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

{"title":"Unraveling the Immune Puzzle: Role of Immunomodulation in Alzheimer's Disease.","authors":"Ashvin, Rishika Dhapola, Sneha Kumari, Prajjwal Sharma, Balachandar Vellingiri, Bikash Medhi, Dibbanti HariKrishnaReddy","doi":"10.1007/s11481-025-10210-9","DOIUrl":"https://doi.org/10.1007/s11481-025-10210-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"47"},"PeriodicalIF":6.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030635","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":"Current Understanding of the Exosomes and Their Associated Biomolecules in the Glioblastoma Biology, Clinical Treatment, and Diagnosis.","authors":"Aghdas Ramezani, Maryam Rahnama, Fatemeh Mahmoudian, Fatemeh Shirazi, Mahmoud Ganji, Shohreh Bakhshi, Bahman Khalesi, Zahra Sadat Hashemi, Saeed Khalili","doi":"10.1007/s11481-025-10204-7","DOIUrl":"https://doi.org/10.1007/s11481-025-10204-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"48"},"PeriodicalIF":6.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036614","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":"Unmasking a Paradox: Roles of the PD-1/PD-L1 Axis in Alzheimer's Disease-Associated Neuroinflammation.","authors":"Ali Moadab, Hossein Khorramdelazad, Mohammad Taha Akbari Javar, Mohammad Saber Mohammadian Nejad, Shahrzad Mirzaie, Sina Hatami, Nima Mahdavi, Saeed Ghaffari, Fatemeh Askari Yazdian","doi":"10.1007/s11481-025-10206-5","DOIUrl":"https://doi.org/10.1007/s11481-025-10206-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"46"},"PeriodicalIF":6.2,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029842","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":"Human Umbilical Cord Mesenchymal Stem Cells Ameliorated Chronic Unpredictable Mild Stress-Induced Depression and Anxiety by Alleviating Neuroinflammation.","authors":"Guangyang Liu, Li Miao, Haichen Niu, Herui Wang, Li Yan, Yaoyao Chen, Chenliang Zhang, Xin Li, Yi Mi, Liqiang Xu, Daohui Wang, Jingwen Zhou, Xiaodan Xu, Guo Li, Haomiao Long, Yongjun Liu","doi":"10.1007/s11481-025-10198-2","DOIUrl":"https://doi.org/10.1007/s11481-025-10198-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"45"},"PeriodicalIF":6.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030214","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":"Cranberry Extract Ameliorates Diabetic Cognitive Impairment in Rats Via LncRNA GAS-5 Downregulation and Pyroptosis Pathway Inhibition.","authors":"Mariam Ali Abo-Saif, Amany E Ragab, Iman M Talaat, Maha Saber-Ayad, Amera O Ibrahim, Hend Mostafa Selim","doi":"10.1007/s11481-025-10199-1","DOIUrl":"https://doi.org/10.1007/s11481-025-10199-1","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"44"},"PeriodicalIF":6.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044085","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":"Novel Trajectories Towards Possible Effects of Semaglutide for Amelioration of Reserpine-induced Fibromyalgia in Rats: Contribution of cAMP/PKA/p-CREB and M1/M2 Microglia Polarization.","authors":"Mena Z Shafiek, Hala F Zaki, Ahmed F Mohamed, Weam W Ibrahim","doi":"10.1007/s11481-025-10196-4","DOIUrl":"https://doi.org/10.1007/s11481-025-10196-4","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"43"},"PeriodicalIF":6.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058128","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":"The Role of Microglial Exosomes in Clozapine Treatment: Effect on Cognition in Schizophrenia.","authors":"Kyle Hewitt, Xu-Feng Huang","doi":"10.1007/s11481-024-10160-8","DOIUrl":"https://doi.org/10.1007/s11481-024-10160-8","url":null,"abstract":"<p><p>Schizophrenia is a complex neuropsychiatric disorder characterized by a spectrum of symptoms including cognitive impairments and psychotic episodes. Clozapine, an atypical antipsychotic drug, is a widely recognised treatment option for patients with drug-resistant schizophrenia, due to it having the highest efficacy out of all the antipsychotic drugs. Despite its efficacy, clozapine's impact on cognition and brain structure in schizophrenia patients remains a subject of ongoing research and debate, with accumulating evidence indicating negative impacts