CNS Neuroscience & Therapeutics最新文献

{"title":"Identification of Schizophrenia-Risk Regulatory Variant rs1399178 in the Non-coding Region With Its Impact on NRF1 Binding","authors":"Lei Ji,&nbsp;Bojian Huang,&nbsp;Decheng Ren,&nbsp;Xiaoxi Wei,&nbsp;Liangjie Liu,&nbsp;Yan Bi,&nbsp;Zhiqiang Li,&nbsp;Fan Yuan,&nbsp;Ke Han,&nbsp;Keyi Li,&nbsp;Fengping Yang,&nbsp;Xingwang Li,&nbsp;Tao Yu,&nbsp;Yi Shi,&nbsp;Lin He,&nbsp;Qing Lu,&nbsp;Guang He","doi":"10.1111/cns.70275","DOIUrl":"https://doi.org/10.1111/cns.70275","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>The challenges in identifying functional variants from genome-wide association studies (GWAS) and unraveling regulatory mechanisms in schizophrenia research persist, particularly in intronic regions. A non-coding regulatory variant, rs1399178, associated with schizophrenia risk, is identified and its impact on NRF1 binding is investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study focuses on schizophrenia GWAS risk loci, using functional genomics, expression analyses and structural analysis to identify 736 schizophrenia risk single-nucleotide polymorphisms (SNPs) that disrupt transcription factor (TF) binding.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among these SNPs, rs1399178 stands out as a bifunctional intergenic SNP that can switch between acting as a promoter and an enhancer, potentially influencing <i>MLH1</i> and <i>LRRFIP2</i> expression via expression quantitative trait loci analysis. Importantly, mutation of the G allele of rs1399178 to A significantly diminishes its binding affinity to nuclear respiratory factor 1 (NRF1). Structural analysis provides further insight into this alteration in the protein–nucleic acid complex formation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Based on our data, a model is proposed in which rs1399178 confers schizophrenia risk by modifying <i>NRF1</i> binding profiles, thereby regulating the abundance of target genes through promoter-enhancer switching. This study provides novel insights into the regulatory mechanisms of schizophrenia risk variants, highlighting the intricate nature of genetic interactions and potential therapeutic targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513574","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":"Clarifying the Specificity of Transcranial Pulse Stimulation in Neuromodulatory-Based Therapeutic Applications","authors":"Onur Alti,&nbsp;Antonino Vallesi","doi":"10.1111/cns.70325","DOIUrl":"https://doi.org/10.1111/cns.70325","url":null,"abstract":"&lt;p&gt;We would like to address and clarify some critical points regarding the review article by Chen et al. [&lt;span&gt;1&lt;/span&gt;], titled: “Transcranial Pulse Stimulation in Alzheimer's Disease”, published in 2024 in the &lt;i&gt;CNS Neurosci Ther&lt;/i&gt; journal. While we appreciate the authors' efforts in reviewing Alzheimer's related empirical studies using Transcranial Pulse Stimulation (TPS), there appears to be significant ambiguity regarding the neuromodulatory techniques actually used in a considerable portion of the studies cited in that review. Specifically, the review conflates TPS, an ultrasound-based intervention, with Transcranial Pulsed Current Stimulation (tPCS), a low-intensity ‘electrical’ brain stimulation technique. This conflation obscures the distinct mechanism of action and potential applications of TPS, leading to confusion for researchers, clinicians and policymakers. In this letter, we clarify these misinterpretations and discuss their implications, while integrating updated insights into TPS mechanisms and principles.&lt;/p&gt;&lt;p&gt;TPS is a non-invasive neuromodulation technique that utilizes focused ultrasound energy to deliver localized brain stimulation. Unlike electrical methods, such as tPCS or Transcranial Direct Current Stimulation (tDCS), TPS leverages the mechanical and acoustic effects of ultrasound, offering distinct mechanisms for inducing neuroplastic changes.&lt;/p&gt;&lt;p&gt;TPS induces neuromodulation via high-pressure acoustic pulses, which create mechanical stress on neural tissue, prompting neuroplasticity [&lt;span&gt;2&lt;/span&gt;]. Unlike tPCS and tDCS, TPS does not use electrodes or electrical current, avoiding skin-related side effects such as redness or tingling. Its unique properties allow for non-invasive, focal stimulation with minimal discomfort, offering promise for treating neurological disorders.