano, Marta Llansola, Vicente Felipo","doi":"10.1007/s11481-024-10153-7","DOIUrl":"https://doi.org/10.1007/s11481-024-10153-7","url":null,"abstract":"<p><p>Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFβ in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking Brain Myeloid Differentiation Factor 2-Toll-like Receptor 4 Signaling Improves Cognition by Diminishing Brain Pathologies and Preserving Adult Hippocampal Neurogenesis in Obese Rats.","authors":"Thura Tun Oo, Natticha Sumneang, Titikorn Chunchai, Nattayaporn Apaijai, Wasana Pratchayasakul, Guang Liang, Nipon Chattipakorn, Siriporn C Chattipakorn","doi":"10.1007/s11481-024-10151-9","DOIUrl":"https://doi.org/10.1007/s11481-024-10151-9","url":null,"abstract":"<p><p>The myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) signaling pathway has been linked to cognitive decline in obese rats. However, more research is required to fully understand the mechanistic role of MD-2-TLR4 signalling pathway in obese-related cognitive impairment. In this study, we used two novel MD-2 inhibitors-MAC28 (a mono-carbonyl analogue of curcumin 28) and 2i-10 (a cinnamamide-derivative compound)-to better comprehend the mechanistic role of the MD-2-TLR4 signalling pathway in obese-related cognitive impairment. A normal diet (ND) (n = 16) and a high-fat diet (HFD) (n = 64) were given to randomly divided groups of male Wistar rats for 16-weeks. At week 13, 2 types of vehicles were randomly administered to ND-fed and HFD-fed rats, whereas MAC28 (3-doses) and 2i-10 (3-doses) were randomly given to HFD-fed rats until week 16. HFD-fed rats developed obesity with metabolic disturbances, a variety of brain pathologies and cognitive decline. In obese rats, blocking the brain MD-2-TLR4 signalling pathway with MAC28 or 2i-10 improved cognition via reducing brain inflammation, neurodegeneration, microglial activation, dendritic spine loss, brain oxidative stress, as well as preserving adult hippocampal neurogenesis. Our findings highlight to better understand the role of MD-2-TLR4 signaling pathway in obese-related cognitive decline, and MD-2 could be a potential therapeutic target for brain pathologies and cognitive decline in obesity.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Toll-like Receptor 4/Nuclear Factor-κB and Nrf2/Heme Oxygenase-1 Crosstalk via Trimetazidine Alleviates Lipopolysaccharide-Induced Depressive-like Behaviors in Mice.","authors":"Sarah S Mohamed, Nora O Abdel Rasheed, Weam W Ibrahim, Nesma A Shiha","doi":"10.1007/s11481-024-10149-3","DOIUrl":"10.1007/s11481-024-10149-3","url":null,"abstract":"<p><p>Depression is a global psychiatric illness that imposes a substantial economic burden. Unfortunately, traditional antidepressants induce many side effects which limit patient compliance thus, exploring alternative therapies with fewer adverse effects became urgent. This study aimed to investigate the effect of trimetazidine (TMZ); a well-known anti-ischemic drug in lipopolysaccharide (LPS) mouse model of depression focusing on its ability to regulate toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) as well as nuclear factor erythroid 2 related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathways. Male Swiss albino mice were injected with LPS (500 µg/kg, i.p) every other day alone or parallel with oral doses of either escitalopram (Esc) (10 mg/kg/day) or TMZ (20 mg/kg/day) for 14 days. Treatment with TMZ attenuated LPS-induced animals' despair with reduced immobility time inforced swimming test. TMZ also diminished LPS- induced neuro-inflammation via inhibition of TLR4/NF-κB pathway contrary to Nrf2/HO-1 cascade activation with consequent increase in reduced glutathione (GSH) and HO-1 levels whereas the pro-inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β were evidently reduced. Besides, TMZ replenished brain serotonin levels via serotonin transporter (SERT) inhibition. Thus, TMZ hindered LPS-induced neuro-inflammation, oxidative stress, serotonin deficiency besides its anti-apoptotic effect which was reflected by decreased caspase-3 level. Neuroprotective effects of TMZ were confirmed by the histological photomicrographs which showed prominent neuronal survival. Here we showed that TMZ is an affluent nominee for depression management via targeting TLR4/NF-κB and Nrf2/HO-1 pathways. Future research addressing TMZ-antidepressant activity in humans is mandatory to enroll it as a novel therapeutic strategy for depression.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MFG-E8 Ameliorates Nerve Injury-Induced Neuropathic Pain by Regulating Microglial Polarization and Neuroinflammation via Integrin β3/SOCS3/STAT3 Pathway in Mice.","authors":"Longqing Zhang, Xinyi Dai, Danyang Li, Jiayi Wu, Shaojie Gao, Fanhe Song, Lin Liu, Yaqun Zhou, Daiqiang Liu, Wei Mei","doi":"10.1007/s11481-024-10150-w","DOIUrl":"10.1007/s11481-024-10150-w","url":null,"abstract":"<p><p>Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin β3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin β3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin β3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin β3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetramerization of PKM2 Alleviates Traumatic Brain Injury by Ameliorating Mitochondrial Damage in Microglia.","authors":"Haiyan Zhu, Huiwen Zhang, Xiao-Jing Zhao, Lingyuan Zhang, Xue Liu, Zhi-Yuan Zhang, Yi-Zhi Ren, Yong Feng","doi":"10.1007/s11481-024-10138-6","DOIUrl":"10.1007/s11481-024-10138-6","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events that determine the outcome of TBI, especially neuronal and cognitive function. Studies have suggested that the metabolic characteristics of microglia dictate their inflammatory response. The pyruvate kinase isoform M2 (PKM2), a key glycolytic enzyme, is involved in the regulation of various cellular metabolic processes, including mitochondrial metabolism. This suggests that PKM2 may also participate in the regulation of microglial activation during TBI. Therefore, the present study aimed to evaluate the role of PKM2 in regulating microglial activation and neuroinflammation and its effects on cognitive function following TBI. A controlled cortical impact (CCI) mouse model and inflammation-induced primary mouse microglial cells in vitro were used to investigate the potential effects of PKM2 inhibition and regulation. PKM2 was significantly increased during the acute and subacute phases of TBI and was predominantly detected in microglia rather than in neurons. Our results demonstrate that shikonin and TEPP-46 can inhibit microglial inflammation, improving mitochondria, improving mouse behavior, reducing brain defect volume, and alleviating pathological changes after TBI. There is a difference in the intervention of shikonin and TEPP-46 on PKM2. Shikonin directly inhibits General PKM2; TEPP-46 can promote the expression of PKM2 tetramer. In vitro experiments, TEPP-46 can promote the expression of PKM2 tetramer, enhance the interaction between PKM2 and MFN2, improve mitochondria, alleviate neuroinflammation. General inhibition and tetramerization activation of PKM2 attenuated cognitive function caused by TBI, whereas PKM2 tetramerization exhibited a better treatment effect. Our experiments demonstrated the non-metabolic role of PKM2 in the regulation of microglial activation following TBI. Both shikonin and TEPP-46 can inhibit pro-inflammatory factors, but only TEPP-46 can promote PKM2 tetramerization and upregulate the release of anti-inflammatory factors from microglia.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.2,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}