Pub Date : 2026-10-17DOI: 10.1016/j.neuint.2026.106279
Hailun Li, Meiting Dong
In recent years, the number of studies on acupuncture intervention for anxiety disorders has been gradually increasing, and its application scope in clinical practice has also been expanding. This article intends to review and discuss the combination of common acupoints, specific operation methods, efficacy evaluation indicators, clinical effects and potential mechanisms of action. Available evidence suggests that acupuncture may influence anxiety-related symptoms through multiple neurobiological pathways, including autonomic regulation, neurotransmitter signaling, neuroendocrine regulation, and neuroplasticity-related mechanisms; however, the causal contribution of individual pathways remains incompletely established. However, there are still some shortcomings in relevant studies, such as limited sample size, lack of uniformity in efficacy criteria, and relatively insufficient follow-up time. Future research should pay more attention to the application of evidence-based medicine methods, strengthen the discussion of mechanisms of action, and try to establish more individualized intervention plans.
{"title":"Implementation rules and research status of acupuncture therapy for anxiety disorders.","authors":"Hailun Li, Meiting Dong","doi":"10.1016/j.neuint.2026.106279","DOIUrl":"10.1016/j.neuint.2026.106279","url":null,"abstract":"<p><p>In recent years, the number of studies on acupuncture intervention for anxiety disorders has been gradually increasing, and its application scope in clinical practice has also been expanding. This article intends to review and discuss the combination of common acupoints, specific operation methods, efficacy evaluation indicators, clinical effects and potential mechanisms of action. Available evidence suggests that acupuncture may influence anxiety-related symptoms through multiple neurobiological pathways, including autonomic regulation, neurotransmitter signaling, neuroendocrine regulation, and neuroplasticity-related mechanisms; however, the causal contribution of individual pathways remains incompletely established. However, there are still some shortcomings in relevant studies, such as limited sample size, lack of uniformity in efficacy criteria, and relatively insufficient follow-up time. Future research should pay more attention to the application of evidence-based medicine methods, strengthen the discussion of mechanisms of action, and try to establish more individualized intervention plans.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106279"},"PeriodicalIF":5.5,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Fucosylated chondroitin sulfate (FCS) is a sulfated polysaccharide derived from the marine organism Apostichopus japonicus. This study aimed to investigate its neuroprotective potential, specifically focusing on microglial modulation and ERK1/2 signaling, in Alzheimer's disease (AD) models.
Methods: An integrated in vitro and in vivo approach was employed. In vitro, Aβ42-stimulated BV2 microglia were treated with FCS, and the broad protein kinase C activator TPA was used as a pharmacological perturbation to examine whether the FCS-associated ERK1/2 signaling changes were reversible. Cytokine levels, microglial phenotype markers (CD86, CD206, iNOS, Arg-1), Aβ handling, and MAPK pathway proteins (p-ERK1/2, p38, JNK) were analyzed. In vivo, 5xFAD transgenic mice received intraperitoneal FCS for 28 days. Aβ plaque burden, soluble/insoluble Aβ levels, cognitive performance (Morris water maze, Y-maze), cortical Iba1-positive cell counts, activation state (Iba1+CD86+, Iba1+CD206+), and expression of p-ERK1/2, iNOS, and Arg-1 were assessed.
Results: In vitro, FCS attenuated Aβ42-induced pro-inflammatory responses (reduced IL-6, TNF-α; increased IL-10), modulated phenotype (decreased CD86/iNOS; increased CD206/Arg-1), and increased the cell-associated Aβ fraction while reducing supernatant Aβ. FCS reduced Aβ42-associated ERK1/2 phosphorylation and the nuclear-to-cytoplasmic p-ERK1/2 fluorescence signal ratio, and these changes were partially attenuated by TPA. In vivo, FCS treatment reduced cerebral Aβ burden, improved spatial and working memory, decreased the number and proportion of cortical Iba1+CD86+ microglia, and increased the Iba1+CD206+ subset. Cortical p-ERK1/2/total ERK1/2 and iNOS expression were downregulated, while Arg-1 was upregulated.
Conclusion: FCS reduced Aβ-related pathological burden, improved selected behavioral outcomes, and modulated microglia-associated inflammatory and phenotype-related readouts in AD models. These effects were accompanied by ERK1/2-related signaling changes, supporting a pathway-associated interpretation rather than definitive proof of ERK1/2 causality in vivo.