&lt;/p&gt;&lt;p&gt;Current evidence suggests that ultrasound neuromodulation is safe, with potential risks being similar for both cortical and deep stimulation [&lt;span&gt;6&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In the discussion section, Chen et al. [&lt;span&gt;1&lt;/span&gt;] state: “The frequency of the stimulation is one of the important parameters that significantly affect the TPS effect [original reference #38]. Previous studies have found that random frequency parameters (1–5 Hz) increase functional connectivity in the brain compared to nonrandom and spurious stimuli [#39-40]. Morales-Quezada et al. [#41] also demonstrated that a random frequency of TPS between 6 and 10 Hz also led to an increase in brain functional connectivity, as shown by the facilitation of electroencephalogram spectral power and connectivity measurements”. This passage references the frequency range of 6–10 Hz, which is outside the feasible limits for ultrasound-based TPS, as TPS devices are typically limited to upper-bound of approximately 5 Hz&lt;sup&gt;2&lt;/sup&gt;. In fact, the studies by Saavedra et al. [&lt;span&gt;7&lt;/span&gt;] [orig. #39] and Morales-Quezada et al. [&lt;span&gt;8&lt;/span&gt;] [orig. #40] investigate the effects of tPCS, an","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70325","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522000","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":"Nonmotor Symptom Changes and Their Association With Falls Among Parkinson's Disease Patients Undergoing Deep Brain Stimulation: A 1-Year Cohort Study","authors":"Ying Gao,&nbsp;Hui You,&nbsp;Jue Wang,&nbsp;Mengsi Yao,&nbsp;Dianyou Li,&nbsp;Bomin Sun,&nbsp;Linbin Wang,&nbsp;Xian Qiu","doi":"10.1111/cns.70310","DOIUrl":"https://doi.org/10.1111/cns.70310","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Fall severely affects the quality of life of Parkinson's disease (PD) patients. Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for PD motor symptoms (MS), but DBS increased the risk of falls in some studies and has mixed effects on nonmotor symptoms (NMS). However, the link between NMS and falls, and how DBS influences this relationship, remain unclear. This study investigated changes in NMS and falls before and after STN-DBS, and the longitudinal association between NMS and falls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study included 136 PD patients undergoing STN-DBS between April 2020 and February 2022. Data were collected preoperatively, at 6 months, and at 12 months postoperatively. Assessments included MS via the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) and NMS via the Nonmotor Symptoms Scale (NMSS). We used the Friedman and chi-square tests to assess changes in NMS and falls. Specific circumstances of falls were assessed through structured interviews. Generalized estimating equations (GEE) were used to explore the longitudinal associations between NMS and fall occurrence, as well as the interaction effects between MS and NMS on fall occurrence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Significant improvements (<i>p</i> &lt; 0.01) were observed in all NMSS domains except gastrointestinal, with no change in fall occurrence. However, there were significant changes in both the locations where falls occurred and whether freezing of gait was present among falling patients (<i>p</i> &lt; 0.01). GEE analysis revealed significant associations between falls and mood/cognition (<i>p</i> = 0.044), gastrointestinal (<i>p</i> = 0.027), and urinary symptoms (<i>p</i> = 0.007), as well as interactions between motor and these NMS domains (<i>p</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>NMS, particularly mood/cognition, gastrointestinal, and urinary symptoms, and their interactions with MS, are associated with falls, underscoring the need for targeted fall prevention strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522001","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":"Upregulation of NR2B Subunits of NMDA Receptors in the Lateral Parabrachial Nucleus Contributes to Chronic Pancreatitis Pain","authors":"Jing-Lai Wu,&nbsp;Wen-Qiong Kuang,&nbsp;Zheng-Yan Zhu,&nbsp;Jing-Heng Dou,&nbsp;Jia-He Yao,&nbsp;Jing Cao,&nbsp;Fu-Chao Zhang,&nbsp;Guang-Yin Xu","doi":"10.1111/cns.70313","DOIUrl":"https://doi.org/10.1111/cns.70313","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Chronic pancreatitis (CP) is a localized or diffuse chronic progressive inflammation of the pancreas that can be caused by a variety of factors and is characterized by abdominal pain. However, the underlying mechanisms are poorly understood. Increasing evidence suggests that central sensitization plays a crucial role in the development of visceral pain, but the precise mechanisms of central neural processing remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CP was induced using repeated intraperitoneal injections of caerulein in mice. Neurospecific anterograde tracing was achieved using herpes simplex virus type 1 (HSV-1). Fiber photometry was used to assess