Pub Date : 2024-10-13DOI: 10.1016/j.brainres.2024.149277
Yolanda Cruz-Martínez , Karla Cantú , Gerardo Ojeda , Vanessa Gálvez-Susano , Stella Arias-Santiago , Andrea P. Ibarra-García , Cesar V. Borlongan , Humberto Carrasco-Vargas , Marco Antonio Vargas-Hernández , Antonio Ibarra
Stroke is a major global health issue, ranking as the second leading cause of death and the primary cause of disability worldwide. However, current therapeutic options remain limited. Nutritional supplementation as a form of primary prevention stands as a potential stroke therapeutic. In particular, the intake of omega-3 fatty acids (omega-3FA) exerts anti-inflammatory and neuroprotective effects that help reduce the risk of stroke. In parallel, treatment with Copolymer-1 (COP-1), a peptide with immunomodulatory properties through Th1/Th2/Th3 phenotype switching, similarly affords neuroprotective and neurorestorative effects in stroke models. To investigate the combined effects of these treatments, we designed a two-phase therapy: the first phase involved preventive supplementation with omega-3FA, while the second phase included COP-1 immunization following stroke injury. Sprague-Dawley rats were randomly assigned to one of the four groups: 1) control, 2) omega-3FA, 3) COP-1, and 4) omega-3FA + COP-1. Omega-3FAs were administered for 28 days before inducing stroke. Thirty minutes after reperfusion, the respective groups were immunized with COP-1. Seven days post-stroke, neurological deficits were assessed using the Zea-Longa scale, infarct volumes with 2,3,5-triphenyltetrazolium chloride (TTC) staining, and levels of neurogenesis via immunofluorescence imaging. The results showed that the two-phase therapy produced significant synergistic effects, markedly reducing neurological deficits, and infarct volumes, while enhancing neurogenic activities in neurogenic niches. This combined approach underscores the potential of integrating nutritional and pharmacological strategies to enhance stroke recovery.
{"title":"Two-phase therapy for improving neuroprotection and neurogenesis: Preventive use of omega fatty acids plus Copolymer-1 immunization after stroke","authors":"Yolanda Cruz-Martínez , Karla Cantú , Gerardo Ojeda , Vanessa Gálvez-Susano , Stella Arias-Santiago , Andrea P. Ibarra-García , Cesar V. Borlongan , Humberto Carrasco-Vargas , Marco Antonio Vargas-Hernández , Antonio Ibarra","doi":"10.1016/j.brainres.2024.149277","DOIUrl":"10.1016/j.brainres.2024.149277","url":null,"abstract":"<div><div>Stroke is a major global health issue, ranking as the second leading cause of death and the primary cause of disability worldwide. However, current therapeutic options remain limited. Nutritional supplementation as a form of primary prevention stands as a potential stroke therapeutic. In particular, the intake of omega-3 fatty acids (omega-3FA) exerts anti-inflammatory and neuroprotective effects that help reduce the risk of stroke. In parallel, treatment with Copolymer-1 (COP-1), a peptide with immunomodulatory properties through Th1/Th2/Th3 phenotype switching, similarly affords neuroprotective and neurorestorative effects in stroke models. To investigate the combined effects of these treatments, we designed a two-phase therapy: the first phase involved preventive supplementation with omega-3FA, while the second phase included COP-1 immunization following stroke injury. Sprague-Dawley rats were randomly assigned to one of the four groups: 1) control, 2) omega-3FA, 3) COP-1, and 4) omega-3FA + COP-1. Omega-3FAs were administered for 28 days before inducing stroke. Thirty minutes after reperfusion, the respective groups were immunized with COP-1. Seven days post-stroke, neurological deficits were assessed using the Zea-Longa scale, infarct volumes with 2,3,5-triphenyltetrazolium chloride (TTC) staining, and levels of neurogenesis via immunofluorescence imaging. The results showed that the two-phase therapy produced significant synergistic effects, markedly reducing neurological deficits, and infarct volumes, while enhancing neurogenic activities in neurogenic niches. This combined approach underscores the potential of integrating nutritional and pharmacological strategies to enhance stroke recovery.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149277"},"PeriodicalIF":2.7,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-13DOI: 10.1016/j.brainres.2024.149279
Li Li , Li Ren , Bing Li , Chaomeng Liu
Major depressive disorder adversely affects mental health. Traditional therapeutic approaches, including medication, psychological intervention, and physical therapy, exert beneficial effects on depression. However, these approaches are associated with some limitations, such as high cost, adverse reactions, recurrent episodes, and low patient adherence. Previous studies have demonstrated that exercise therapy can effectively mitigate depressive symptoms, although the underlying mechanism has not been elucidated. Recent studies have suggested that depression is a microglial disease. Microglia regulate the inflammatory response, synaptic plasticity, neurogenesis, kynurenine pathway and the activation of hypothalamic-pituitary-adrenal axis, all of which affect depression. Exercise therapy is reported to shift the balance of microglial M1/M2 polarization in the hippocampus, frontal lobe, and striatum, suppressing the release of pro-inflammatory factors and consequently alleviating behavioral deficits in animal models of depression. Further studies are needed to examine the specific effects of different exercise regimens on microglia to identify the exercise regimen with the best therapeutic effect.