{"title":"Fucosylated Chondroitin Sulfate Modulates Microglia-Associated Responses and Reduces Aβ Burden with ERK1/2-Related Signaling Changes.","authors":"Xiaodan Xiao, Feng Gao, Jiaxing Xie, Yongkeng Lu, Kaizhao Lv, Huiyu Mo, Jiaxin Chen, Jianqi Liu, Qiguang Meng, Yanfei Guan, Qingzhuang Chen","doi":"10.1016/j.neuint.2026.106278","DOIUrl":"https://doi.org/10.1016/j.neuint.2026.106278","url":null,"abstract":"<p><strong>Introduction: </strong>Fucosylated chondroitin sulfate (FCS) is a sulfated polysaccharide derived from the marine organism Apostichopus japonicus. This study aimed to investigate its neuroprotective potential, specifically focusing on microglial modulation and ERK1/2 signaling, in Alzheimer's disease (AD) models.</p><p><strong>Methods: </strong>An integrated in vitro and in vivo approach was employed. In vitro, Aβ42-stimulated BV2 microglia were treated with FCS, and the broad protein kinase C activator TPA was used as a pharmacological perturbation to examine whether the FCS-associated ERK1/2 signaling changes were reversible. Cytokine levels, microglial phenotype markers (CD86, CD206, iNOS, Arg-1), Aβ handling, and MAPK pathway proteins (p-ERK1/2, p38, JNK) were analyzed. In vivo, 5xFAD transgenic mice received intraperitoneal FCS for 28 days. Aβ plaque burden, soluble/insoluble Aβ levels, cognitive performance (Morris water maze, Y-maze), cortical Iba1-positive cell counts, activation state (Iba1<sup>+</sup>CD86<sup>+</sup>, Iba1<sup>+</sup>CD206<sup>+</sup>), and expression of p-ERK1/2, iNOS, and Arg-1 were assessed.</p><p><strong>Results: </strong>In vitro, FCS attenuated Aβ42-induced pro-inflammatory responses (reduced IL-6, TNF-α; increased IL-10), modulated phenotype (decreased CD86/iNOS; increased CD206/Arg-1), and increased the cell-associated Aβ fraction while reducing supernatant Aβ. FCS reduced Aβ42-associated ERK1/2 phosphorylation and the nuclear-to-cytoplasmic p-ERK1/2 fluorescence signal ratio, and these changes were partially attenuated by TPA. In vivo, FCS treatment reduced cerebral Aβ burden, improved spatial and working memory, decreased the number and proportion of cortical Iba1<sup>+</sup>CD86<sup>+</sup> microglia, and increased the Iba1<sup>+</sup>CD206<sup>+</sup> subset. Cortical p-ERK1/2/total ERK1/2 and iNOS expression were downregulated, while Arg-1 was upregulated.</p><p><strong>Conclusion: </strong>FCS reduced Aβ-related pathological burden, improved selected behavioral outcomes, and modulated microglia-associated inflammatory and phenotype-related readouts in AD models. These effects were accompanied by ERK1/2-related signaling changes, supporting a pathway-associated interpretation rather than definitive proof of ERK1/2 causality in vivo.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106278"},"PeriodicalIF":5.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-06-01Epub Date: 2026-04-15DOI: 10.1016/j.neuint.2026.106154
Emadeldin M Kamel, Sally Mostafa Khadrawy, Mohamed A M Ali, Noha A Ahmed, Nour Y S Yassin, Saleh Alkhedhairi, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi
Polyglutamine-binding protein 1 (PQBP1) has emerged as a multifaceted regulator of gene expression, acting not only in the nucleus to influence transcription and splicing but also in the cytoplasm to control protein synthesis. A recent discovery identified a direct interaction between PQBP1 and the translation elongation factor eEF2, unveiling a new checkpoint in the elongation phase of protein synthesis. PQBP1 binds preferentially to the non-phosphorylated form of eEF2 and protects it from phosphorylation at Thr56 by its kinase eEF2K. Through this mechanism, PQBP1 promotes continuous elongation under conditions where unchecked eEF2K activity would otherwise stall ribosomes. The PQBP1-eEF2 complex plays critical roles in maintaining global proteome homeostasis and enabling activity-dependent protein synthesis in neurons. Disruption of this protein-protein interaction (PPI), whether by genetic mutations in PQBP1 or by sequestration of PQBP1 in cellular aggregates, has been linked to pathological states ranging from intellectual disability and impaired synaptic plasticity to altered innate immune responses and possibly tumorigenesis. In this review, we summarize the current understanding of the PQBP1-eEF2 interaction, its structural basis and regulation, the physiological processes it governs, and the consequences of its disruption in disease. We also discuss therapeutic considerations - when stabilizing this interaction might be beneficial (e.g. to restore synaptic function in neurodegeneration) versus when inhibiting it could be advantageous (e.g. to dampen excessive translation in cancer). Finally, we highlight experimental strategies and open questions for future research on this newly recognized nexus of translation control.
