Pub Date : 2024-12-31DOI: 10.1016/j.brainres.2024.149442
He Li , Ying Li , Yingju Wang , Yuchen Sheng
Artemisinin (ART), a natural product isolated from the traditional Chinese plant Artemisia annua L., has shown neuroprotective properties in addition to its well-established antimalarial activities. This study investigates the therapeutic effect of ART in ischemic stroke (IS) and delves into its functional mechanism. Bioinformatics analyses revealed lysine demethylase 1A (KDM1A) as a promising target of ART aberrantly overexpressed in the context of IS. Increased KDM1A expression was detected in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons and transient middle cerebral artery occlusion (tMCAO)-challenged mice. Treatment with ART reduced KDM1A protein level, thus protecting mouse hippocampal neurons from OGD/R-induced oxidative stress and apoptosis. In vivo, ART reduced infarct size, reduced brain content, enhanced neurological function, and enhanced neuronal survival in tMCAO. Regarding the downstream cascade, KDM1A was found to repress transcription of sphingosine kinase 2 (SPHK2) by removing H3K4me2 modification near the SPHK2 promoter. Either KDM1A overexpression or SPHK2 knockdown abrogated the neuroprotective effects of ART. The ample evidence of this study suggests that ART fulfills neuroprotective functions in the context of IS by protecting SPHK2 from KDM1A-mediated transcription repression, highlighting ART as a promising regimen for the treatment of IS.
{"title":"Neuronal protective effect of Artemisinin in ischemic stroke: Achieved by blocking lysine demethylase 1A-mediated demethylation of sphingosine kinase 2","authors":"He Li , Ying Li , Yingju Wang , Yuchen Sheng","doi":"10.1016/j.brainres.2024.149442","DOIUrl":"10.1016/j.brainres.2024.149442","url":null,"abstract":"<div><div>Artemisinin (ART), a natural product isolated from the traditional Chinese plant <em>Artemisia annua</em> L., has shown neuroprotective properties in addition to its well-established antimalarial activities. This study investigates the therapeutic effect of ART in ischemic stroke (IS) and delves into its functional mechanism. Bioinformatics analyses revealed lysine demethylase 1A (KDM1A) as a promising target of ART aberrantly overexpressed in the context of IS. Increased KDM1A expression was detected in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons and transient middle cerebral artery occlusion (tMCAO)-challenged mice. Treatment with ART reduced KDM1A protein level, thus protecting mouse hippocampal neurons from OGD/R-induced oxidative stress and apoptosis. <em>In vivo</em>, ART reduced infarct size, reduced brain content, enhanced neurological function, and enhanced neuronal survival in tMCAO. Regarding the downstream cascade, KDM1A was found to repress transcription of sphingosine kinase 2 (SPHK2) by removing H3K4me2 modification near the SPHK2 promoter. Either KDM1A overexpression or SPHK2 knockdown abrogated the neuroprotective effects of ART. The ample evidence of this study suggests that ART fulfills neuroprotective functions in the context of IS by protecting SPHK2 from KDM1A-mediated transcription repression, highlighting ART as a promising regimen for the treatment of IS.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1849 ","pages":"Article 149442"},"PeriodicalIF":2.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920689","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 : 2024-12-30DOI: 10.1016/j.brainres.2024.149434
Karim Johari, Fatemeh Tabari
Transient disruption or permanent damage to the left Frontal Aslant Tract (FAT) is associated with deficits in speech production. The present study examined the application of theta (4 Hz) high-definition transcranial alternating current stimulation (HD-tACS) over the left SMA and IFG –as a part of FAT- as a potential multisite protocol to modulate neural and behavioral correlates of speech motor control. Twenty-one young adults participated in three counterbalanced sessions in which they received in-phase, anti-phase, and sham theta HD-tACS. In each session, 4 Hz stimulation was applied over the left IFG and SMA, and subsequently EEG data was recorded while participants performed a speech Go/No-Go task. Relative to sham and anti-phase, in-phase HD-tACS significantly improved speech reaction time. Neural data showed an increase in the power of frontal theta activity prior to speech initiation for the in-phase condition compared to sham. Moreover, in-phase stimulation increased the phase synchrony of theta activity between the left central and frontal electrodes. For speech inhibition, the power of theta activity increased following the in-phase condition over frontocentral electrodes. Furthermore, the in-phase condition enhanced the connectivity between the left central and frontal electrodes. Overall findings suggest that in-phase theta HD-tACS of FAT enhanced the neural markers of cognitive control required for motor preparation and inhibition during a speech task and have translational implications.
