CNS Neuroscience & Therapeutics最新文献

{"title":"Association of Increased Brain Iron Levels With Anxiety and Motor Dysfunction in Cerebral Small Vessel Disease","authors":"Chaofan Sui,&nbsp;Qihao Zhang,&nbsp;Kelly Gillen,&nbsp;Yian Gao,&nbsp;Nan Zhang,&nbsp;Mengmeng Feng,&nbsp;Haotian Xin,&nbsp;Changhu Liang,&nbsp;Lingfei Guo,&nbsp;Yi Wang","doi":"10.1111/cns.70355","DOIUrl":"https://doi.org/10.1111/cns.70355","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study explored the relationships between brain iron levels, emotion, and cognitive and motor function in cerebral small vessel disease (CSVD) patients using quantitative susceptibility mapping (QSM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 208 subjects were enrolled in this study. A brain QSM map was calculated from multiecho GRE data via morphology-enabled dipole inversion with an automatic uniform cerebrospinal fluid zero reference algorithm (MEDI+0). Multiple linear regression analysis was applied to explore the clinical factors influencing cerebral susceptibility in CSVD patients. Correlation analysis and pathway-specific mediation effects between brain iron levels and motor function were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were significant differences in the MoCA scores, depression scores, five-repetition sit-to-stand test (5R-STS) time, and susceptibility values of the caudate nucleus and putamen among the three groups (<i>p</i> &lt; 0.05, FDR correction). Age and history of diabetes played crucial roles in brain iron levels in the caudate nucleus and putamen, which may increase iron levels in the basal ganglia, associated with cognitive decline. Notably, the susceptibility values of the left caudate nucleus and putamen were positively correlated with the 5R-STS time in CSVD subjects, and there were significant mediating effects of anxiety on the prediction of motor dysfunction with respect to iron levels in the left putamen in CSVD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Age, diabetes status, and anxiety may serve as effective intervention targets for individuals with CSVD, especially individuals with cognitive and motor dysfunction. A greater brain iron burden may be a quantitative imaging marker of cognitive and motor dysfunction in CSVD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ISRCTN20008650</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70355","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gradients of Nigrostriatal Iron Deposition in Healthy Aging and Synucleinopathies","authors":"Jiaqi Wen,&nbsp;Tao Guo,&nbsp;Xiaojie Duanmu,&nbsp;Chenqing Wu,&nbsp;Haoting Wu,&nbsp;Cheng Zhou,&nbsp;Qianshi Zheng,&nbsp;Weijin Yuan,&nbsp;Jianmei Qin,&nbsp;Zihao Zhu,&nbsp;Jingjing Wu,&nbsp;Jingwen Chen,&nbsp;Jingjing Xu,&nbsp;Yaping Yan,&nbsp;Jun Tian,&nbsp;Baorong Zhang,&nbsp;Hongjian He,&nbsp;Minming Zhang,&nbsp;Xiaojun Guan,&nbsp;Xiaojun Xu","doi":"10.1111/cns.70359","DOIUrl":"https://doi.org/10.1111/cns.70359","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To investigate the gradients of nigrostriatal iron deposition in aging, Parkinson's disease (PD), and multiple system atrophy (MSA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included 100 young healthy controls, 171 old healthy controls (OHC), 231 PD, and 24 MSA patients. The brain iron content was quantified by quantitative susceptibility mapping. A spatial function method was employed to map the iron gradient along the principal axis of the subcortical structure. General linear models were used to compare differences in iron gradients between groups. Partial correlation was used to analyze the relationship between iron content and symptoms of synucleinopathies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Nigrostriatal iron deposition in all gradient directions was observed during aging (<i>p</i> &lt; 0.05). Compared to OHC, iron deposition was significant in nearly all substantia nigra (SN) segments in both PD and MSA (<i>p</i> &lt; 0.05). MSA showed significant iron deposition in the posterolateral putamen compared to PD (<i>p</i> &lt; 0.05). Iron deposition in the SN in PD and putamen in MSA correlated with disease severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Iron deposition in all gradient directions occurred in the nigrostriatal system during healthy aging, and this was more evident in the SN in both PD and MSA, with MSA displaying additional iron deposition in the posterolateral putamen.