聚谷氨酰胺结合蛋白1 （Polyglutamine-binding protein 1, PQBP1）作为基因表达的多层面调控因子，不仅在细胞核中影响转录和剪接，还在细胞质中控制蛋白质合成。最近的一项发现确定了PQBP1和翻译延伸因子eEF2之间的直接相互作用，揭示了蛋白质合成延伸阶段的新检查点。PQBP1优先结合eEF2的非磷酸化形式，并通过其激酶eEF2K保护其免受Thr56位点的磷酸化。通过这一机制，PQBP1在eEF2K活性不受抑制的情况下促进了核糖体的持续延伸。PQBP1-eEF2复合物在维持全球蛋白质组稳态和激活神经元活性依赖性蛋白合成中起关键作用。这种蛋白-蛋白相互作用（PPI）的破坏，无论是通过PQBP1的基因突变还是通过PQBP1在细胞聚集体中的隔离，都与智力残疾、突触可塑性受损、先天免疫反应改变和可能的肿瘤发生等病理状态有关。在这篇综述中，我们总结了目前对PQBP1-eEF2相互作用的理解，它的结构基础和调控，它所控制的生理过程，以及它在疾病中的破坏后果。我们还讨论了治疗方面的考虑——什么时候稳定这种相互作用可能是有益的（例如，在神经退行性疾病中恢复突触功能），什么时候抑制这种相互作用可能是有利的（例如，抑制癌症中的过度翻译）。最后，我们强调了实验策略和开放的问题，为未来的研究这一新认识的联系翻译控制。
{"title":"Disrupting PQBP1-eEF2 protein-protein interaction: From synaptic translation to immunity and cancer.","authors":"Emadeldin M Kamel, Sally Mostafa Khadrawy, Mohamed A M Ali, Noha A Ahmed, Nour Y S Yassin, Saleh Alkhedhairi, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1016/j.neuint.2026.106154","DOIUrl":"10.1016/j.neuint.2026.106154","url":null,"abstract":"<p><p>Polyglutamine-binding protein 1 (PQBP1) has emerged as a multifaceted regulator of gene expression, acting not only in the nucleus to influence transcription and splicing but also in the cytoplasm to control protein synthesis. A recent discovery identified a direct interaction between PQBP1 and the translation elongation factor eEF2, unveiling a new checkpoint in the elongation phase of protein synthesis. PQBP1 binds preferentially to the non-phosphorylated form of eEF2 and protects it from phosphorylation at Thr56 by its kinase eEF2K. Through this mechanism, PQBP1 promotes continuous elongation under conditions where unchecked eEF2K activity would otherwise stall ribosomes. The PQBP1-eEF2 complex plays critical roles in maintaining global proteome homeostasis and enabling activity-dependent protein synthesis in neurons. Disruption of this protein-protein interaction (PPI), whether by genetic mutations in PQBP1 or by sequestration of PQBP1 in cellular aggregates, has been linked to pathological states ranging from intellectual disability and impaired synaptic plasticity to altered innate immune responses and possibly tumorigenesis. In this review, we summarize the current understanding of the PQBP1-eEF2 interaction, its structural basis and regulation, the physiological processes it governs, and the consequences of its disruption in disease. We also discuss therapeutic considerations - when stabilizing this interaction might be beneficial (e.g. to restore synaptic function in neurodegeneration) versus when inhibiting it could be advantageous (e.g. to dampen excessive translation in cancer). Finally, we highlight experimental strategies and open questions for future research on this newly recognized nexus of translation control.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"196 ","pages":"106154"},"PeriodicalIF":5.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-20DOI: 10.1016/j.neuint.2026.106134
Seo Hyun Yoo , Dongyun Kim , Gyu-Bum Yeon , Jaeyeon Choi , Jaewook Lee , Dong-Wook Kim , Hyunggee Kim , Dae-Sung Kim
Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transformation is the metabolic shift that supports inflammatory signaling and cytokine production. Retinoic acid (RA) modulates immune responses in the peripheral system; however, its role in astrocyte reactivity remains poorly understood. In this study, we investigated alterations in RA metabolism using an in vitro model of reactive astrocytes derived from human pluripotent stem cells. Reactivity was induced by treatment with tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), collectively referred to as TIC, and characterized using comprehensive morphological, molecular and functional analyses. We found that the induced reactive astrocytes exhibited a marked downregulation of key biosynthetic enzymes in RA metabolism, leading to a net decrease in intracellular RA levels. Exogenous RA supplementation attenuated TIC-induced expression of pro- and anti-inflammatory mediators, including IL-6, IL-8, nitric oxide, IL-10, and TGFβ. Mechanistically, RA suppressed these inflammatory responses by inhibiting NF-κB activation, likely through upstream attenuation of ERK and p38 MAPK pathways via upregulation of MAPK phosphatase 1 (MKP-1). In neuron and TIC-treated astrocyte co-cultures, RA treatment reduced the density of cleaved caspase 3-positive apoptotic-like neurons, an effect accompanied by decreased nitric oxide levels. These observations coincided with the restoration of mitochondrial integrity and mitophagy. Taken together, these findings identify RA metabolism as a key regulatory node in astrocyte reactivity and suggest a potential therapeutic role for RA in neuroinflammatory conditions.