{"title":"Therapeutic effects of exercise on depression: The role of microglia","authors":"Li Li , Li Ren , Bing Li , Chaomeng Liu","doi":"10.1016/j.brainres.2024.149279","DOIUrl":"10.1016/j.brainres.2024.149279","url":null,"abstract":"<div><div>Major depressive disorder<!--> <!-->adversely affects mental health. Traditional therapeutic approaches, including medication, psychological intervention, and physical therapy, exert beneficial effects on depression. However, these approaches are associated with some limitations, such as high cost, adverse reactions, recurrent episodes, and low patient adherence. Previous studies have demonstrated that exercise therapy can effectively mitigate depressive symptoms, although the underlying mechanism has not been elucidated. Recent studies have suggested that depression is a microglial disease. Microglia regulate the inflammatory response, synaptic plasticity, neurogenesis, kynurenine pathway and the activation of hypothalamic-pituitary-adrenal axis, all of which affect depression. Exercise therapy is reported to shift the balance of microglial M1/M2 polarization in the hippocampus, frontal lobe, and striatum, suppressing the release of pro-inflammatory factors and consequently alleviating behavioral deficits in animal models of depression. Further studies are needed to examine the specific effects of different exercise regimens on microglia to identify the exercise regimen with the best therapeutic effect.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149279"},"PeriodicalIF":2.7,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.brainres.2024.149275
Jinyun Ma , Qijin Lu , Yan Zhao , Xiaohan Wang, Guiqing Ding, Yuanhua Wang, Xiaodong Cheng
The crosstalk between microglia inflamed in multiple sclerosis (MIMS) and astrocytes inflamed in MS (AIMS) is a crucial factor in the formation of the central inflammatory microenvironment and neurotoxicity. Astragalus polysaccharides (APS), an important bioactive component extracted from the dried root of Astragalus, was previously found by our team to attenuate the formation of pro-inflammatory microglia and neurological dysfunction in the experimental autoimmune encephalomyelitis (EAE) mice, a classic model of MS. To investigate the effect of APS on the MIMS-AIMS crosstalk and its underlying mechanism, in this study, a mouse model of EAE and a co-culture model of microglia-astrocytes in vitro were established. It was discovered that APS can alleviate the neurological dysfunction of EAE mice and effectively inhibit the formation of MIMS and AIMS both in vivo and in vitro. Furthermore, it was found that APS can suppress the inflammatory factors of MIMS-AIMS crosstalk in EAE mice and the resulting neurotoxicity in vivo and in vitro. The Sema4D-PlexinB2 signaling is essential for MIMS-AIMS crosstalk and promotes CNS inflammation. We demonstrated that APS can inhibit this signaling in vivo and in vitro. Treatment of recombinant Sema4D protein on cultured astrocytes in vitro significantly increases pro-inflammatory and neurotoxic factors, while APS significantly inhibits them. Conversely, after knockdown of Sema4D expression in microglia, APS no longer improves the neurotoxicity from MIMS-AIMS crosstalk. Overall, these results indicate that APS may modulate MIMS-AIMS crosstalk via the Sema4D-PlexinB2 signaling. This study provides a scientific basis for APS as a potential treatment candidate for demyelinating diseases.