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70359","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Alleviates Behavioral and Neurodevelopmental Abnormalities in Offspring Caused by Prenatal Stress","authors":"Dong Wu,&nbsp;Jingyi Du,&nbsp;Tiantian Zhao,&nbsp;Naigang Li,&nbsp;Xinghui Qiao,&nbsp;Fan Peng,&nbsp;Dongshuang Wang,&nbsp;Jiaming Shi,&nbsp;Shu Zhang,&nbsp;Can Diao,&nbsp;Liyan Wang,&nbsp;Wenjuan Zhou,&nbsp;Aijun Hao","doi":"10.1111/cns.70347","DOIUrl":"https://doi.org/10.1111/cns.70347","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Prenatal stress (PNS) is a significant risk factor impacting the lifelong health of offspring, and it has been widely recognized as being closely linked to the increased prevalence of neurodevelopmental disorders and psychiatric illnesses. However, effective pharmacological interventions to mitigate its detrimental effects remain limited. Melatonin (Mel), an endogenous hormone, has demonstrated considerable potential in treating neurological diseases due to its anti-inflammatory, antioxidant, and neuroprotective properties, as well as its favorable safety profile and broad clinical applicability.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aims to investigate the protective effects and mechanisms of melatonin on neurodevelopmental and behavioral abnormalities in offspring induced by prenatal stress.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using a prenatal stress mouse model, we evaluated the effects of melatonin on emotional and cognitive deficits in offspring. Neurogenesis and synaptic development were assessed, and RNA sequencing was performed to analyze microglial gene enrichment and immune-related pathways. Both in vivo and in vitro experiments were conducted to validate the findings, focusing on the PI3K/AKT/NF-κB signaling pathway in microglia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Melatonin administration alleviated emotional and cognitive deficits in offspring mice exposed to prenatal stress, addressing abnormalities in neurogenesis and synaptic development. Additionally, RNA sequencing revealed that melatonin suppresses microglial gene enrichment and the upregulation of immune-related pathways. Both in vivo and in vitro validation indicated that melatonin modulates the PI3K/AKT/NF-κB signaling pathway in microglia, reducing the elevated expression of CXCL10 in the dentate gyrus, thereby restoring normal neuro-supportive functions and optimizing the neurodevelopmental environment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that melatonin significantly improves neurodevelopmental disorders and behavioral abnormalities caused by prenatal stress by inhibiting pathological microglial activation and promoting hippocampal neurogenesis and synaptic plasticity. This provides new insights into melatonin's potential as a neuroprotective agent for treating prenatal stress-related disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noradrenergic Locus Coeruleus-CA3 Activation Alleviates Neuropathic Pain and Anxiety- and Depression-Like Behaviors by Suppressing Microglial Neuroinflammation in SNI Mice","authors":"Helin Zou,&nbsp;Weiyu Pu,&nbsp;Junli Zhou,&nbsp;Juan Li,&nbsp;Lulin Ma,&nbsp;Shuxian Wang,&nbsp;Chengxi Liu,&nbsp;Jing Mou,&nbsp;Xingfeng Liu,&nbsp;Tian Yu,&nbsp;Yiyong Wei,&nbsp;Haihui Xie,&nbsp;Song Cao","doi":"10.1111/cns.70360","DOIUrl":"https://doi.org/10.1111/cns.70360","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Neuropathic pain (NP) arises from neuroimmune interactions following nerve injury and is often accompanied by anxiety and depression. The aim of the study is to evaluate the effects of the noradrenergic locus coeruleus (LC), a key regulator of pain and emotional states, projects extensively to the hippocampus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We investigated the effects of chronic NP on LC integrity and its projections to the hippocampal CA3 region in spared nerve injury (SNI) mice with behavioral tests, immunohistochemistry, neurochemical analyses, and Gq-DREADD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Chronic NP induced LC neuronal loss, reduced hippocampal norepinephrine (NE) release, and triggered microglial activation and neuroinflammation in CA3. Selective activation of LC-CA3 noradrenergic neurons using Gq-DREADD chemogenetics alleviated NP and comorbid anxiety- and depression-like behaviors. This intervention suppressed microglial activation, decreased proinflammatory cytokines (TNF-α and IL-1β), and restored NE levels in CA3.