{"title":"HD-tACS over the left frontal aslant tract entrains theta activity associated with speech motor control","authors":"Karim Johari, Fatemeh Tabari","doi":"10.1016/j.brainres.2024.149434","DOIUrl":"10.1016/j.brainres.2024.149434","url":null,"abstract":"<div><div>Transient disruption or permanent damage to the left Frontal Aslant Tract (FAT) is associated with deficits in speech production. The present study examined the application of theta (4 Hz) high-definition transcranial alternating current stimulation (HD-tACS) over the left SMA and IFG –as a part of FAT- as a potential multisite protocol to modulate neural and behavioral correlates of speech motor control. Twenty-one young adults participated in three counterbalanced sessions in which they received in-phase, anti-phase, and sham theta HD-tACS. In each session, 4 Hz stimulation was applied over the left IFG and SMA, and subsequently EEG data was recorded while participants performed a speech Go/No-Go task. Relative to sham and anti-phase, in-phase HD-tACS significantly improved speech reaction time. Neural data showed an increase in the power of frontal theta activity prior to speech initiation for the in-phase condition compared to sham. Moreover, in-phase stimulation increased the phase synchrony of theta activity between the left central and frontal electrodes. For speech inhibition, the power of theta activity increased following the in-phase condition over frontocentral electrodes. Furthermore, the in-phase condition enhanced the connectivity between the left central and frontal electrodes. Overall findings suggest that in-phase theta HD-tACS of FAT enhanced the neural markers of cognitive control required for motor preparation and inhibition during a speech task and have translational implications.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1850 ","pages":"Article 149434"},"PeriodicalIF":2.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913845","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}
Chronic traumatic encephalopathy (CTE) has attracted attention due to sports-related head trauma or repetitive mild traumatic brain injury (mTBI). However, the pathology of CTE remains underexplored. Reproducible and quantitative model of CTE has yet to be established. The aim of this study is to establish a highly reproducible model of CTE with behavioral and histological manifestations. First, the pathological symptoms of mTBI with no intracranial hemorrhage or contusion using the weight drop model of 52 g ball from a height of 30 cm was determined using hematoxylin and eosin staining. Adult rats that received single, double, or triple head impacts were compared with sham behaviorally and histologically. Results revealed that rats exposed to repetitive mTBI showed motor impairment with gradual recovery over time, which was prolonged as the number of head impact increased. Similarly, cognitive function was impaired by repetitive mTBI and the recovery depended on the number of head impact. Histologically, GFAP positive astrocytes increased with repetitive mTBI, although Iba-1 positive microglial aggregation was limited. At 4w, phosphorylated Tau significantly accumulated in the prefrontal cortex, corpus callosum, CA1, and dentate gyrus of rats that received triple mTBI, compared to sham or those exposed to single, or double mTBI. This repetitive mTBI rat model provides a highly reproducible and quantifiable brain and behavioral pathology reminiscent of CTE.
{"title":"Repeated non-hemorrhagic and non-contusional mild traumatic brain injury in rats elicits behavioral impairment with microglial activation, astrogliosis, and tauopathy: Reproducible and quantitative model of chronic traumatic encephalopathy","authors":"Chiaki Sugahara , Kyohei Kin , Tatsuya Sasaki , Susumu Sasada , Satoshi Kawauchi , Satoru Yabuno , Takayuki Nagase , Takahiro Hirayama , Kaori Masai , Kakeru Hosomoto , Yosuke Okazaki , Koji Kawai , Shun Tanimoto , Yuichi Hirata , Hayato Miyake , Hiromichi Naito , Takao Yasuhara , Cesar V Borlongan , Isao Date , Shota Tanaka","doi":"10.1016/j.brainres.2024.149412","DOIUrl":"10.1016/j.brainres.2024.149412","url":null,"abstract":"<div><div>Chronic traumatic encephalopathy (CTE) has attracted attention due to sports-related head trauma or repetitive mild traumatic brain injury (mTBI). However, the pathology of CTE remains underexplored. Reproducible and quantitative model of CTE has yet to be established. The aim of this study is to establish a highly reproducible model of CTE with behavioral and histological manifestations. First, the pathological symptoms of mTBI with no intracranial hemorrhage or contusion using the weight drop model of 52 g ball from a height of 30 cm was determined using hematoxylin and eosin staining. Adult rats that received single, double, or triple head impacts were compared with sham behaviorally and histologically. Results revealed that rats exposed to repetitive mTBI showed motor impairment with gradual recovery over time, which was prolonged as the number of head impact increased. Similarly, cognitive function was impaired by repetitive mTBI and the recovery depended on the number of head impact. Histologically, GFAP positive astrocytes increased with repetitive mTBI, although Iba-1 positive microglial aggregation was limited. At 4w, phosphorylated Tau significantly accumulated in the prefrontal cortex, corpus callosum, CA1, and dentate gyrus of rats that received triple mTBI, compared to sham or those exposed to single, or double mTBI. This repetitive mTBI rat model provides a highly reproducible and quantifiable brain and behavioral pathology reminiscent of CTE.