{"title":"Microglia-astrocyte crosstalk is regulated by Astragalus polysaccharides mediated through suppression of Sema4D-PlexinB2 signaling in experimental autoimmune encephalomyelitis","authors":"Jinyun Ma , Qijin Lu , Yan Zhao , Xiaohan Wang, Guiqing Ding, Yuanhua Wang, Xiaodong Cheng","doi":"10.1016/j.brainres.2024.149275","DOIUrl":"10.1016/j.brainres.2024.149275","url":null,"abstract":"<div><div>The crosstalk between microglia inflamed in multiple sclerosis (MIMS) and astrocytes inflamed in MS (AIMS) is a crucial factor in the formation of the central inflammatory microenvironment and neurotoxicity. Astragalus polysaccharides (APS), an important bioactive component extracted from the dried root of Astragalus, was previously found by our team to attenuate the formation of pro-inflammatory microglia and neurological dysfunction in the experimental autoimmune encephalomyelitis (EAE) mice, a classic model of MS. To investigate the effect of APS on the MIMS-AIMS crosstalk and its underlying mechanism, in this study, a mouse model of EAE and a co-culture model of microglia-astrocytes <em>in vitro</em> were established. It was discovered that APS can alleviate the neurological dysfunction of EAE mice and effectively inhibit the formation of MIMS and AIMS both <em>in vivo</em> and <em>in vitro</em>. Furthermore, it was found that APS can suppress the inflammatory factors of MIMS-AIMS crosstalk in EAE mice and the resulting neurotoxicity <em>in vivo</em> and <em>in vitro</em>. The Sema4D-PlexinB2 signaling is essential for MIMS-AIMS crosstalk and promotes CNS inflammation. We demonstrated that APS can inhibit this signaling <em>in vivo</em> and <em>in vitro</em>. Treatment of recombinant Sema4D protein on cultured astrocytes <em>in vitro</em> significantly increases pro-inflammatory and neurotoxic factors, while APS significantly inhibits them. Conversely, after knockdown of Sema4D expression in microglia, APS no longer improves the neurotoxicity from MIMS-AIMS crosstalk. Overall, these results indicate that APS may modulate MIMS-AIMS crosstalk via the Sema4D-PlexinB2 signaling. This study provides a scientific basis for APS as a potential treatment candidate for demyelinating diseases.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149275"},"PeriodicalIF":2.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.brainres.2024.149272
Lin Zhao , Dongdong Zhou , Xiaoqing He , Xinyu Peng , Jinhui Hu , Lingli Ma , Xinyi Liu , Wanqing Tao , Ran Chen , Zhenghao Jiang , Chenyu Zhang , Jing Liao , Jiaojiao Xiang , Qi Zeng , Linqi Dai , Qi Zhang , Su Hong , Wo Wang , Li Kuang
Objective
Adolescents with depression is characterized by high rates of recurrence and functional impairment, with a significant association with suicide risk. Antidepressants are commonly prescribed to treat depression, yet few reproducible neurobiological markers for depression and antidepressant treatment response have been identified. Therefore, discovering a stable and reliable neurobiological marker holds significant value for both the clinical diagnosis and treatment of depression in adolescents.
Methods
One hundred and seven patients with major depressive disorder (MDD group, 30 males, 77 females, mean age: 14.80 years), and 25 healthy subjects (HC group, 13 males, 12 females, mean age: 15.72 years) were recruited to perform a two-choice oddball task related to negative emotional cues. All participants completed a self-administered questionnaire to gather demographic information. A trained psychiatrist administered the Hamilton Depression Scale (HAMD-17) to assess depression severity. Of the 107 adolescents with depression, 61 received antidepressant medication for 8 weeks, and 61 of these patients were followed up. Multichannel EEG was recorded continuously from 64 scalp electrodes using the Curry 8 system. EEG signal preprocessing and analysis was performed offline using the EEGLAB toolbox in MATLAB. The ERP component characteristics associated with emotional processing were extracted from the difference waves and statistically analyzed.
Results
Adolescents with depression exhibited significantly larger P300 amplitudes than healthy controls in response to both neutral and negative emotional cues. Following sertraline treatment, both depression scores and P300 amplitudes decreased significantly in adolescents with depression. Moreover, a strong positive correlation was observed between changes in depression scores and changes in P300 amplitude in response to negative emotional cues before and after treatment.
Conclusions
Changes in neural reactivity to negative emotional stimuli among adolescents with depression can be selectively modulated by sertraline and are significantly associated with improvements in depressive symptoms.
Significance
Changes in P300 amplitude to negative emotional stimuli significantly correlate with treatment responsiveness to sertraline in adolescents with depression.