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings highlighted the therapeutic potential of targeting LC-CA3 projections to mitigate chronic NP and its neuropsychiatric comorbidities via modulation of hippocampal neuroinflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Frequency rTMS Improves Visual Working Memory in Patients With aMCI: A Cognitive Neural Mechanism Study","authors":"Meng Liu,&nbsp;Ren Ren-Li,&nbsp;Jin Nan Sun,&nbsp;Janelle S. Y. Yeo,&nbsp;Jing Ma,&nbsp;Jia-Xin Yan,&nbsp; BuMaYiLaMu-XueKeEr,&nbsp;Zhao-Xi Tu,&nbsp;Yun-Xia Li","doi":"10.1111/cns.70301","DOIUrl":"https://doi.org/10.1111/cns.70301","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Visual working memory (VWM), which is an essential component of higher cognitive processes, declines with age and is associated with the progression from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). Cognitive impairment, particularly in VWM, is prominent in aMCI and may indicate disease progression. This study investigates the cognitive neural mechanisms responsible for VWM impairment in aMCI, with a focus on identifying the VWM processing stages affected. The study targets the dorsolateral prefrontal cortex (DLPFC) for repetitive transcranial magnetic stimulation (rTMS) to investigate its influence on VWM in aMCI patients. The role of the DLPFC in the top-down control of VWM processing is central to understanding rTMS effects on the stages of information processing in aMCI-related VWM impairments.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A 7-day rTMS intervention was performed in 25 aMCI patients and 15 healthy elderly controls to investigate its effects on VWM and cognitive functions. Tasks included VWM change detection, digital symbol transformation, and the Stroop task for attention and executive functions. EEG analyses consisting of ERP, ERSP, and functional connectivity (wPLI) were integrated. The first part of the study addressed the cognitive neural mechanism of VWM impairment in aMCI and differentiated the processing stages using EEG. The second part investigated the effects of rTMS on EEG processing at different VWM stages and revealed cognitive neural mechanisms that improve visual working memory in aMCI.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The results indicated a significant deterioration of VWM tasks in aMCI, especially in accuracy and memory capacity, with prolonged reaction time and increased duration of the Stroop task. In the VWM memory encoding phase, N2pc amplitude, α-oscillation in the parieto-occipital region, and θ-band synchronization in the frontoparietal connectivity decreased. Conversely, rTMS improved N2pc amplitude, α-oscillation, and θ-band synchronization, which correlated with improved frontoparietal connectivity, parieto-occipital α-oscillation, and attentional capacity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Patients with aMCI experience significant deterioration in VWM function, particularly during the encoding phase. This deterioration manifests in reduced accuracy and capacity of memory performance, accompanied by a significant decrease in N2pc amplitude, alpha oscillations, and theta-band connectivity in frontoparietal an","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Compound QO-83 Alleviates Acute and Chronic Epileptic Seizures in Rodents by Modulating KV7 Channel Activity","authors":"Xiangyu Wang,&nbsp;Yang Zhang,&nbsp;Hui Liu,&nbsp;Jiahao Wang,&nbsp;Boxuan Zhang,&nbsp;Tenghui He,&nbsp;Huiran Zhang,&nbsp;Zhumei Xiong,&nbsp;Xingang Liu,&nbsp;Jincan Li,&nbsp;Weidong Zhao,&nbsp;Xiao Liu,&nbsp;Wei Zhang,&nbsp;Le Yang,&nbsp;Qian Li,&nbsp;Hailin Zhang,&nbsp;Jinlong Qi,&nbsp;Qingzhong Jia","doi":"10.1111/cns.70334","DOIUrl":"https://doi.org/10.1111/cns.70334","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>K_V7 channels are promising targets for antiepileptic therapy. However, the classic K_V7 channel opener retigabine has been withdrawn due to severe adverse reactions. We developed a novel K_V7 channel opener, QO-83, with good chemical stability and blood–brain barrier penetration, and sought to evaluate its K_V7-opening activity, antiepileptic effects, and mechanisms of action.