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1850 ","pages":"Article 149412"},"PeriodicalIF":2.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913846","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 : 2024-12-28DOI: 10.1016/j.brainres.2024.149435
Yuanruhua Tian , Wenke Li , Yongbo Zhang
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) and leading to cellular senescence and cognitive deficits. Cellular senescence contributes significantly to the pathogenesis of AD through the senescence-associated secretory phenotype (SASP), exacerbating Aβ deposition. This study investigates the protective effects of 3-N-Butylphthalide (NBP), a compound derived from Apium graveolens Linn (Chinese celery), on Aβ-induced cellular senescence in U87 cells. Using RNA-sequencing and biochemical assays, we demonstrate that NBP ameliorate Aβ oligomer-induced cellular senescence and apoptosis, and regulated the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) and components of the cyclin-dependent kinase 2 (CDK2)- phosphorylated retinoblastoma 1 (pRB1)-Caspase3 pathway. Moreover, NBP was shown to suppress the expression of SASP-related genes. These findings suggest that NBP rescues U87 cells from Aβ oligomer-induced senescence and apoptosis through modulating the CDK2-pRB1-Caspase3 axis and SASP expression. Our results underscore the potential of NBP as a senostatic agent for AD which have not been reported in previous studies, offering insights into its mechanisms of action and paving the way for future studies on its efficacy in vivo and in clinical settings. Thus, we contribute to growing evidence supporting the use of senolytic and senostatic agents in the treatment of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是淀粉样蛋白- β (a β)的积累，并导致细胞衰老和认知缺陷。细胞衰老通过衰老相关分泌表型（senescence associated secretory phenotype， SASP）加剧了Aβ的沉积，对AD的发病机制起着重要作用。本文研究了从芹菜中提取的化合物3- n -丁基酞（NBP）对a β诱导的U87细胞衰老的保护作用。通过rna测序和生化分析，我们证明NBP改善了Aβ寡聚物诱导的细胞衰老和凋亡，并调节细胞周期蛋白依赖性激酶抑制剂2A （CDKN2A）和细胞周期蛋白依赖性激酶2 (CDK2)-磷酸化视网膜母细胞瘤1 (pRB1)- caspase3通路组分的表达。此外，NBP还能抑制sasp相关基因的表达。这些结果表明，NBP通过调节CDK2-pRB1-Caspase3轴和SASP表达，使U87细胞免于Aβ寡聚物诱导的衰老和凋亡。我们的研究结果强调了NBP作为一种在以前的研究中未被报道过的AD的静感药物的潜力，提供了对其作用机制的见解，并为其在体内和临床环境中的有效性的未来研究铺平了道路。因此，我们提供了越来越多的证据支持使用抗衰老和抗感药物治疗AD。
{"title":"3-N-Butylphthalide alleviate Aβ-induced cellular senescence through the CDK2-pRB1-Caspase3 axis","authors":"Yuanruhua Tian , Wenke Li , Yongbo Zhang","doi":"10.1016/j.brainres.2024.149435","DOIUrl":"10.1016/j.brainres.2024.149435","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) and leading to cellular senescence and cognitive deficits. Cellular senescence contributes significantly to the pathogenesis of AD through the senescence-associated secretory phenotype (SASP), exacerbating Aβ deposition. This study investigates the protective effects of 3-N-Butylphthalide (NBP), a compound derived from Apium graveolens Linn (Chinese celery), on Aβ-induced cellular senescence in U87 cells. Using RNA-sequencing and biochemical assays, we demonstrate that NBP ameliorate Aβ oligomer-induced cellular senescence and apoptosis, and regulated the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A) and components of the cyclin-dependent kinase 2 (CDK2)- phosphorylated retinoblastoma 1 (pRB1)-Caspase3 pathway. Moreover, NBP was shown to suppress the expression of SASP-related genes. These findings suggest that NBP rescues U87 cells from Aβ oligomer-induced senescence and apoptosis through modulating the CDK2-pRB1-Caspase3 axis and SASP expression. Our results underscore the potential of NBP as a senostatic agent for AD which have not been reported in previous studies, offering insights into its mechanisms of action and paving the way for future studies on its efficacy in vivo and in clinical settings. Thus, we contribute to growing evidence supporting the use of senolytic and senostatic agents in the treatment of AD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1849 ","pages":"Article 149435"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906493","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 : 2024-12-28DOI: 10.1016/j.brainres.2024.149437
Binbin Wang , Miao Ling , Chao Guo , Shengqiao Sun , Xingnan Zhang , Chenhao Hu , Hanjie Liu , Dezhi Li , Michael Schumacher , Binbin Sui , Song Liu
Objective
Peripheral nerve injury results in functional alterations of the corresponding active brain areas, which are closely related to functional recovery. Whether such functional plasticity induces relative anatomical structural changes remains to be investigated.