{"title":"Changes in P300 amplitude to negative emotional stimuli correlate with treatment responsiveness to sertraline in adolescents with depression","authors":"Lin Zhao , Dongdong Zhou , Xiaoqing He , Xinyu Peng , Jinhui Hu , Lingli Ma , Xinyi Liu , Wanqing Tao , Ran Chen , Zhenghao Jiang , Chenyu Zhang , Jing Liao , Jiaojiao Xiang , Qi Zeng , Linqi Dai , Qi Zhang , Su Hong , Wo Wang , Li Kuang","doi":"10.1016/j.brainres.2024.149272","DOIUrl":"10.1016/j.brainres.2024.149272","url":null,"abstract":"<div><h3>Objective</h3><div>Adolescents with depression is characterized by high rates of recurrence and functional impairment, with a significant association with suicide risk. Antidepressants are commonly prescribed to treat depression, yet few reproducible neurobiological markers for depression and antidepressant treatment response have been identified. Therefore, discovering a stable and reliable neurobiological marker holds significant value for both the clinical diagnosis and treatment of depression in adolescents.</div></div><div><h3>Methods</h3><div>One hundred and seven patients with major depressive disorder (MDD group, 30 males, 77 females, mean age: 14.80 years), and 25 healthy subjects (HC group, 13 males, 12 females, mean age: 15.72 years) were recruited to perform a two-choice oddball task related to negative emotional cues. All participants completed a self-administered questionnaire to gather demographic information. A trained psychiatrist administered the Hamilton Depression Scale (HAMD-17) to assess depression severity. Of the 107 adolescents with depression, 61 received antidepressant medication for 8 weeks, and 61 of these patients were followed up. Multichannel EEG was recorded continuously from 64 scalp electrodes using the Curry 8 system. EEG signal preprocessing and analysis was performed offline using the EEGLAB toolbox in MATLAB. The ERP component characteristics associated with emotional processing were extracted from the difference waves and statistically analyzed.</div></div><div><h3>Results</h3><div>Adolescents with depression exhibited significantly larger P300 amplitudes than healthy controls in response to both neutral and negative emotional cues. Following sertraline treatment, both depression scores and P300 amplitudes decreased significantly in adolescents with depression. Moreover, a strong positive correlation was observed between changes in depression scores and changes in P300 amplitude in response to negative emotional cues before and after treatment.</div></div><div><h3>Conclusions</h3><div>Changes in neural reactivity to negative emotional stimuli among adolescents with depression can be selectively modulated by sertraline and are significantly associated with improvements in depressive symptoms.</div></div><div><h3>Significance</h3><div>Changes in P300 amplitude to negative emotional stimuli significantly correlate with treatment responsiveness to sertraline in adolescents with depression.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149272"},"PeriodicalIF":2.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.brainres.2024.149261
Haolong Su , Gege Zhan , Yifang Lin , Lu Wang , Jie Jia , Lihua Zhang , Zhongxue Gan , Xiaoyang Kang
Different movement paradigms have varying effects on stroke rehabilitation, and their mechanisms of action on the brain are not fully understood. This study aims to investigate disparities in brain network and functional connectivity of three movement paradigms (active, motor imagery, passive) on stroke recovery. EEG signals were recorded from 11 S patients (SP) and 13 healthy controls (HC) during fist clenching and opening tasks under the three paradigms. Brain networks were constructed to analyze alterations in brain network connectivity, node strength (NS), clustering coefficients (CC), characteristic path length (CPL), and small-world index(S). Our findings revealed increased activity in the contralateral motor area in SP and higher activity in the ipsilateral motor area in HC. In the beta band, SP exhibited significantly higher CC in motor imagery (MI) than in active and passive tasks. Furthermore, the small world index of SP during MI tasks in the beta band was significantly smaller than in the active and passive tasks. NS in the gamma band for SP during the MI paradigm was significantly higher than in the active and passive paradigms. These findings suggest reorganization within both ipsilateral and contralateral motor areas of stroke patients during MI tasks, providing evidence for neural restructuring. Collectively, these findings contribute to a deeper understanding of task-state brain network changes and the rehabilitative mechanism of MI on motor function.
不同的运动范式对中风康复有不同的影响，而它们对大脑的作用机制还不完全清楚。本研究旨在探讨三种运动范式（主动、运动想象、被动）对脑卒中康复的脑网络和功能连接的差异。本研究记录了 11 名中风患者（SP）和 13 名健康对照组（HC）在三种范式下握拳和张开任务时的脑电信号。我们构建了脑网络，以分析脑网络连通性、节点强度（NS）、聚类系数（CC）、特征路径长度（CPL）和小世界指数（S）的变化。我们的研究结果显示，SP 对侧运动区的活动增加，而 HC 同侧运动区的活动增加。在β波段，SP在运动想象（MI）中表现出的CC明显高于主动和被动任务中的CC。此外，在贝塔波段的运动想象任务中，SP 的小世界指数明显小于主动和被动任务。MI范式中SP在伽马波段的NS明显高于主动和被动范式。这些研究结果表明，中风患者在进行MI任务时，同侧和对侧运动区都发生了重组，为神经重组提供了证据。总之，这些研究结果有助于加深对任务态脑网络变化和脑干损伤对运动功能的康复机制的理解。
{"title":"Analysis of brain network differences in the active, motor imagery, and passive stoke rehabilitation paradigms based on the task-state EEG","authors":"Haolong Su , Gege Zhan , Yifang Lin , Lu Wang , Jie Jia , Lihua Zhang , Zhongxue Gan , Xiaoyang Kang","doi":"10.1016/j.brainres.2024.149261","DOIUrl":"10.1016/j.brainres.2024.149261","url":null,"abstract":"<div><div>Different movement paradigms have varying effects on stroke rehabilitation, and their mechanisms of action on the brain are not fully understood. This study aims to investigate disparities in brain network and functional connectivity of three movement paradigms (active, motor imagery, passive) on stroke recovery. EEG signals were recorded from 11 S patients (SP) and 13 healthy controls (HC) during fist clenching and opening tasks under the three paradigms. Brain networks were constructed to analyze alterations in brain network connectivity, node strength (NS), clustering coefficients (CC), characteristic path length (CPL), and small-world index(S). Our findings revealed increased activity in the contralateral motor area in SP and higher activity in the ipsilateral motor area in HC. In the beta band, SP exhibited significantly higher CC in motor imagery (MI) than in active and passive tasks. Furthermore, the small world index of SP during MI tasks in the beta band was significantly smaller than in the active and passive tasks. NS in the gamma band for SP during the MI paradigm was significantly higher than in the active and passive paradigms. These findings suggest reorganization within both ipsilateral and contralateral motor areas of stroke patients during MI tasks, providing evidence for neural restructuring. Collectively, these findings contribute to a deeper understanding of task-state brain network changes and the rehabilitative mechanism of MI on motor function.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149261"},"PeriodicalIF":2.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ferroptosis is an iron-dependent form of programmed cell death associated with lipid peroxidation. Though diabetes worsens cerebral injury and clinical outcomes in stroke, it is poorly understood whether ferroptosis contributes to diabetes-exacerbated stroke. This study aimed to identify ferroptosis-associated differentially expressed genes in ischemic stroke under diabetic condition and then explore their roles using comprehensive bioinformatics analyses.