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used patch-clamp electrophysiology, electroencephalogram recordings, dynamic simulations, and various epilepsy models to investigate the mechanisms and antiepileptic activity of QO-83.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compound QO-83 exhibits greater potency at K_V7.2/7.3 channels compared to K_V7.4 or K_V7.5 channels. It shows superior efficacy for K_V7.2 with voltage-dependent opening than retigabine, with W236 identified as the key binding site for the K_V7.2 channel. QO-83 significantly inhibited epileptiform discharge and influenced hippocampal sEPSC and sIPSC amplitudes. QO-83 has a more effective dose of 1 mg/kg in acute and chronic epilepsy models smaller than that of retigabine (10 mg/kg). The higher potency of QO-83 may be attributed to its greater stability at the K_V7.2 binding pocket compared to retigabine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>QO-83, as a newly developed Kv7.2 opener, has the advantages of stable properties, strong affinity, and high activity compared with retigabine, and is expected to become a new antiepileptic drug.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aloe-Emodin Improves Mitophagy in Alzheimer's Disease via Activating the AMPK/PGC-1α/SIRT3 Signaling Pathway","authors":"Yulu Wang,&nbsp;Yunzhi Ge,&nbsp;Siyu Hua,&nbsp;Chenrui Shen,&nbsp;Biao Cai,&nbsp;Han Zhao","doi":"10.1111/cns.70346","DOIUrl":"https://doi.org/10.1111/cns.70346","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Impaired mitophagy results in the accumulation of defective mitochondria that are unable to be cleared effectively in Alzheimer's disease (AD). Aloe-emodin (AE), a key component of the traditional Chinese medicine Rhubarb, exhibits neuroprotective effects against Alzheimer's disease, though the underlying mechanism remains unclear. Studying aloe-emodin's role in enhancing mitophagy is vital for improving cognitive function and reducing neuronal damage in Alzheimer's disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The APP/PS1 double transgenic mice were adopted as models for AD to assess the effects of aloe-emodin upon cognitive function and its neuroprotective impact on hippocampal neurons. Additionally, we investigated the regulatory mechanisms of proteins within the aforementioned pathway, and the morphological characteristics of mitophagy-related proteins. An AD hippocampal neuron model was developed using Aβ25-35 to evaluate the mitochondrial function, the protein expression of such a pathway and the mitophagy. This approach aims to elucidate the effects and underlying mechanisms of aloe-emodin in relation to AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>AE activates mitophagy in neurons, improves cognitive dysfunction, reduces hippocampal damage, and alleviates AD symptoms in model mice. AE activates the expression of AMPK, PGC-1α and SIRT3. Increased expression of SIRT3 in mitochondria promotes mitophagy and regulates the function of mitochondrial proteins. When mitochondrial autophagy is enhanced, the expression of Beclin1, LC3, P62, Parkin, and PINK1-related proteins changes. Further in vitro experiments showed that AE can enhance mitochondrial function in Alzheimer's disease cell models. The mitochondrial membrane potential, GSH, ROS and Ca2+ levels gradually recover, alleviating the pathological manifestations of AD. Knocking down SIRT3 leads to increased mitochondrial damage and a reduction in mitophagy in HT22 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Experimental results show that AE can activate mitophagy through AMPK/PGC-1α/SIRT3 pathway, alleviate cognitive dysfunction in AD, and reduce damage to hippocampal neurons.