Methods
In this study, we investigated the changes in brain cortical thickness in patients with facial paralysis following neurorrhaphy treatment at different follow-up times. Using magnetic resonance imaging (MRI) and the CAT12 toolbox, voxel-based whole-brain morphometric (VBM) analysis and region of interest (ROI) of cortical thickness estimation were performed in 11 patients with left facial paralysis before and after hypoglossal-facial nerve neurorrhaphy, and the results were compared to those of 20 healthy controls. All subjects were right-handed and had a left dominant hemisphere. Based on the ROIs, correlation analysis among the cortical structural changes, the House–Brackmann (H-B) grading scale and the compound muscle action potential (cMAP) amplitudes of the facial paralyzed/reinnervated muscles in the patients was conducted.
Results
The results show dynamic changes in the thickness in the contralateral right cortex at corresponding functional areas in patients. The thickness of the ROIs was negatively correlated with the duration of facial paralysis from onset to neurorrhaphy but was positively correlated with the improvement in H-B grades and cMAP wave amplitudes recorded in the paralyzed/reinnervated facial muscles of patients. Interestingly, a significant increase in cortical thickness was observed in the ipsilateral left cortex of patients before surgery. However, the increased thickness of the left cortex was then gradually decreased and returned to the reference level of healthy controls following neurorrhaphy and reinnervation of paralyzed facial muscles.
Conclusion
We concluded that dynamic changes in both sides of the brain cortex could reflect the state and effect of functional recovery in patients from the onset of facial paralysis before treatment to reinnervation and the return of lost function following neurorrhaphy, suggesting potential observation and treatment targets to predict prognosis and further promote functional recovery.
{"title":"Structural remodeling of the brain cortex and functional recovery following hypoglossal-facial neurorrhaphy in patients with facial paralysis","authors":"Binbin Wang , Miao Ling , Chao Guo , Shengqiao Sun , Xingnan Zhang , Chenhao Hu , Hanjie Liu , Dezhi Li , Michael Schumacher , Binbin Sui , Song Liu","doi":"10.1016/j.brainres.2024.149437","DOIUrl":"10.1016/j.brainres.2024.149437","url":null,"abstract":"<div><h3>Objective</h3><div>Peripheral nerve injury results in functional alterations of the corresponding active brain areas, which are closely related to functional recovery. Whether such functional plasticity induces relative anatomical structural changes remains to be investigated.</div></div><div><h3>Methods</h3><div>In this study, we investigated the changes in brain cortical thickness in patients with facial paralysis following neurorrhaphy treatment at different follow-up times. Using magnetic resonance imaging (MRI) and the CAT12 toolbox, voxel-based whole-brain morphometric (VBM) analysis and region of interest (ROI) of cortical thickness estimation were performed in 11 patients with left facial paralysis before and after hypoglossal-facial nerve neurorrhaphy, and the results were compared to those of 20 healthy controls. All subjects were right-handed and had a left dominant hemisphere. Based on the ROIs, correlation analysis among the cortical structural changes, the House–Brackmann (H-B) grading scale and the compound muscle action potential (cMAP) amplitudes of the facial paralyzed/reinnervated muscles in the patients was conducted.</div></div><div><h3>Results</h3><div>The results show dynamic changes in the thickness in the contralateral right cortex at corresponding functional areas in patients. The thickness of the ROIs was negatively correlated with the duration of facial paralysis from onset to neurorrhaphy but was positively correlated with the improvement in H-B grades and cMAP wave amplitudes recorded in the paralyzed/reinnervated facial muscles of patients. Interestingly, a significant increase in cortical thickness was observed in the ipsilateral left cortex of patients before surgery. However, the increased thickness of the left cortex was then gradually decreased and returned to the reference level of healthy controls following neurorrhaphy and reinnervation of paralyzed facial muscles.</div></div><div><h3>Conclusion</h3><div>We concluded that dynamic changes in both sides of the brain cortex could reflect the state and effect of functional recovery in patients from the onset of facial paralysis before treatment to reinnervation and the return of lost function following neurorrhaphy, suggesting potential observation and treatment targets to predict prognosis and further promote functional recovery.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1849 ","pages":"Article 149437"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906520","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 : 2024-12-28DOI: 10.1016/j.brainres.2024.149436
Zhaoxu Zhang , Shuangmei Zhang , Shen Liu , Yang He , Anrong Wang
Background
Maintaining autophagic homeostasis has been proved to play an important role in Alzheimer’s disease.