{"title":"Retinoic acid signaling regulates astrocyte reactivity by modulating MAPK/NF-κB pathways and mitochondrial integrity","authors":"Seo Hyun Yoo , Dongyun Kim , Gyu-Bum Yeon , Jaeyeon Choi , Jaewook Lee , Dong-Wook Kim , Hyunggee Kim , Dae-Sung Kim","doi":"10.1016/j.neuint.2026.106134","DOIUrl":"10.1016/j.neuint.2026.106134","url":null,"abstract":"<div><div>Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transformation is the metabolic shift that supports inflammatory signaling and cytokine production. Retinoic acid (RA) modulates immune responses in the peripheral system; however, its role in astrocyte reactivity remains poorly understood. In this study, we investigated alterations in RA metabolism using an <em>in vitro</em> model of reactive astrocytes derived from human pluripotent stem cells. Reactivity was induced by treatment with tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), collectively referred to as TIC, and characterized using comprehensive morphological, molecular and functional analyses. We found that the induced reactive astrocytes exhibited a marked downregulation of key biosynthetic enzymes in RA metabolism, leading to a net decrease in intracellular RA levels. Exogenous RA supplementation attenuated TIC-induced expression of pro- and anti-inflammatory mediators, including IL-6, IL-8, nitric oxide, IL-10, and TGFβ. Mechanistically, RA suppressed these inflammatory responses by inhibiting NF-κB activation, likely through upstream attenuation of ERK and p38 MAPK pathways via upregulation of MAPK phosphatase 1 (MKP-1). In neuron and TIC-treated astrocyte co-cultures, RA treatment reduced the density of cleaved caspase 3-positive apoptotic-like neurons, an effect accompanied by decreased nitric oxide levels. These observations coincided with the restoration of mitochondrial integrity and mitophagy. Taken together, these findings identify RA metabolism as a key regulatory node in astrocyte reactivity and suggest a potential therapeutic role for RA in neuroinflammatory conditions.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106134"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-03DOI: 10.1016/j.neuint.2026.106123
Aurora Patti , Cristiana Lucia Rita Lipari , Armando Genazzani , Maria Angela Sortino , Sara Merlo
Multiple factors contribute to the physiopathology of inflammatory bowel diseases (IBD) and the enteric nervous system is emerging as a key player in this context. In particular, enteric glial cells (EGCs) share very similar properties with central astrocytes, play a homeostatic function under basal conditions, but can be activated by inflammatory stimuli further contributing to mucosal damage. Calcineurin (CN) is an important mediator of astrocyte inflammation and has been described also in EGCs. The aim of this study was to establish an in vitro model of EGCs challenged with an inflammatory insult to better delineate the role of CN in their inflammatory reaction and interaction with immune cells. EGCs stimulated with LPS + ATP (5 μg/mL-2 mM) for 24 h showed typical inflammatory features with increased expression of the astrocyte marker GFAP, the inflammasome component NLRP3 and the alarmin HMGB1. Inhibition of CN by cyclosporin A (CsA, 1 μM) counteracted these effects and increased the expression of nuclear HMGB1. Nuclear translocation of NF-κB p65 induced by LPS + ATP was also blunted by CsA pre-treatment. The migration of RAW 264.7 macrophages co-cultured with LPS + ATP-stimulated EGCs was enhanced, an effect prevented by CsA. This was accompanied by activation of macrophages to a pro-inflammatory phenotype, as shown by increased COX-2, IL-1β and TNF-α gene expression. Inhibition of CN in EGCs reduced this response while increasing the phagocytic capacity of macrophages. Altogether the results here reported identify a central role for CN in the inflammatory response of EGCs and their crosstalk with cells of the immune system, supporting potential new sites of intervention for drugs targeting CN.