Methods
Type 1 diabetes (T1D) model was established in male mice at 8–10 weeks of age by one intraperitoneal injection of streptozotocin (110 mg/kg). Ischemic stroke was induced by a transient 45-minute middle cerebral artery occlusion and evaluated three days thereafter. Ischemic brain cortex was dissected 24 h after the reperfusion and subjected to bulk tissue RNA sequencing followed by bioinformatics analysis and verification of key findings via quantitative real-time PCR.
Results
Enlarged infarct size was seen in diabetic, as compared with non-diabetic mice, in conjunction with worsened neurological behaviors. Both body and spleen weights were reduced in diabetic as compared with non-diabetic mice. There was a trend for reduced survival rate in diabetic mice following the stroke. In RNA sequencing analysis, we identified 1299 differentially expressed genes in ischemic brain between diabetic and non-diabetic mice, with upregulation and downregulation for 732 and 567 genes, respectively. Among these genes, 27 genes were associated with ferroptosis. Further analysis reveals that solute carrier family 25 member 28(SLC25A28) and sterol carrier protein 2(SCP2) were the top genes associated with ferroptosis in diabetic mice following ischemic stroke. In several bioinformatics analyses, we found SLC25A28, one of the top ferroptosis-related genes, is involved in several metabolic and regulatory pathways as well as the regulatory complexity of microRNAs and circular RNAs, which demonstrates the potential role of SLC25A28 in diabetes-exacerbated stroke. Drug network analysis suggests SLC25A28 as a potential therapeutic target for ameliorating ischemic injury in diabetes.
Conclusions
Our bulk RNA sequencing and bioinformatics analyses show that altered ferroptosis signaling pathway was associated with the exacerbation of experimental stroke injury under diabetic condition. Especially, additional investigation into the mechanisms of SLC25A28 and SCP2 in diabetes-exacerbated stroke will be explored in the future study.
{"title":"Ferroptosis-associated alterations in diabetes following ischemic stroke: Insights from RNA sequencing","authors":"Ying Zhu , Qike Wu , Jiayi Guo , Baohui Xu , Heng Zhao , Cuiying Liu","doi":"10.1016/j.brainres.2024.149274","DOIUrl":"10.1016/j.brainres.2024.149274","url":null,"abstract":"<div><h3>Objective</h3><div>Ferroptosis is an iron-dependent form of programmed cell death associated with lipid peroxidation. Though diabetes worsens cerebral injury and clinical outcomes in stroke, it is poorly understood whether ferroptosis contributes to diabetes-exacerbated stroke. This study aimed to identify ferroptosis-associated differentially expressed genes in ischemic stroke under diabetic condition and then explore their roles using comprehensive bioinformatics analyses.</div></div><div><h3>Methods</h3><div>Type 1 diabetes (T1D) model was established in male mice at 8–10 weeks of age by one intraperitoneal injection of streptozotocin (110 mg/kg). Ischemic stroke was induced by a transient 45-minute middle cerebral artery occlusion and evaluated three days thereafter. Ischemic brain cortex was dissected 24 h after the reperfusion and subjected to bulk tissue RNA sequencing followed by bioinformatics analysis and verification of key findings via quantitative real-time PCR.</div></div><div><h3>Results</h3><div>Enlarged infarct size was seen in diabetic, as compared with non-diabetic mice, in conjunction with worsened neurological behaviors. Both body and spleen weights were reduced in diabetic as compared with non-diabetic mice. There was a trend for reduced survival rate in diabetic mice following the stroke. In RNA sequencing analysis, we identified 1299 differentially expressed genes in ischemic brain between diabetic and non-diabetic mice, with upregulation and downregulation for 732 and 567 genes, respectively. Among these genes, 27 genes were associated with ferroptosis. Further analysis reveals that solute carrier family 25 member 28(SLC25A28) and sterol carrier protein 2(SCP2) were the top genes associated with ferroptosis in diabetic mice following ischemic stroke. In several bioinformatics analyses, we found SLC25A28, one of the top ferroptosis-related genes, is involved in several metabolic and regulatory pathways as well as the regulatory complexity of microRNAs and circular RNAs, which demonstrates the potential role of SLC25A28 in diabetes-exacerbated stroke. Drug network analysis suggests SLC25A28 as a potential therapeutic target for ameliorating ischemic injury in diabetes.</div></div><div><h3>Conclusions</h3><div>Our bulk RNA sequencing and bioinformatics analyses show that altered ferroptosis signaling pathway was associated with the exacerbation of experimental stroke injury under diabetic condition. Especially, additional investigation into the mechanisms of SLC25A28 and SCP2 in diabetes-exacerbated stroke will be explored in the future study.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149274"},"PeriodicalIF":2.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1016/j.brainres.2024.149265
Jinwei Lang , Li-Zhuang Yang , Hai Li