Object
The aim of this study was to investigate the effect of Fuzhisan(FZS) on autophagic function in Alzheimer’s disease and to elucidate its potential mechanism through the P62 regulatory pathways.
Methods
FZS was extracted by water extraction-rotary evaporation method. The novel object recognition test, morris water maze test and Y maze test were used to observe the cognitive and memory ability of APP/PS1 mice. The effects of FZS on the ultrastructure of mice hippocampus were examined by transmission electron microscopy. Molecular level changes were also further detected, including Aβ deposition, tau hyperphosphorylation, SOD, CAT and autophagy related proteins (p62, Nrf2, keap1, mTOR, LC3II/I, Beclin1, Atgs).
Results
FZS could alleviate memory and cognitive impairment in APP/PS1 mice, increase the autophagic vesicles and organelle abundance in hippocampus. FZS also reduced the levels of Aβ and tau hyperphosphorylation in the hippocampus of model mice, upregulated the levels of SOD, CAT and autophagy related proteins (Nrf2, LC3II/LC3I, Beclin1, Atg7 and Atg12) as well as downregulated the expression of P62, keap1 and p-mTOR/mTOR proteins. Co-Ip results showed that FZS elevated the levels of p62/LC3 and P62-keap1-Nrf2 complex, but decreased the P62 and keap1 association.
Conclusion
Our findings indicate that FZS may affect autophagy function and oxidative stress by regulating P62 and related pathways to promote the clearance of Aβ and phosphorylated tau, thereby improving the cognitive ability of AD, which provided a novel perspective for exploring the potential mechanism of FZS upon AD.
{"title":"Fuzhisan ameliorates cognitive ability in Alzheimer’s disease by p62 and related autophagy regulatory pathways","authors":"Zhaoxu Zhang , Shuangmei Zhang , Shen Liu , Yang He , Anrong Wang","doi":"10.1016/j.brainres.2024.149436","DOIUrl":"10.1016/j.brainres.2024.149436","url":null,"abstract":"<div><h3>Background</h3><div>Maintaining autophagic homeostasis has been proved to play an important role in Alzheimer’s disease.</div></div><div><h3>Object</h3><div>The aim of this study was to investigate the effect of Fuzhisan(FZS) on autophagic function in Alzheimer’s disease and to elucidate its potential mechanism through the P62 regulatory pathways.</div></div><div><h3>Methods</h3><div>FZS was extracted by water extraction-rotary evaporation method. The novel object recognition test, morris water maze test and Y maze test were used to observe the cognitive and memory ability of APP/PS1 mice. The effects of FZS on the ultrastructure of mice hippocampus were examined by transmission electron microscopy. Molecular level changes were also further detected, including Aβ deposition, tau hyperphosphorylation, SOD, CAT and autophagy related proteins (p62, Nrf2, keap1, mTOR, LC3II/I, Beclin1, Atgs).</div></div><div><h3>Results</h3><div>FZS could alleviate memory and cognitive impairment in APP/PS1 mice, increase the autophagic vesicles and organelle abundance in hippocampus. FZS also reduced the levels of Aβ and tau hyperphosphorylation in the hippocampus of model mice, upregulated the levels of SOD, CAT and autophagy related proteins (Nrf2, LC3II/LC3I, Beclin1, Atg7 and Atg12) as well as downregulated the expression of P62, keap1 and p-mTOR/mTOR proteins. Co-Ip results showed that FZS elevated the levels of p62/LC3 and P62-keap1-Nrf2 complex, but decreased the P62 and keap1 association.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that FZS may affect autophagy function and oxidative stress by regulating P62 and related pathways to promote the clearance of Aβ and phosphorylated tau, thereby improving the cognitive ability of AD, which provided a novel perspective for exploring the potential mechanism of FZS upon AD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1849 ","pages":"Article 149436"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906506","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 : 2024-12-26DOI: 10.1016/j.brainres.2024.149425
Jannik Nicklas Eliasen, Uffe Kristiansen, Kristi A. Kohlmeier
Psychedelics show promise in treating psychiatric disorders. Therapeutic effects appear to involve activation of the 5-Hydroxytryptamine 2A receptor (5-HT2AR), a G protein-coupled receptor (GPCR). Several SNPs of the 5-HT2AR naturally occur, which are associated with differences in receptor function and altered responsiveness to treatments. New compounds suspected to act at the 5-HT2AR are actively being generated. HEK cells are not commonly used to study membrane effects induced by agonists of GPCRs. In this study, for the first time, membrane actions of two psychedelics, dimethyltryptamine (DMT) and ibogaine on HEK cells transiently transfected with either the human wildtype (WT) or the human I197V mutated 5-HT2AR were investigated using whole-cell electrophysiology. Membrane effects were observed in both genotypes and with both drugs in most cells, while no responses were observed in non-transfected HEK cells suggesting that responses were due to 5-HT2AR activation. In HEK cells transfected with the I197V SNP, a significantly shorter duration of the DMT response was observed, however there were no differences in drug-elicited amplitudes between drug or receptor genotype. I-V curves showed a significant effect of drug exposure for both DMT and ibogaine at the highest concentration evaluated. Taken together, our data show transfection of the 5-HT2AR, a GPCR, in HEK cells is able to activate downstream ion channels following exposure to two different 5-HT2AR agonists. Accordingly, investigations of novel compounds suspected to act at 5-HT2ARs can include examination of elicitation of ionic currents in 5-HT2AR transfected HEK cells, and drug effects at SNPs can also be evaluated.