{"title":"Calcineurin inhibition mitigates activation of enteric glia in vitro and affects their crosstalk with macrophages","authors":"Aurora Patti , Cristiana Lucia Rita Lipari , Armando Genazzani , Maria Angela Sortino , Sara Merlo","doi":"10.1016/j.neuint.2026.106123","DOIUrl":"10.1016/j.neuint.2026.106123","url":null,"abstract":"<div><div>Multiple factors contribute to the physiopathology of inflammatory bowel diseases (IBD) and the enteric nervous system is emerging as a key player in this context. In particular, enteric glial cells (EGCs) share very similar properties with central astrocytes, play a homeostatic function under basal conditions, but can be activated by inflammatory stimuli further contributing to mucosal damage. Calcineurin (CN) is an important mediator of astrocyte inflammation and has been described also in EGCs. The aim of this study was to establish an <em>in vitro</em> model of EGCs challenged with an inflammatory insult to better delineate the role of CN in their inflammatory reaction and interaction with immune cells. EGCs stimulated with LPS + ATP (5 μg/mL-2 mM) for 24 h showed typical inflammatory features with increased expression of the astrocyte marker GFAP, the inflammasome component NLRP3 and the alarmin HMGB1. Inhibition of CN by cyclosporin A (CsA, 1 μM) counteracted these effects and increased the expression of nuclear HMGB1. Nuclear translocation of NF-κB p65 induced by LPS + ATP was also blunted by CsA pre-treatment. The migration of RAW 264.7 macrophages co-cultured with LPS + ATP-stimulated EGCs was enhanced, an effect prevented by CsA. This was accompanied by activation of macrophages to a pro-inflammatory phenotype, as shown by increased COX-2, IL-1β and TNF-α gene expression. Inhibition of CN in EGCs reduced this response while increasing the phagocytic capacity of macrophages. Altogether the results here reported identify a central role for CN in the inflammatory response of EGCs and their crosstalk with cells of the immune system, supporting potential new sites of intervention for drugs targeting CN.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106123"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-18DOI: 10.1016/j.neuint.2026.106133
Yu-long Zhao , Hui-yuan Yi , Xue-mei Hou , Xiao-chen La , Sani Sa'idu Baba , Yi-xiao Guo , Rong-rong Yao , Xiao-cui Yuan , Qi-rui Zhang , Hong Jia , Yu-ying Wang , Fu-quan Huo
Neuropathic pain is frequently comorbid with depression, which exacerbates patient suffering and complicates clinical management. Although the ventrolateral orbital cortex (VLO) is involved in pain processing and emotional regulation, its specific role in neuropathic pain-induced depression remains unclear. Emerging evidence implicates 5-HT1A receptors in modulating both pain and mood disorders via GABAergic transmission, yet their specific contributions in the VLO are not fully understood. Here, we aimed to investigate whether and how VLO 5-HT1A receptors mediate depressive-like behaviors associated with neuropathic pain in male rats. Using a spared nerve injury (SNI) model, combined with neuropharmacological, chemogenetic, and cell-type-specific adeno-associated virus (AAV) approaches, we found that activating VLO 5-HT1A receptor produced dose-dependent antidepressant effects, which were blocked by a selective antagonist. Mechanistically, 5-HT1A receptor-mediated antidepressant effects were enhanced by a GABAA receptor antagonist and suppressed by a GABAA receptor agonist. Chemogenetic activation of VLO GABAergic neurons abolished the antidepressant effects of 5-HT1A receptor stimulation. Furthermore, SNI-induced depressive-like behaviors correlated with reduced 5-HT1A receptor expression in the VLO. AAV-mediated 5-HT1A receptor overexpression specifically on GABAergic neurons alleviated depressive-like behaviors in SNI rats, while knockdown induced depressive-like phenotypes in wild-type rats. In conclusion, our findings demonstrate that 5-HT1A receptors in the VLO alleviate neuropathic pain-induced depressive-like behaviors through a GABAergic disinhibition mechanism. This study highlights 5-HT1A receptors in the VLO as promising therapeutic targets for mood disturbances associated with neuropathic pain, offering a cortical framework for comorbid pain-depression pathophysiology.