The networks observed in the brain during resting-state activity are not entirely “task-free.” Instead, they hint at a hierarchical structure prepared for adaptive cognitive functions. Recent studies have increasingly demonstrated the potential of resting-state fMRI to predict local activations or global connectomes during task performance. However, uncertainties remain regarding the unique and shared task-specific components within resting-state brain networks, elucidating local activations and global connectome patterns. A coherent framework is also required to integrate these task-specific components to predict local activations and global connectome patterns. In this work, we introduce the Rest2Task model based on the partial least squares-based multivariate regression algorithm, which effectively integrates mappings from resting-state connectivity to local activations and global connectome patterns. By analyzing the coefficients of the regression model, we extracted task-specific resting-state components corresponding to brain local activation or global connectome of various tasks and applied them to the brain lateralization prediction and psychiatric disorders diagnostic. Our model effectively substitutes traditional whole-brain functional connectivity (FC) in predicting functional lateralization and diagnosing brain disorders. Our research represents the inaugural effort to quantify the contribution of patterns (components) within resting-state FC to different tasks, endowing these components with specific task-related contextual information. The task-specific resting-state components offer new insights into brain lateralization processing and disease diagnosis, potentially providing fresh perspectives on the adaptive transformation of brain networks in response to tasks.
{"title":"Rest2Task: Modeling task-specific components in resting-state functional connectivity and applications","authors":"Jinwei Lang , Li-Zhuang Yang , Hai Li","doi":"10.1016/j.brainres.2024.149265","DOIUrl":"10.1016/j.brainres.2024.149265","url":null,"abstract":"<div><div>The networks observed in the brain during resting-state activity are not entirely “task-free.” Instead, they hint at a hierarchical structure prepared for adaptive cognitive functions. Recent studies have increasingly demonstrated the potential of resting-state fMRI to predict local activations or global connectomes during task performance. However, uncertainties remain regarding the unique and shared task-specific components within resting-state brain networks, elucidating local activations and global connectome patterns. A coherent framework is also required to integrate these task-specific components to predict local activations and global connectome patterns. In this work, we introduce the Rest2Task model based on the partial least squares-based multivariate regression algorithm, which effectively integrates mappings from resting-state connectivity to local activations and global connectome patterns. By analyzing the coefficients of the regression model, we extracted task-specific resting-state components corresponding to brain local activation or global connectome of various tasks and applied them to the brain lateralization prediction and psychiatric disorders diagnostic. Our model effectively substitutes traditional whole-brain functional connectivity (FC) in predicting functional lateralization and diagnosing brain disorders. Our research represents the inaugural effort to quantify the contribution of patterns (components) within resting-state FC to different tasks, endowing these components with specific task-related contextual information. The task-specific resting-state components offer new insights into brain lateralization processing and disease diagnosis, potentially providing fresh perspectives on the adaptive transformation of brain networks in response to tasks.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149265"},"PeriodicalIF":2.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1016/j.brainres.2024.149271
Geoffrey P. Dobson, Jodie L. Morris, Hayley L. Letson
Severe traumatic brain injury (TBI) is a devastating injury with a mortality of ∼ 25–30 %. Despite decades of high-quality research, no drug therapy has reduced mortality. Why is this so? We argue two contributing factors for the lack of effective drug therapies include the use of specific-pathogen free (SPF) animals for translational research and the flawed practice of single-nodal targeting for drug design. A revolution is required to better understand how the whole body responds to TBI, identify new markers of its progression, and discover new system-acting drugs to treat it. In this review, we present a brief history of TBI, discuss its system’s pathophysiology and propose a new research strategy for the 21st century. TBI progression develops from injury signals radiating from the primary impact, which can cause local ischemia, hemorrhage, excitotoxicity, cellular depolarization, immune dysfunction, sympathetic hyperactivity, blood-brain barrier breach, coagulopathy and whole-body dysfunction. Metabolic reprograming of immune cells drives neuroinflammation and secondary injury processes. We propose if sympathetic hyperactivity and immune cell activation can be corrected early, cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored, and secondary injury minimized with improved patient outcomes. The therapeutic goal is to switch the injury phenotype to a healing phenotype by restoring homeostasis and maintaining sufficient tissue O2 delivery. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat TBI and have shown that it blunts the CNS-stress response, supports cardiovascular function and reduces secondary injury. Future research will investigate its suitability for human translation.