on cognitive performance and changes in brain volume. Changes in the immune system are linked to variations in cognitive functioning in schizophrenia. Previous research has indicated that microglia, the primary innate immune cells of the brain, have been associated with decreased cognitive performance when dysfunctional. Evidence suggests that brain structure may mediate the observed relationship between microglia and cognition. Microglial exosomes, integral to neuroinflammation and cellular communication, could provide insight into the neurobiological mechanisms underpinning the effects of clozapine treatment. This review focuses on the proposition that alterations in microglial exosome composition, particularly miRNAs, are involved in mediating clozapine's diverse effects on cognition by influencing brain macrostructure. This review aims to highlight new directions for future research that could lead to more effective and targeted therapeutic approaches in the management of schizophrenia.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"42"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032167","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":"Abscisic Acid Rescues Behavior in Adult Female Mice in Attention Deficit Disorder with Hyperactivity Model of Dopamine Depletion by Regulating Microglia and Increasing Vesicular GABA Transporter Expression.","authors":"Maria Meseguer-Beltrán, Sandra Sánchez-Sarasúa, Nóra Kerekes, Marc Landry, Matías Real-López, Ana María Sánchez-Pérez","doi":"10.1007/s11481-025-10186-6","DOIUrl":"https://doi.org/10.1007/s11481-025-10186-6","url":null,"abstract":"<p><p>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome typically diagnosed in childhood that may persist into adulthood. Its etiology encompasses both genetic and environmental factors, with genetic studies indicating catecholamine dysfunction and epidemiological evidence emphasizing neuroinflammation as a potential trigger. To investigate the roles of inflammation and development processes in ADHD, we conducted a longitudinal behavioral study using female Swiss mice with a dopamine deficit model. We explored the impact of neonatal dopaminergic lesions, treatment with abscisic acid (ABA)-an anti-inflammatory hormone-and developmental changes by comparing behavioral patterns in juvenile and adult mice. Postmortem analyses assessed neuroinflammation through microglial morphology, NLRP3, cytokine expression, and the excitatory/inhibitory (E/I) ratio in specific brain regions. Neonatal dopaminergic lesions induced hyperactivity and hypersensitivity in juvenile mice that persisted into adulthood. In adults, increased social interaction and memory impairment were observed in lesioned mice. Brain development mitigated impulsivity, while ABA treatment reduced locomotor activity, downregulated pain sensitivity, and influenced social interaction, although it did not completely resolve cognitive deficits in lesioned adult mice. In brain regions such as the anterior cingulate cortex (ACC), posterior insular cortex (pIC), and hippocampus, lesions significantly altered microglial morphology. In the ACC, lesions increased IL-1β and TNFα levels, decreased Arg1 mRNA levels, and disrupted the E/I balance. Importantly, ABA treatment restored microglial morphology, normalized IL-1β and Arg1 expression and upregulated vGAT levels. This study demonstrates that dopamine deficits lead to microglia alterations and E/I imbalance, contributing to ADHD symptoms. While some symptoms improve with brain development, targeting microglial health in specific brain regions emerges as a promising therapeutic approach for managing ADHD.