{"title":"Dimethyltryptamine (DMT) and ibogaine elicit membrane effects in HEK cells transiently transfected with the human 5-HT2A receptor","authors":"Jannik Nicklas Eliasen, Uffe Kristiansen, Kristi A. Kohlmeier","doi":"10.1016/j.brainres.2024.149425","DOIUrl":"10.1016/j.brainres.2024.149425","url":null,"abstract":"<div><div>Psychedelics show promise in treating psychiatric disorders. Therapeutic effects appear to involve activation of the 5-Hydroxytryptamine 2A receptor (5-HT<sub>2A</sub>R), a G protein-coupled receptor (GPCR). Several SNPs of the 5-HT<sub>2A</sub>R naturally occur, which are associated with differences in receptor function and altered responsiveness to treatments. New compounds suspected to act at the 5-HT<sub>2A</sub>R are actively being generated. HEK cells are not commonly used to study membrane effects induced by agonists of GPCRs. In this study, for the first time, membrane actions of two psychedelics, dimethyltryptamine (DMT) and ibogaine on HEK cells transiently transfected with either the human wildtype (WT) or the human I197V mutated 5-HT<sub>2A</sub>R were investigated using whole-cell electrophysiology. Membrane effects were observed in both genotypes and with both drugs in most cells, while no responses were observed in non-transfected HEK cells suggesting that responses were due to 5-HT<sub>2A</sub>R activation. In HEK cells transfected with the I197V SNP, a significantly shorter duration of the DMT response was observed, however there were no differences in drug-elicited amplitudes between drug or receptor genotype. I-V curves showed a significant effect of drug exposure for both DMT and ibogaine at the highest concentration evaluated. Taken together, our data show transfection of the 5-HT<sub>2A</sub>R, a GPCR, in HEK cells is able to activate downstream ion channels following exposure to two different 5-HT<sub>2A</sub>R agonists. Accordingly, investigations of novel compounds suspected to act at 5-HT<sub>2A</sub>Rs can include examination of elicitation of ionic currents in 5-HT<sub>2A</sub>R transfected HEK cells, and drug effects at SNPs can also be evaluated.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1850 ","pages":"Article 149425"},"PeriodicalIF":2.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892032","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}
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex etiology, including genetic and environmental factors. A growing body of evidence (preclinical and clinical studies) implicates a potential role of gut microbiome dysregulation in ASD pathophysiology. This review focuses on the microbial metabolite p-Cresol, produced by certain gut bacteria such as Clostridium, and its potential role in ASD. The review summarizes studies investigating the gut microbiome composition in ASD patients, particularly the increased abundance of Clostridium species and associated gastrointestinal symptoms. The potential neurotoxic effects of p-Cresol are explored, including its influence on neurotransmitter metabolism (especially dopamine), neuroinflammation, and brain development. The mechanistic findings from the preclinical studies of p-Cresol’s induction of ASD-like behaviors and its impact on the dopaminergic system are discussed. Literature studies indicated increased levels of p-Cresol in the urine of patients with ASD. This increasing evidence suggests that p-Cresol may serve as a crucial biomarker for understanding the relationship between gut microbiota and ASD, opening avenues for potential diagnostic and therapeutic interventions.