{"title":"Activation of 5-HT1A receptors in the ventrolateral orbital cortex alleviates neuropathic pain-induced depressive-like behaviors via GABAergic neurons in male rats","authors":"Yu-long Zhao , Hui-yuan Yi , Xue-mei Hou , Xiao-chen La , Sani Sa'idu Baba , Yi-xiao Guo , Rong-rong Yao , Xiao-cui Yuan , Qi-rui Zhang , Hong Jia , Yu-ying Wang , Fu-quan Huo","doi":"10.1016/j.neuint.2026.106133","DOIUrl":"10.1016/j.neuint.2026.106133","url":null,"abstract":"<div><div>Neuropathic pain is frequently comorbid with depression, which exacerbates patient suffering and complicates clinical management. Although the ventrolateral orbital cortex (VLO) is involved in pain processing and emotional regulation, its specific role in neuropathic pain-induced depression remains unclear. Emerging evidence implicates 5-HT<sub>1A</sub> receptors in modulating both pain and mood disorders via GABAergic transmission, yet their specific contributions in the VLO are not fully understood. Here, we aimed to investigate whether and how VLO 5-HT<sub>1A</sub> receptors mediate depressive-like behaviors associated with neuropathic pain in male rats. Using a spared nerve injury (SNI) model, combined with neuropharmacological, chemogenetic, and cell-type-specific adeno-associated virus (AAV) approaches, we found that activating VLO 5-HT<sub>1A</sub> receptor produced dose-dependent antidepressant effects, which were blocked by a selective antagonist. Mechanistically, 5-HT<sub>1A</sub> receptor-mediated antidepressant effects were enhanced by a GABA<sub>A</sub> receptor antagonist and suppressed by a GABA<sub>A</sub> receptor agonist. Chemogenetic activation of VLO GABAergic neurons abolished the antidepressant effects of 5-HT<sub>1A</sub> receptor stimulation. Furthermore, SNI-induced depressive-like behaviors correlated with reduced 5-HT<sub>1A</sub> receptor expression in the VLO. AAV-mediated 5-HT<sub>1A</sub> receptor overexpression specifically on GABAergic neurons alleviated depressive-like behaviors in SNI rats, while knockdown induced depressive-like phenotypes in wild-type rats. In conclusion, our findings demonstrate that 5-HT<sub>1A</sub> receptors in the VLO alleviate neuropathic pain-induced depressive-like behaviors through a GABAergic disinhibition mechanism. This study highlights 5-HT<sub>1A</sub> receptors in the VLO as promising therapeutic targets for mood disturbances associated with neuropathic pain, offering a cortical framework for comorbid pain-depression pathophysiology.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106133"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146256939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-13DOI: 10.1016/j.neuint.2026.106125
Nashanthea J. Roland, Johnny W. Zigmond, Jane E. Manganaro, L. Daniel Estrella, Kelly L. Stauch
Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.
{"title":"APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice","authors":"Nashanthea J. Roland, Johnny W. Zigmond, Jane E. Manganaro, L. Daniel Estrella, Kelly L. Stauch","doi":"10.1016/j.neuint.2026.106125","DOIUrl":"10.1016/j.neuint.2026.106125","url":null,"abstract":"<div><div>Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106125"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-16DOI: 10.1016/j.neuint.2026.106130
Yasmin Tarek Anderson, Katherine Priest, Jason Zastre
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitamin B1 (thiamine) supplementation has demonstrated cognitive benefits in clinical AD studies, however, the mechanisms underlying thiamine's neuroprotective effects remain unclear. Here, we investigated whether thiamine mitigates Aβ1-42-induced neurotoxicity by suppressing hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional stress factor regulating many proapoptotic and progressive amyloidogenic pathways. Exposure of neuronal cells to Aβ1-42 oligomers increased reactive oxygen species (ROS) accumulation, decreased intracellular Fe2+, and induced HIF-1α stabilization. HIF-1α activation by Aβ1-42 promoted apoptosis through increased endoplasmic reticulum (ER) stress and increased mitochondrial dimerization of BNIP3. Thiamine supplementation significantly reduced cellular ROS levels, preserved intracellular Fe2+ levels, and restored prolyl hydroxylase (PHD) activity to promote HIF-1α hydroxylation and degradation. Suppression of HIF-1α by thiamine attenuated ER and BNIP3-driven apoptotic pathways and preserved neuronal viability. Thiamine further mitigated HIF-1α-mediated amyloidogenic progression, limiting feedback toxicity caused by Aβ1-42. These results demonstrate that thiamine protects against Aβ1-42-mediated neurotoxicity by reducing ROS, preserving Fe2+, and inhibiting HIF-1α-driven pathological cascades. Overall, this study identified a novel mechanism for thiamine's neuroprotective role, further supporting its therapeutic potential to limit neurodegenerative progression in AD.