neuronal activity. Optogenetic, chemogenetic, or pharmacological approaches were applied to manipulate the lateral parabrachial nucleus (LPB) glutamatergic neurons. The abdominal withdrawal threshold (AWT) was measured to evaluate the CP pain. A glutamate sensor was used to detect glutamate release in the LPB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the present study, we demonstrated that glutamatergic neurons in the LPB are activated in CP mice, leading to the development of CP pain. Notably, glutamatergic release is increased in the LPB, and the increased release primarily mediates CP pain by binding to the N-methyl-D-aspartate (NMDA) receptor rather than α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Specifically, this process involves the binding of the N-Methyl-D-Aspartate Receptor Subunit 2B (NR2B) in the LPB, leading to the development of CP pain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study identified the NR2B subunits of NMDA receptors in the LPB as playing a critical role in the regulation of CP pain.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522002","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":"The Relationship Between the Average Infusion Rate of Propofol and the Incidence of Delirium During Invasive Mechanical Ventilation: A Retrospective Study Based on the MIMIC IV Database","authors":"Qi-Yue Ge,&nbsp;Chao Zheng,&nbsp;Xiao-Bin Song,&nbsp;Zhuang-Zhuang Cong,&nbsp;Jing Luo,&nbsp;Hao-Tian Zheng,&nbsp;Peng-Long Zhao,&nbsp;Yan-Qing Wang,&nbsp;Bing-Wei Chen,&nbsp;Yi Shen","doi":"10.1111/cns.70273","DOIUrl":"https://doi.org/10.1111/cns.70273","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Delirium is a common complication observed in intensive care units (ICUs). Propofol is one of the most widely used sedatives and is believed to be closely connected with the incidence of delirium. The study was carried out to explore the relationship between delirium and the average rate of propofol infusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients who underwent invasive mechanical ventilation (IMV) while receiving propofol from the Medical Information Mart for Intensive Care IV (MIMIC IV) database were included in the study. The primary outcome was to identify the potential risk factors for the incidence of delirium and investigate the relationship between the average rate of propofol infusion and the incidence of delirium. The secondary outcome was to further analyze the relationship by subgroup analysis. Propensity score matching (PSM) was employed to minimize bias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 16,956 patients (delirium: 5805; control: 11,151) were ultimately included in the study after PSM. The median diagnostic time of delirium was 18 h. An average propofol infusion rate ≥ 20 μg/(kg*h) during the initial 18 h was found to be independently significant [OR = 1.84, 95% CI = (1.72, 1.98), <i>p</i> &lt; 0.001], while an average propofol infusion rate ≤ 40 μg/(kg*h) in the first hour showed no statistically significant difference in the incidence of delirium [OR = 0.95, 95% CI = (0.88, 1.02), <i>p</i> = 0.163]. Besides, an average propofol infusion rate ≥ 20 μg/(kg*h) was also found to be statistically significant in all the subgroup analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>An average propofol infusion rate ≥ 20 μg/(kg*h) during the initial 18 h was identified as an independent risk factor for delirium, suggesting that the accumulation of propofol might be associated with an increased incidence of delirium.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513577","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":"Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman-Induced Status Epilepticus in Male Rats","authors":"Peter M. Andrew,&nbsp;Jeremy A. MacMahon,&nbsp;Xiuzhen Liu,&nbsp;Naomi H. Saito,&nbsp;Kyle E. Berger,&nbsp;Julia E. Morgan,&nbsp;Ashish Dhir,&nbsp;Danielle J. Harvey,&nbsp;Hilary S. McCarren,&nbsp;Michael A. Rogawski,&nbsp;Pamela J. Lein","doi":"10.1111/cns.70215","DOIUrl":"https://doi.org/10.1111/cns.70215","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP-induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman-induced SE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Soman-intoxicated male rats with robust seizure behavior and high-amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman-induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine-refractory, soman-induced SE, and in mitigating its acute neuropathological consequences.