{"title":"Exploring the neurotoxic effects of microbial metabolites: A potential link between p-Cresol and autism spectrum disorders?","authors":"Mahi Basra , Lauren Miceli , Vatsala Mundra , Alison Stern-Harbutte , Hemangi Patel , Jenifer Haynes , Mayur S. Parmar","doi":"10.1016/j.brainres.2024.149427","DOIUrl":"10.1016/j.brainres.2024.149427","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex etiology, including genetic and environmental factors. A growing body of evidence (preclinical and clinical studies) implicates a potential role of gut microbiome dysregulation in ASD pathophysiology. This review focuses on the microbial metabolite p-Cresol, produced by certain gut bacteria such as <em>Clostridium</em>, and its potential role in ASD. The review summarizes studies investigating the gut microbiome composition in ASD patients, particularly the increased abundance of <em>Clostridium</em> species and associated gastrointestinal symptoms. The potential neurotoxic effects of p-Cresol are explored, including its influence on neurotransmitter metabolism (especially dopamine), neuroinflammation, and brain development. The mechanistic findings from the preclinical studies of p-Cresol’s induction of ASD-like behaviors and its impact on the dopaminergic system are discussed. Literature studies indicated increased levels of p-Cresol in the urine of patients with ASD. This increasing evidence suggests that p-Cresol may serve as a crucial biomarker for understanding the relationship between gut microbiota and ASD, opening avenues for potential diagnostic and therapeutic interventions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1850 ","pages":"Article 149427"},"PeriodicalIF":2.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892034","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 : 2024-12-25DOI: 10.1016/j.brainres.2024.149424
Yinglan Su , Qian Yuan
Background
Postoperative cognitive dysfunction (POCD) is a significant surgery-related complication marked by cognitive decline. Studies indicated that neuroinflammation, ferroptosis, and mitochondrial fatty acid metabolism might play parts in POCD, and might be mediated by Carnitine palmitoyl transferase 1a (CPT1A), but requires further investigations. Therefore, this study aims to investigate the mechanism of mitochondrial fatty acid oxidase CPT1A on mitochondrial function, ferroptosis, and inflammation in POCD pathogenesis.
Methods
SVG P12 astrocytes were used to investigate CPT1A’s control over mitochondrial function, ferroptosis, and inflammation affecting neurons. CPT1A was overexpressed using shRNA, with or without oligomycin to modulate mitochondrial function. Co-culture of these astrocytes with neurons, under similar conditions, assessed CPT1A’s impact on neuron damage via ferroptosis and inflammation. Gene and protein expressions of CPT1A, SYN, PSD95 were measured via RT-PCR and WB. Detection of JC-1, mitochondrial oxygen consumption rate (OCR), ROS, Fe2+ concentration, MOD, SOD and GSH/GSSG using kits was conducted to explore mitochondrial function and ferroptosis. Inflammation was quantified by ELISA for IL-6, IL-1β, and TGF-β.
Results
We successfully established CPT1A overexpression and knockdown models in astrocytes, confirming CPT1A’s ability to enhance mitochondrial membrane potential. Elevated CPT1A levels led to improved mitochondrial function, synaptic integrity, reduced oxidative stress, maintained iron homeostasis, and attenuated neuroinflammation, as reflected by increased SYN, PSD95, OCR, GSH and SOD, decreased ROS,GSSG, MDA, iron levels, and lowered inflammatory factors expression. Treatment with oligomycin reversed these protective effects, demonstrating the dependency of CPT1A’s benefits on intact mitochondrial respiration. In co-culture experiments with hippocampal neurons, astrocytes with manipulated CPT1A levels, particularly those co-treated with oligomycin, exacerbated neuronal mitochondrial dysfunction, oxidative stress, iron accumulation, and inflammation.
Conclusion
Overexpression of mitochondrial fatty acid oxidase CPT1A might improve synaptic integrity and rescue POCD by ameliorating astrocyte ferroptosis and neuroinflammation.