{"title":"Traumatic brain injury: Symptoms to systems in the 21st century","authors":"Geoffrey P. Dobson, Jodie L. Morris, Hayley L. Letson","doi":"10.1016/j.brainres.2024.149271","DOIUrl":"10.1016/j.brainres.2024.149271","url":null,"abstract":"<div><div>Severe traumatic brain injury (TBI) is a devastating injury with a mortality of ∼ 25–30 %. Despite decades of high-quality research, no drug therapy has reduced mortality. Why is this so? We argue two contributing factors for the lack of effective drug therapies include the use of specific-pathogen free (SPF) animals for translational research and the flawed practice of single-nodal targeting for drug design. A revolution is required to better understand how the whole body responds to TBI, identify new markers of its progression, and discover new system-acting drugs to treat it. In this review, we present a brief history of TBI, discuss its system’s pathophysiology and propose a new research strategy for the 21st century. TBI progression develops from injury signals radiating from the primary impact, which can cause local ischemia, hemorrhage, excitotoxicity, cellular depolarization, immune dysfunction, sympathetic hyperactivity, blood-brain barrier breach, coagulopathy and whole-body dysfunction. Metabolic reprograming of immune cells drives neuroinflammation and secondary injury processes. We propose if sympathetic hyperactivity and immune cell activation can be corrected early, cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored, and secondary injury minimized with improved patient outcomes. The therapeutic goal is to switch the injury phenotype to a healing phenotype by restoring homeostasis and maintaining sufficient tissue O<sub>2</sub> delivery. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat TBI and have shown that it blunts the CNS-stress response, supports cardiovascular function and reduces secondary injury. Future research will investigate its suitability for human translation.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149271"},"PeriodicalIF":2.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.brainres.2024.149270
Amanda Kunz Godói , Lara Canever , Eduardo Pacheco Rico , Gustavo Mastella , Marina Tonello , Natália Veadrigo , Beatriz de Bem Tomé , Isabela da Silva Lemos , Emílio Luiz Streck , Alexandra l. Zugno
The incidence of schizophrenia in young adulthood may be associated with intrauterine factors, such as gestational alcohol consumption. This study investigated the relationship between a single high dose of alcohol during pregnancy in Wistar rats and the development of schizophrenia in the adult life of the offspring. On the 11th day of gestation, pregnant rats received either water or alcohol via intragastric gavage. Male and female offspring were subjected to behavioral tests at 30 days of age according to the maternal group. At 60 days of age, offspring received intraperitoneal injections of ketamine (ket) or saline (SAL). After the final ketamine administration, the adult offspring underwent behavioral tests, and their brain structures were removed for biochemical analysis. Alcohol binge drinking during pregnancy induces hyperlocomotion in both young female and male offspring, with males of alcohol-exposed mothers showing reduced social interactions. In adult offspring, ketamine induced hyperlocomotion; however, only females in the alcohol + ket group exhibited increased locomotor activity, and a decrease in the time to first contact was observed in the alcohol group. Cognitive impairment was exclusively observed in male animals in the alcohol group. Increased serotonin and dopamine levels were observed in male rats in the alcohol + ket group. Biochemical alterations indicate the effects of intrauterine alcohol exposure associated with ketamine in adult animals. These behavioral and biochemical changes suggest that the impact of prenatal stressors such as alcohol persists throughout the animals’ lives and may be exacerbated by a second stressor in adulthood, such as ketamine.