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143521999","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":"Acupuncture Improves Chronic Cerebral Ischemia by Inhibiting the CKLF1/HIF-1α/VEGF/Notch1 Signaling Pathway","authors":"Jilong Guo,&nbsp;Guangqi Wang,&nbsp;Tian Liu,&nbsp;Jianjun Zhang,&nbsp;Qinqing Li,&nbsp;Yousong Zhu,&nbsp;Huijuan Luo","doi":"10.1111/cns.70246","DOIUrl":"https://doi.org/10.1111/cns.70246","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Acupuncture significantly improves cognitive dysfunction in rats with chronic cerebral ischemia. However, the underlying signaling pathways remain unclear. This study investigates the role of the CKLF1/HIF-1α/VEGF/Notch1 signaling pathway in the acupuncture-mediated improvement of cognitive function in rats with chronic cerebral ischemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male SD rats were randomly divided into the normal control group, sham-operated group, 2-VO model group, 2-VO + acupuncture group, and 2-VO + Ginaton group (<i>Ginkgo biloba</i> extract 14.4 mg/kg/day), with 10 rats in each group. The 2-VO + acupuncture group received acupuncture at the Shuigou, Baihui, bilateral Fengchi, and bilateral Zusanli points for 14 consecutive sessions over 2 weeks. The rats' memory function was assessed using the Morris water maze and novel object recognition tests. Cerebral blood volume changes were measured using laser speckle imaging. Ultrastructural changes in microvessels were observed via transmission electron microscopy. Neuronal and myelin alterations were evaluated using HE staining, Nissl staining, and LFB myelin staining. The expression levels of CKLF1, CCR5, HIF-1α, VEGF, and Notch1 proteins were measured using Western blot, and multiple immunofluorescence staining was performed to assess the colocalization of CKLF1 and neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with the 2-VO model group, acupuncture treatment reduced the latency period and increased the number of platform crossings in the Morris water maze test, and the 2-VO model group had a higher recognition index in the novel object recognition test. We found that acupuncture improved the condition of endothelial cells, repaired the morphology of the vascular lumen, and alleviated astrocyte edema. We also showed that acupuncture could ameliorate pathological damage in rats with chronic cerebral ischemia. Moreover, acupuncture reduced the expression of CKLF1, CCR5, and HIF-1α proteins in the hippocampus, decreased the fluorescence intensity of CKLF1 expression, and increased the fluorescence intensity of neurons in the hippocampal CA1 region.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Acupuncture may exert neuroprotective effects and improve cognitive dysfunction caused by chronic cerebral ischemia by regulating the CKLF1/HIF-1α/VEGF/Notch1 pathway to inhibit inflammatory factors and increase cerebral blood flow.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513576","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":"Prenatal Valproic Acid Exposure Impairs Offspring Cognition Through Disturbing Interneuron Development","authors":"Kaiyuan Shen,&nbsp;Yandong Zhang,&nbsp;Yunyun Huang,&nbsp;Yunli Xie,&nbsp;Jing Ding,&nbsp;Xin Wang","doi":"10.1111/cns.70303","DOIUrl":"https://doi.org/10.1111/cns.70303","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Valproic acid (VPA) exposure during the gestational period has been found to impair the cognition of the offspring. The study aimed to investigate whether VPA leads to offspring cognitive impairment through disturbing interneuron development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pregnant mice were injected with VPA peritoneally to establish the prenatal VPA exposure model. Cortical interneurons were labeled with Rosa26-EYFP/− reporter mice activated by Nkx2.1-Cre. Interneuron subtypes both in the cortex and the hippocampus were detected by immunofluorescence. A battery of behavioral tests was conducted on postnatal Day 28 to assess the cognition and anxiety of the offspring. RNA-Seq analysis was performed to investigate the underlying molecular mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that after the exposure to VPA, all the groups of the male offspring exerted anxiety. When VPA injection was performed on gestational Day 12.5, the memory of the offspring was impaired. Mechanistically, the distribution of cortical interneurons was disrupted. The distribution of interneuron subtypes was abnormal both in the cortex and hippocampus after the VPA exposure, which affected the somatostatin-positive neurons but not the parvalbumin-positive neurons, indicating the effects of VPA were subtype specific. Biological processes related to ion homeostasis were greatly changed after VPA exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Prenatal VPA exposure during the neurogenic period impaired the cognition of the offspring by disrupting interneuron migration and differentiation. The