{"title":"Vitamin B1 protects against Aβ1-42-induced HIF-1α activation and neurotoxicity","authors":"Yasmin Tarek Anderson, Katherine Priest, Jason Zastre","doi":"10.1016/j.neuint.2026.106130","DOIUrl":"10.1016/j.neuint.2026.106130","url":null,"abstract":"<div><div>Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and extensive neuronal loss, largely driven by amyloid beta (Aβ) accumulation and associated cellular stress. Vitamin B1 (thiamine) supplementation has demonstrated cognitive benefits in clinical AD studies, however, the mechanisms underlying thiamine's neuroprotective effects remain unclear. Here, we investigated whether thiamine mitigates Aβ<sub>1-42</sub>-induced neurotoxicity by suppressing hypoxia-inducible factor-1 alpha (HIF-1α), a transcriptional stress factor regulating many proapoptotic and progressive amyloidogenic pathways. Exposure of neuronal cells to Aβ<sub>1-42</sub> oligomers increased reactive oxygen species (ROS) accumulation, decreased intracellular Fe<sup>2+</sup>, and induced HIF-1α stabilization. HIF-1α activation by Aβ<sub>1-42</sub> promoted apoptosis through increased endoplasmic reticulum (ER) stress and increased mitochondrial dimerization of BNIP3. Thiamine supplementation significantly reduced cellular ROS levels, preserved intracellular Fe<sup>2+</sup> levels, and restored prolyl hydroxylase (PHD) activity to promote HIF-1α hydroxylation and degradation. Suppression of HIF-1α by thiamine attenuated ER and BNIP3-driven apoptotic pathways and preserved neuronal viability. Thiamine further mitigated HIF-1α-mediated amyloidogenic progression, limiting feedback toxicity caused by Aβ<sub>1-42</sub>. These results demonstrate that thiamine protects against Aβ<sub>1-42</sub>-mediated neurotoxicity by reducing ROS, preserving Fe<sup>2+</sup>, and inhibiting HIF-1α-driven pathological cascades. Overall, this study identified a novel mechanism for thiamine's neuroprotective role, further supporting its therapeutic potential to limit neurodegenerative progression in AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106130"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-17DOI: 10.1016/j.neuint.2026.106131
Siqi Liu , Yan Cheng , Xiaolei Zhang , Yuanyu Shen , Shuohua Wu , Yue Chen , Dafa Shi , Caiyu Zhuang , Beibei Chen , Yazhi Zhong , Xinxin Wang , Yaqi Wen , Xinhui Zheng , Yanlong Jia , Jitian Guan , Gen Yan , Renhua Wu
Electromagnetic fields (EMFs) have been shown to be beneficial in treating Alzheimer's disease (AD), but the underlying neurophysiological mechanisms remain unclear. It has been proposed that EMF promotes GABAergic neurogenesis and that abnormal GABA levels are an important influence on the progression of AD. To achieve in vivo GABA-weighted imaging in the brain in APP/PS1 mice, we utilized variable delay multi-pulse (VDMP)-chemical exchange saturation transfer (CEST)- magnetic resonance imaging (MRI) and pathological validation to measure GABA levels in APP/PS1 mice under microwave EMF and explore the therapeutic mechanism. The APP/PS1 mice received a 4-week microwave EMF treatment. The findings show that microwave EMF stimulation significantly increased GABA-weighted signals on MRI of APP/PS1 mouse hippocampus. VDMP-CEST was sensitive in detecting GABA-weighted signals. ELISA showed that microwave EMF stimulation elevated GABA levels in the hippocampus. Compared to in vitro levels, VDMP-CEST accurately detected GABA-weighted signal changes. With the pathological validations, we found that microwave EMF exposure can elevate hippocampal GABA levels by promoting AQP4 polarizion, reducing Aβ accumulation and neuronal degeneration, improving cognitive impairment, and may have slowed AD progression. Collectively, microwave EMF treatment could increase GABA-related changes, which corresponded to the accumulation of Aβ and improvement in the water maze. VDMP-CEST detected levels are highly consistent with pathological evidence, implying that VDMP-CEST is an effective modality for in vivo GABA-weighted imaging during microwave EMF treatment, providing more objective imaging-based diagnostic evidence for monitoring GABA-related pathological changes in AD.
{"title":"Assessing effects of microwave electromagnetic field in APP/PS1 mice by in vivo GABA-weighted imaging via variable delay multipulse-chemical exchange saturation transfer MRI","authors":"Siqi Liu , Yan Cheng , Xiaolei Zhang , Yuanyu Shen , Shuohua Wu , Yue Chen , Dafa Shi , Caiyu Zhuang , Beibei Chen , Yazhi Zhong , Xinxin Wang , Yaqi Wen , Xinhui Zheng , Yanlong Jia , Jitian Guan , Gen Yan , Renhua Wu","doi":"10.1016/j.neuint.2026.106131","DOIUrl":"10.1016/j.neuint.2026.106131","url":null,"abstract":"<div><div>Electromagnetic fields (EMFs) have been shown to be beneficial in treating Alzheimer's disease (AD), but the underlying neurophysiological mechanisms remain unclear. It has been proposed that EMF promotes GABAergic neurogenesis and that abnormal GABA levels are an important influence on the progression of AD. To achieve in vivo GABA-weighted imaging in the brain in APP/PS1 mice, we utilized variable delay multi-pulse (VDMP)-chemical exchange saturation transfer (CEST)- magnetic resonance imaging (MRI) and pathological validation to measure GABA levels in APP/PS1 mice under microwave EMF and explore the therapeutic mechanism. The APP/PS1 mice received a 4-week microwave EMF treatment. The findings show that microwave EMF