{"title":"The relationship between alcohol bingeing in the gestational period of wistar rats and the development of schizophrenia in the offspring adult life","authors":"Amanda Kunz Godói , Lara Canever , Eduardo Pacheco Rico , Gustavo Mastella , Marina Tonello , Natália Veadrigo , Beatriz de Bem Tomé , Isabela da Silva Lemos , Emílio Luiz Streck , Alexandra l. Zugno","doi":"10.1016/j.brainres.2024.149270","DOIUrl":"10.1016/j.brainres.2024.149270","url":null,"abstract":"<div><div>The incidence of schizophrenia in young adulthood may be associated with intrauterine factors, such as gestational alcohol consumption. This study investigated the relationship between a single high dose of alcohol during pregnancy in Wistar rats and the development of schizophrenia in the adult life of the offspring. On the 11th day of gestation, pregnant rats received either water or alcohol via intragastric gavage. Male and female offspring were subjected to behavioral tests at 30 days of age according to the maternal group. At 60 days of age, offspring received intraperitoneal injections of ketamine (ket) or saline (SAL). After the final ketamine administration, the adult offspring underwent behavioral tests, and their brain structures were removed for biochemical analysis. Alcohol binge drinking during pregnancy induces hyperlocomotion in both young female and male offspring, with males of alcohol-exposed mothers showing reduced social interactions. In adult offspring, ketamine induced hyperlocomotion; however, only females in the alcohol + ket group exhibited increased locomotor activity, and a decrease in the time to first contact was observed in the alcohol group. Cognitive impairment was exclusively observed in male animals in the alcohol group. Increased serotonin and dopamine levels were observed in male rats in the alcohol + ket group. Biochemical alterations indicate the effects of intrauterine alcohol exposure associated with ketamine in adult animals. These behavioral and biochemical changes suggest that the impact of prenatal stressors such as alcohol persists throughout the animals’ lives and may be exacerbated by a second stressor in adulthood, such as ketamine.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149270"},"PeriodicalIF":2.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1016/j.brainres.2024.149269
Carlos J. Martínez-Magaña, Janet Murbartián
Several signaling pathways that converge in NF-kB activation have been linked to developing and maintaining different types of pathological pain. In addition, some mechanisms implied in the establishment of chronic pain have been demonstrated to have a sex-dependent correlation. This study aimed to determine if the IKKs/NF-kB signaling pathway is involved in establishing REM sleep deprivation (REMSD) induced mechanical allodynia in rats and its possible regulation depending on estradiol and estrogen receptors. Intrathecal administration of BMS-345541 or minocycline, two drugs that reduce the IKKs/NF-kB activity, avoided the development of mechanical allodynia in female but not in male rats subjected to 48 h of REMSD. Ovariectomy in female rats abolished the effect of BMS-345541 and minocycline. Meanwhile, the 17-β-estradiol restitution restored it. Intrathecal administration of MPP, a selective ERα antagonist, but not PHTPP, a selective ERβ antagonist, avoided the effect of BMS-345541 in female rats without hormonal manipulation. In addition, the transient run-down of ERα in female rats abolished the effect of BMS-345541. All data suggest an important role of ERα as a regulator of the IKKs/NF-kB activity. REMSD increased the ERα protein expression in the dorsal root ganglia and the dorsal spinal cord in females but not in male rats. Interestingly, ERα activation or ERα overexpression allowed the effect of BMS-345541 in male rats. Data suggest an important regulatory role of ERα in the IKKs/NF-kB activity on establishing mechanical allodynia induced by REMSD in female rats.
{"title":"Estrogen receptor α regulates the IKKs/NF-kB activity involved in the development of mechanical allodynia induced by REM sleep deprivation in rats","authors":"Carlos J. Martínez-Magaña, Janet Murbartián","doi":"10.1016/j.brainres.2024.149269","DOIUrl":"10.1016/j.brainres.2024.149269","url":null,"abstract":"<div><div>Several signaling pathways that converge in NF-kB activation have been linked to developing and maintaining different types of pathological pain. In addition, some mechanisms implied in the establishment of chronic pain have been demonstrated to have a sex-dependent correlation. This study aimed to determine if the IKKs/NF-kB signaling pathway is involved in establishing REM sleep deprivation (REMSD) induced mechanical allodynia in rats and its possible regulation depending on estradiol and estrogen receptors. Intrathecal administration of BMS-345541 or minocycline, two drugs that reduce the IKKs/NF-kB activity, avoided the development of mechanical allodynia in female but not in male rats subjected to 48 h of REMSD. Ovariectomy in female rats abolished the effect of BMS-345541 and minocycline. Meanwhile, the 17-β-estradiol restitution restored it. Intrathecal administration of MPP, a selective ERα antagonist, but not PHTPP, a selective ERβ antagonist, avoided the effect of BMS-345541 in female rats without hormonal manipulation. In addition, the transient run-down of ERα in female rats abolished the effect of BMS-345541. All data suggest an important role of ERα as a regulator of the IKKs/NF-kB activity. REMSD increased the ERα protein expression in the dorsal root ganglia and the dorsal spinal cord in females but not in male rats. Interestingly, ERα activation or ERα overexpression allowed the effect of BMS-345541 in male rats. Data suggest an important regulatory role of ERα in the IKKs/NF-kB activity on establishing mechanical allodynia induced by REMSD in female rats.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1845 ","pages":"Article 149269"},"PeriodicalIF":2.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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