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"39"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047084","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":"Preparation and In vitro/In vivo Evaluation of Fingolimod hydrochloride Loaded Polymeric Mixed Nano-Micelles for Treatment of Multiple Sclerosis.","authors":"Ladan Dayani, Fatemeh Haddadi, Mehdi Aliomrani, Azade Taheri","doi":"10.1007/s11481-025-10203-8","DOIUrl":"https://doi.org/10.1007/s11481-025-10203-8","url":null,"abstract":"<p><p>Fingolimod (FYN) is one of the approved medicines for treatment of multiple sclerosis (MS) while exhibiting several side effects such as liver enzyme elevation and cardiac damage. This study was aimed to prepare the mixed micelles of ascorbyl palmitate (AP) and alpha-tocopherol polyethylene glycol succinate (TPGS) as a delivery system for FYN. The mixed micelles were prepared by thin film hydration method at different ratios of AP/TPGS. Saturation solubility of the micelles was compared with the pure drug. The optimized formulation was characterized by scanning electron microscopy (SEM) and subjected for stability study at 5 ± 3 °C for 3 months. The effect of the prepared fingolimod loaded micelles (FYN-Micelle) was finally assessed by experimental autoimmune encephalomyelitis (EAE) model at the dose of 0.3, 1, and 3 mg/kg of fingolimod, which was administrated intraperitoneally. The results indicated that the prepared mixed micelles at the AP/TPGS ratio of 1:5 showed a particle size, zeta potential, and an entrapment efficiency of 116.86 ± 2.41 nm, 23.61 ± 4.56 mV, and 63.28 ± 5.31%, respectively. Also, this formulation was stable after a 3-month incubation at 5 ± 3 °C. SEM images displayed an amorphous state of the drug in the micelles. Animal studies confirmed that this formulation at the dose of 1 mg/kg could enhance the myelin density of the brain while reducing cardiac and hepatic impairment. Therefore, these findings suggested that FYN-Micelle could be exploited as an effective delivery system for fingolimod hydrochloride to treat MS.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"41"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144025761","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":"Evaluation of the Anti-Inflammatory Effects of Novel Fatty Acid-Binding Protein 4 Inhibitors in Microglia.","authors":"Yi Ling Low, Ethan Kreutzer, Indu R Chandrashekaran, Luke A Adams, Jason Pun, Bradley C Doak, Yijun Pan, Jennifer L Short, Martin J Scanlon, Joseph A Nicolazzo","doi":"10.1007/s11481-025-10191-9","DOIUrl":"https://doi.org/10.1007/s11481-025-10191-9","url":null,"abstract":"<p><p>Fatty acid-binding protein 4 (FABP4) is a key lipid binding protein expressed in microglia, which has been demonstrated to play a critical role in microglial-mediated neuroinflammation, a component of many neurodegenerative diseases. Compounds able to inhibit the function of FABP4 have shown promise in reducing microglial-mediated neuroinflammation, however, their physicochemical properties would prevent their ability to be easily formulated and traverse the blood-brain barrier (BBB) in order to access microglial FABP4. To this end, this study assessed the ability of a series of FABP4 inhibitors, with more desirable physicochemical properties, to attenuate microglial inflammation in an in vitro setting. Four inhibitors with varying affinity to FABP4, as measured by isothermal titration calorimetry (MFP-0011462, MFP-0012314, MFP-0012318, and MFP-0012328), were assessed for their ability to induce toxicity and attenuate reactive oxygen species (ROS) generation and tumour necrosis factor-α (TNF-α) release from lipopolysaccharide (LPS)-activated BV-2 microglia. All FABP4 inhibitors were determined to be soluble in the aqueous buffers at the highest concentration used in the assays (100 µM). Isothermal titration calorimetry demonstrated that the compounds had varying affinities for FABP4 (K_D values of 316 nM to > 100 µM). The ability of FABP4 inhibitors to reduce LPS-mediated ROS production aligned with their K_D for FABP4, with the most effective inhibitor (MFP-0012328) also able to reduce TNF-α production (by RT-qPCR) and TNF-α release from LPS-activated BV-2 cells by 17% and 25%, respectively. These studies have demonstrated that a series of FABP4 inhibitors with more appropriate physicochemical properties for BBB penetration are able to reduce microglial-mediated inflammation, which may be of benefit in diseases where overactivation of microglia leads to neurodegeneration.</p>","PeriodicalId":73858,"journal":{"name":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","volume":"20 1","pages":"40"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060689","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}