{"title":"Mitochondrial fatty acid oxidase CPT1A ameliorates postoperative cognitive dysfunction by regulating astrocyte ferroptosis","authors":"Yinglan Su , Qian Yuan","doi":"10.1016/j.brainres.2024.149424","DOIUrl":"10.1016/j.brainres.2024.149424","url":null,"abstract":"<div><h3>Background</h3><div>Postoperative cognitive dysfunction (POCD) is a significant surgery-related complication marked by cognitive decline. Studies indicated that neuroinflammation, ferroptosis, and mitochondrial fatty acid metabolism might play parts in POCD, and might be mediated by Carnitine palmitoyl transferase 1a (CPT1A), but requires further investigations. Therefore, this study aims to investigate the mechanism of mitochondrial fatty acid oxidase CPT1A on mitochondrial function, ferroptosis, and inflammation in POCD pathogenesis.</div></div><div><h3>Methods</h3><div>SVG P12 astrocytes were used to investigate CPT1A’s control over mitochondrial function, ferroptosis, and inflammation affecting neurons. CPT1A was overexpressed using shRNA, with or without oligomycin to modulate mitochondrial function. Co-culture of these astrocytes with neurons, under similar conditions, assessed CPT1A’s impact on neuron damage via ferroptosis and inflammation. Gene and protein expressions of CPT1A, SYN, PSD95 were measured via RT-PCR and WB. Detection of JC-1, mitochondrial oxygen consumption rate (OCR), ROS, Fe<sup>2+</sup> concentration, MOD, SOD and GSH/GSSG using kits was conducted to explore mitochondrial function and ferroptosis. Inflammation was quantified by ELISA for IL-6, IL-1β, and TGF-β.</div></div><div><h3>Results</h3><div>We successfully established CPT1A overexpression and knockdown models in astrocytes, confirming CPT1A’s ability to enhance mitochondrial membrane potential. Elevated CPT1A levels led to improved mitochondrial function, synaptic integrity, reduced oxidative stress, maintained iron homeostasis, and attenuated neuroinflammation, as reflected by increased SYN, PSD95, OCR, GSH and SOD, decreased ROS,GSSG, MDA, iron levels, and lowered inflammatory factors expression. Treatment with oligomycin reversed these protective effects, demonstrating the dependency of CPT1A’s benefits on intact mitochondrial respiration. In co-culture experiments with hippocampal neurons, astrocytes with manipulated CPT1A levels, particularly those co-treated with oligomycin, exacerbated neuronal mitochondrial dysfunction, oxidative stress, iron accumulation, and inflammation.</div></div><div><h3>Conclusion</h3><div>Overexpression of mitochondrial fatty acid oxidase CPT1A might improve synaptic integrity and rescue POCD by ameliorating astrocyte ferroptosis and neuroinflammation.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1850 ","pages":"Article 149424"},"PeriodicalIF":2.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892035","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}
Alzheimer’s disease is a progressive neurodegenerative disease affecting memory, language, and thinking with no curative treatment. Symptoms appear gradually, and pathological brain changes may occur twenty years before the physical and psychological signs, pointing to the urgent development of preventive interventions. Physical activity has been investigated as a preventive tool to defeat the main biological features of AD: pathological amyloid protein plaques, tau tangles, myelin degeneration, and iron deposits in the brain. This work quantifies tau tangles, amyloid, iron, and ferroptosis in oligodendrocytes in the aged rat hippocampal formation and statistically correlates neuron-neuron, neuron-glia, and glia-glia crosstalk and the effect of physical exercise on it. Our results indicate that iron overload in the oligodendrocytes is an inducer of ferroptosis; physical exercise reduces inflammaging, and improves axon-myelin volume relations; tau, amyloid, iron, and hippocampal formation cells present statistical correlations. Our data suggest the beneficial effects of physical exercise in AD and a mathematical relationship between the hippocampal formation cells in sedentary and active individuals, which should be considered in human and animal studies as a guide to a better understanding of crosstalk physiology.
{"title":"Tau, amyloid, iron, oligodendrocytes ferroptosis, and inflammaging in the hippocampal formation of aged rats submitted to an aerobic exercise program","authors":"R.C. Gutierre , P.R. Rocha , A.L. Graciani , A.A. Coppi , R.M. Arida","doi":"10.1016/j.brainres.2024.149419","DOIUrl":"10.1016/j.brainres.2024.149419","url":null,"abstract":"<div><div>Alzheimer’s disease is a progressive neurodegenerative disease affecting memory, language, and thinking with no curative treatment. Symptoms appear gradually, and pathological brain changes may occur twenty years before the physical and psychological signs, pointing to the urgent development of preventive interventions. Physical activity has been investigated as a preventive tool to defeat the main biological features of AD: pathological amyloid protein plaques, tau tangles, myelin degeneration, and iron deposits in the brain. This work quantifies tau tangles, amyloid, iron, and ferroptosis in oligodendrocytes in the aged rat hippocampal formation and statistically correlates neuron-neuron, neuron-glia, and glia-glia crosstalk and the effect of physical exercise on it. Our results indicate that iron overload in the oligodendrocytes is an inducer of ferroptosis; physical exercise reduces inflammaging, and improves axon-myelin volume relations; tau, amyloid, iron, and hippocampal formation cells present statistical correlations. Our data suggest the beneficial effects of physical exercise in AD and a mathematical relationship between the hippocampal formation cells in sedentary and active individuals, which should be considered in human and animal studies as a guide to a better understanding of crosstalk physiology.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1850 ","pages":"Article 149419"},"PeriodicalIF":2.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892044","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}
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