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastrodin Alleviates Tau Pathology by Targeting the Alzheimer's Risk Gene FERMT2, Reversing the Reduction in Brain Viscoelasticity","authors":"Li Wang,&nbsp;Bo Li,&nbsp;Zhi Tang,&nbsp;Yang Wang,&nbsp;Yaqian Peng,&nbsp;Ting Sun,&nbsp;Anni Zhang,&nbsp;Xiaolan Qi","doi":"10.1111/cns.70283","DOIUrl":"10.1111/cns.70283","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The pathogenesis of Alzheimer's disease (AD) remains incompletely elucidated, and there is a notable deficiency in effective and safe therapeutic interventions. The influence of brain matrix viscoelasticity on the progression of AD has frequently been underestimated. It is imperative to elucidate these overlooked pathogenic factors and to innovate novel therapeutic strategies for AD. Gastrodin, a bioactive constituent derived from the traditional Chinese medicinal herb Gastrodia elata, exhibits a range of pharmacological properties, notably in the enhancement of neural function. Nevertheless, the underlying mechanisms of its action remain insufficiently elucidated. Consequently, this study seeks to examine the therapeutic effects and underlying mechanisms of gastrodin in the context of AD, with particular emphasis on its potential influence on the viscoelastic properties of the brain matrix.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study employs a range of methodologies, including the Morris water maze test, Y-maze spontaneous alternation test, atomic force microscopy (AFM), immunofluorescence, transmission electron microscopy, molecular docking, and Cellular Thermal Shift Assay (CETSA), to demonstrate that gastrodin mitigates tau pathology by modulating FERMT2, thereby reversing the deterioration of mechanical viscoelasticity in the brain.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gastrodin administration via gavage has been demonstrated to mitigate cognitive decline associated with AD, attenuate the hyperphosphorylation of tau protein in the hippocampus and cortex, and ameliorate synaptic damage. Additionally, gastrodin was observed to counteract the reduction in brain matrix viscoelasticity in 3xTg-AD mice, as evidenced by the upregulation of extracellular matrix components pertinent to viscoelasticity, notably collagen types I and IV. Furthermore, molecular docking and CETSA revealed a strong binding affinity between gastrodin and FERMT2. Gastrodin treatment resulted in a reduction of FERMT2 fluorescence intensity, which is selectively expressed in astrocytes. Additionally, gastrodin contributed to the restoration of the blood–brain barrier (BBB) and modulated the expression levels of inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and matrix metallopeptidase 8 (MMP8).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gastrodin treatment has the potential to mitigate tau pathology, thereby enhancing learning and memory in AD mouse models. This effect may be m","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Possible GABAkine-Mediated Sedative-Like Antidepressant Effects of Phytol: Molecular Interventions Through In Vitro, In Vivo and In Silico Approaches","authors":"Md. Torequl Islam,&nbsp;Jannatul Ferdous,&nbsp;Md. Sakib Al Hasan,&nbsp;Md. Shimul Bhuia,&nbsp;Irfan Aamer Ansari,&nbsp;Siddique Akber Ansari,&nbsp;Md. Amirul Islam,&nbsp;Md. Saifuzzaman","doi":"10.1111/cns.70350","DOIUrl":"10.1111/cns.70350","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A previous report suggests that phytol (PHY) may exert its antidepressant effects in mice, possibly through GABA_A receptor interaction pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>We aimed to check its antidepressant effect with possible molecular mechanisms through behavioral and <i>in silico</i> studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>For this, adult mice were randomly divided into different groups (<i>n</i> = 6), namely control (vehicle), standards (DZP: diazepam at 2 mg/kg, FLU: flumazenil at 0.1 mg/kg, FLUX: fluoxetine at 20 mg/kg), PHY (25, 50, and 75 mg/kg), and combined groups (PHY-75 with DZP-2 and/or FLU-0.1, and FLUX-20). Thirty minutes after treatment, each animal was subjected to tail suspension and forced swimming tests, and their immobility time (IMT) was counted for 5 min. In silico studies were performed with the GABA_A receptor α1, α2, α3, α5, and γ2 subunits and 5HT_1A to investigate possible molecular mechanisms. Additionally, in vitro GABA activity of PHY and/or reference drugs was also performed by using the colorimetric method.