study provides a novel perspective on the influence of VPA over neurodevelopment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497403","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 Concentration Hydrogen Protects Sepsis-Associated Encephalopathy by Enhancing Pink1/Parkin-Mediated Mitophagy and Inhibiting cGAS-STING-IRF3 Pathway","authors":"Yan Cui,&nbsp;Jianfeng Liu,&nbsp;Yu Song,&nbsp;Chen Chen,&nbsp;Yuehao Shen,&nbsp;Keliang Xie","doi":"10.1111/cns.70305","DOIUrl":"https://doi.org/10.1111/cns.70305","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sepsis-associated encephalopathy (SAE) leads to increased mortality. Hydrogen (H₂) has been proven to be effective in protecting against SAE. This study aimed to investigate the protective mechanism of a high concentration of H₂ (HCH) (67%) against SAE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A mouse sepsis model was established via cecal ligation and puncture (CLP). 67% H₂ was inhaled for 1 h at 1 h and 6 h after the operation. First, mice were randomly divided into 5 groups: Sham, CLP, CLP + CQ (a mitophagy inhibitor), CLP + H₂, and CLP + H₂ + CQ. Seven-day survival, cognitive function, and hippocampal damage were assessed. Then, mice were randomly divided into four groups: Sham, CLP, CLP + UA (a mitophagy agonist), and CLP + H₂. Seven-day survival was recorded, cognitive function was assessed via Y-maze and Morris water maze tests, and hippocampal damage was evaluated via Nissl staining. Phosphorylated tau, inflammatory factors, ATP, and antioxidant enzyme levels and mitochondrial membrane potential (MMP) were detected. Mitochondria were observed via transmission electron microscopy. The protein levels of the PINK1/Parkin pathway and STING-TBK-IRF3 pathway were detected via western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HCH inhalation improves 7-day survival and cognitive function in septic mice and reduces brain tissue damage, proinflammatory cytokine levels, and phosphorylated tau levels. These effects were reversed by a mitophagy inhibitor. HCH significantly improves mitochondrial function, enhances PINK1/Parkin-mediated mitophagy, and reduces the activity of the STING-TBK-IRF3 pathway in brain tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>HCH inhalation effectively improved the survival rate of septic mice, alleviated SAE, and reduced tau phosphorylation. The mechanism may involve HCH enhancing PINK1/Parkin-mediated mitophagy, which inhibits the activity of the cGAS-STING-IRF3 pathway, thereby reducing neuroinflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513840","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":"Cleaving PINK1 or PGAM5? Involvement of PARL in Methamphetamine-Induced Excessive Mitophagy and Neuronal Necroptosis","authors":"Di An,&nbsp;Chuling Zhang,&nbsp;Peng Zhou,&nbsp;Yifei Wang,&nbsp;Sining Meng,&nbsp;Yanlong Chen,&nbsp;Weixiao Xu,&nbsp;Jiankang Xuan,&nbsp;Jianping Xiong,&nbsp;Jie Cheng,&nbsp;Rong Gao,&nbsp;Jun Wang,&nbsp;Xufeng Chen","doi":"10.1111/cns.70293","DOIUrl":"https://doi.org/10.1111/cns.70293","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Methamphetamine (Meth) is a potent psychoactive stimulant that triggers complex neurotoxicity characterized by autophagy-associated neuronal death. However, the potential mechanisms remain poorly understood. This study aimed to decipher the Meth-induced neuronal necroptosis involving mitochondrial defect-initiated excessive mitophagy caused by aberrant presenilin-associated rhomboid-like (PARL) cleavage of PTEN-induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>With the transcriptome analysis, Meth exposure significantly affected autophagy, mitophagy, and necroptosis pathways; meanwhile, the proteomic analysis revealed a marked decline in the level of PARL, which led to an imbalance in intramembrane proteolysis of PINK1 and PGAM5. In behavioral tests, Meth administration elicited pronounced cognitive decline in mice, accompanied by decreased neuronal numbers, massive autophagosomes, and mitochondrial fragmentation, and these processes can be dramatically reversed by knockin of PARL and knockdown of PGAM5 in the mouse hippocampus, molecularly manifesting as decreased necrosome formation and phosphorylated mixed lineage kinase domain-like (p-MLKL) mitochondrial membrane translocation, and improved autophagic flux.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, these findings collectively underscore the key roles of the PARL-PGAM5 axis in Meth-mediated neuronal necroptosis and that targeting this axis may provide promising therapeutic strategies for mitigating Meth-induced neurotoxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497402","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}