stimulation significantly increased GABA-weighted signals on MRI of APP/PS1 mouse hippocampus. VDMP-CEST was sensitive in detecting GABA-weighted signals. ELISA showed that microwave EMF stimulation elevated GABA levels in the hippocampus. Compared to in vitro levels, VDMP-CEST accurately detected GABA-weighted signal changes. With the pathological validations, we found that microwave EMF exposure can elevate hippocampal GABA levels by promoting AQP4 polarizion, reducing Aβ accumulation and neuronal degeneration, improving cognitive impairment, and may have slowed AD progression. Collectively, microwave EMF treatment could increase GABA-related changes, which corresponded to the accumulation of Aβ and improvement in the water maze. VDMP-CEST detected levels are highly consistent with pathological evidence, implying that VDMP-CEST is an effective modality for in vivo GABA-weighted imaging during microwave EMF treatment, providing more objective imaging-based diagnostic evidence for monitoring GABA-related pathological changes in AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106131"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson's disease (PD) entails dopaminergic neuronal loss in a gradual manner, which is typically linked to oxidative stress, neuroinflammation, and the neurotransmitter homeostasis disruption. This research compares the neurochemical and neuroprotective impacts of lauric acid (LA), ribose-cysteine (RC), and levodopa (LD) in a transgenic Drosophila melanogaster model where human α-synuclein (α-syn) was expressed in dopaminergic neurons. The transgenic flies received treatment with LA, RC, or LD (250 mg/kg diet) for three weeks and were then evaluated by behavioral assays in conjunction with biochemical and molecular analyses of redox status, inflammatory and apoptotic signaling, neurotransmitter levels, and dopaminergic gene expression. Expression of α-syn caused significant deficiencies of locomotor behavior, oxidative damage, activation of neuroinflammation, changes of dopamine, GABA, and glutamate levels, and reduction of dopa decarboxylase expression. All interventions led to substantial increments in behavioral outcomes and oxidative stress status when compared to untreated PD flies. Out of the three treatments, the RC-induced effects on total antioxidant capacity and cell viability were most notable, along with reduction of lipid peroxidation, TNF-α, and caspase-3 activity. LD was the best at restoring locomotor performance and dopamine levels, whereas LA and RC were more potent at apoptotic signaling reduction and dopaminergic gene expression enhancement. Overall, RC effected broader neurochemical modulation than LA across most parameters. The results from this study suggest that LA, RC, and LD have different yet complementary neuroprotective effects in α-syn-induced neurotoxicity and that RC is particularly effective in modulating oxidative and inflammatory pathways that are involved in PD pathophysiology.
{"title":"Comparative neurochemical and neuroprotective effects of lauric acid, ribose-cysteine, and levodopa in an α-synuclein Drosophila model of Parkinson's disease","authors":"Olumayowa Kolawole Idowu , Ademola Ayodele Oremosu , Olufunke Olubusola Dosumu","doi":"10.1016/j.neuint.2026.106135","DOIUrl":"10.1016/j.neuint.2026.106135","url":null,"abstract":"<div><div>Parkinson's disease (PD) entails dopaminergic neuronal loss in a gradual manner, which is typically linked to oxidative stress, neuroinflammation, and the neurotransmitter homeostasis disruption. This research compares the neurochemical and neuroprotective impacts of lauric acid (LA), ribose-cysteine (RC), and levodopa (LD) in a transgenic <em>Drosophila melanogaster</em> model where human α-synuclein (α-syn) was expressed in dopaminergic neurons. The transgenic flies received treatment with LA, RC, or LD (250 mg/kg diet) for three weeks and were then evaluated by behavioral assays in conjunction with biochemical and molecular analyses of redox status, inflammatory and apoptotic signaling, neurotransmitter levels, and dopaminergic gene expression. Expression of α-syn caused significant deficiencies of locomotor behavior, oxidative damage, activation of neuroinflammation, changes of dopamine, GABA, and glutamate levels, and reduction of dopa decarboxylase expression. All interventions led to substantial increments in behavioral outcomes and oxidative stress status when compared to untreated PD flies. Out of the three treatments, the RC-induced effects on total antioxidant capacity and cell viability were most notable, along with reduction of lipid peroxidation, TNF-α, and caspase-3 activity. LD was the best at restoring locomotor performance and dopamine levels, whereas LA and RC were more potent at apoptotic signaling reduction and dopaminergic gene expression enhancement. Overall, RC effected broader neurochemical modulation than LA across most parameters. The results from this study suggest that LA, RC, and LD have different yet complementary neuroprotective effects in α-<em>syn</em>-induced neurotoxicity and that RC is particularly effective in modulating oxidative and inflammatory pathways that are involved in PD pathophysiology.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"194 ","pages":"Article 106135"},"PeriodicalIF":4.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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