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results demonstrated that PHY and/or DZP significantly (<i>p</i> &lt; 0.05) and concentration-dependently inhibited GABA, while FLU alone or its combination with PHY reversed it. In mice, PHY dose-dependently reduced the IMT in both protocols, while FLUX-20 showed lower IMT compared to the control and DZP, indicating elevated locomotion in mice. It showed a reduced IMT value in male animals than in female animals. In both sexes, PHY at 75 mg/kg significantly (<i>p</i> &lt; 0.05) increased the IMT values with DZP-2, while reducing this parameter with FLU-0.1. <i>In silico</i> studies demonstrated that PHY exhibited higher binding affinities with the α2 and α3 subunits of the GABA_A and 5HT_1A receptors by −6.5, −7.2 and 6.7 kcal/mol, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, PHY exerted sedative-<i>like</i> antidepressant effects in mice and modulated the effects of GABAergic drugs DZP and FLU and serotonergic drug FLUX. PHY may be a potential candidate for the management of depression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asparagine Endopeptidase Inhibition Attenuates Tissue Plasminogen Activator-Induced Brain Hemorrhagic Transformation After Ischemic Stroke","authors":"Guanfeng Xie,&nbsp;Gege Jiang,&nbsp;Liqin Huang,&nbsp;Shangqi Sun,&nbsp;Xiaoyi Li,&nbsp;Bingjie Wu,&nbsp;Hualong Wang,&nbsp;Zhentao Zhang,&nbsp;Keqiang Ye,&nbsp;Ying Yu,&nbsp;Jing Xiong","doi":"10.1111/cns.70345","DOIUrl":"10.1111/cns.70345","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Thrombolytic treatment with tissue plasminogen activator (tPA) is one of the approved pharmacological therapies for acute ischemic stroke. However, the use of tPA is limited due to hemorrhagic transformation (HT) and the narrow therapeutic time window. Previous studies demonstrated that asparagine endopeptidase (AEP), a widely expressed pH-dependent endo-lysosomal cysteine protease, can induce neuronal death during ischemia-reperfusion injury. But whether AEP is engaged in HT during ischemia-reperfusion injury is unclear. In the current study, we expanded the role of AEP on HT after delayed tPA administration.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In order to investigate the effects of AEP on HT after delayed tPA administration following ischemic stroke, the middle cerebral artery occlusion/reperfusion (MCAO/R) was performed in wild-type (WT) and AEP knockout (KO) transgenic mice, followed by delayed administration of tPA (10 mg/kg, 3 h after occlusion). Additionally, we explored the potential of R13, a specific TrkB agonist with a strong inhibitory impact on AEP, to mitigate injury induced by tPA. 24 h after tPA administration, the following parameters were assessed: infarct volume, behavioral tests, hemorrhagic levels, Evans blue leakage, tight and adherens junction protein expression, blood–brain barrier (BBB) function, cerebral vascular structure, matrix metalloproteinases (MMPs), and BBB-regulated protein low-density lipoprotein receptor-related protein 1 (LRP-1) expression. To construct an in vitro model to examine the effects of AEP on ischemia-reperfusion injury after tPA treatment, human umbilical vein endothelial cells (HUVECs) were exposed to 4 h of oxygen–glucose deprivation (OGD), followed by treatment with tPA (500 ng/mL). 7,8-dihydroxyflavone (7,8-DHF), a natural TrkB agonist with an inhibitory effect on AEP, was applied before OGD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Compared with tPA-treated WT mice, AEP KO mice treated with tPA showed improved infarct volume, neurological function, brain edema, brain hemoglobin levels, Evans blue leakage, vascular tight junctions, and basement membrane structure combined with reduced AEP expression and activity within the peri-infarct area. In addition, the mice treated with R13 exhibited protective effects on the BBB. Furthermore, we found that the expression of MMP2, MMP9, and LRP-1 in the brain was inhibited by both AEP knockout and R13 treatment. Moreover, HUVECs treated with 7,8-DHF showed improvements in tight and adherens junction proteins and suppressed levels of MMP2, MMP9, and LRP-1.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 ","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}