CNS Neuroscience & Therapeutics最新文献

{"title":"Hydrogen Sulfide Sustained Release Donor Alleviates Spinal Cord Ischemia–Reperfusion-Induced Neuron Death by Inhibiting Ferritinophagy-Mediated Ferroptosis","authors":"Lei Xie,&nbsp;Qiuping He,&nbsp;Hang Wu,&nbsp;Weipeng Shi,&nbsp;Xiao Xiao,&nbsp;Tengbo Yu","doi":"10.1111/cns.70366","DOIUrl":"https://doi.org/10.1111/cns.70366","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Spinal cord ischemia–reperfusion injury (SCIRI) is a disastrous complication that cannot be completely prevented in thoracoabdominal aneurysm surgery, leading to sensory and motor dysfunction and even paraparesis, causing tremendous socioeconomic burden. Ferritinophagy is a form of autophagic ferroptosis, which is a contributor to SCIRI. Hydrogen sulfide (H₂S) has been reported to be neuroprotective in various diseases. However, it remains unclear whether H₂S alleviates SCIRI-induced neural death via regulating ferritinophagy-mediated ferroptosis. The aim of this study was to explore their relationship and interaction in SCIRI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results demonstrate that Nissl bodies and motor function were obviously lost in SCIRI rats. Meanwhile, SCIRI led to a significant increase in DHE-positive neurons, TUNEL-positive neurons, LC3-positive neurons, and ferritin-positive neurons, downregulation of GPx4, Slc7a11, p62, and ferritin expression, and upregulation of LC3 II/I and NCOA4 expression. Additionally, there was upregulation of the level of MDA, GSH, and Fe²⁺. Finally, we found that H₂S could significantly relieve neuronal death and loss of motor function in SCIRI rats by inhibiting ferritinophagy and ferroptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ferroptosis and ferritinophagy play a crucial role in the etiopathogenesis of SCIRI, and H₂S exerts neuroprotection by inhibiting ferritinophagy-mediated ferroptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70366","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749741","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":"GAD65 Antibody-Associated Neurologic Syndrome Overlapping Hemophagocytic Lymphohistiocytosis","authors":"Ya Chen,&nbsp;Doujia Chen,&nbsp;Zhongxiang Xu,&nbsp;Zucai Xu","doi":"10.1111/cns.70364","DOIUrl":"https://doi.org/10.1111/cns.70364","url":null,"abstract":"&lt;p&gt;Glutamic acid decarboxylase 65 (GAD65) antibody-associated neurologic syndrome is a rare neurologic syndrome mediated by autoimmune response injury including autoimmune epilepsy, autoimmune cerebellar ataxia, stiff-person syndrome, and limbic encephalitis [&lt;span&gt;1&lt;/span&gt;]. Hemophagocytic lymphohistiocytosis (HLH) is a systemic inflammatory disease that can present with a variety of clinical manifestations [&lt;span&gt;2&lt;/span&gt;]. Both are associated with immunoinflammation, but no coexistence has been reported. Here, we report the first case of GAD65 antibody-associated neurologic syndrome overlap hemophagocytic lymphohistiocytosis.&lt;/p&gt;&lt;p&gt;A previously healthy 49-year-old man had a first generalized tonic-clonic seizure in May 2022. Two months after the initial presentation, he presented symptoms associated with cerebellar dysfunction, including dizziness, unstable walking. In September, he had another seizure with electroencephalogram showing low-to-medium amplitude sharp waves scattered in the focal left hemisphere and was treated with sodium valproate sustained-release tablets 500 mg twice daily. He presented with progressive dizziness and instability. In January 2023, he showed left tinnitus, deafness, diplopia, and was admitted to our hospital.&lt;/p&gt;&lt;p&gt;The neurologic examination revealed slight bradylalia, horizontal gaze nystagmus, diplopia but no limitation of eye movement, diminished tingling on the left side of the face, and an unstable heel-to-shin test. Brain magnetic resonance imaging (MRI) showed multiple abnormal signals without contrast enhancement lesions (Figure 1A). Electroencephalogram showed normal. An extensive screening for rheumatological disorders showed negative results, as did screening tests for metabolic, tumor, and infectious causes. Cerebrospinal fluid (CSF) examination revealed normal open pressure, 10 × 10&lt;sup&gt;6&lt;/sup&gt;/L leukocytes, 597 mg/L total protein, no heteromorphic cells, and normal glucose and chloride levels. There were CSF-specific oligoclonal bands (type II). Mitochondrial genetic testing, broad CSF microbiological examination, and CSF metagenomic next-generation sequencing were unremarkable. Other autoimmune encephalitis and paraneoplastic antibodies remained negative except positive anti-GAD65 antibodies detected by cell-based immunoassays in serum (1:30) and in CSF (1:10). After excluding other diseases, he was diagnosed with GAD65 antibody-associated neurologic syndrome. Meanwhile, hidden-malignancy screenings for chest, abdomen computed tomography, thyroid, superficial lymph nodes and breast ultrasound, gastroscopy, and colonoscopy were negative. He was prescribed intravenous methylprednisolone pulse therapy (1 g/day) for 5 days and gradually reduced the dosage to oral tapering prednisone, which alleviated his symptoms, especially diplopia and dizziness. The patient had been seizure-free since taking valproate.&lt;/p&gt;&lt;p&gt;After being discharged for 30 days, the patient became very weak and was readmitted for ab","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70364","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717127","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":"Cognitive Sequelae of COVID-19: Mechanistic Insights and Therapeutic Approaches","authors":"Yu-Hao Chen,&nbsp;Jing-Shiun Jan,&nbsp;Chih-Hao Yang,&nbsp;Ting-Lin Yen,&nbsp;Tran Thanh Duy Linh,&nbsp;Saileela Annavajjula,&nbsp;Mantosh Kumar Satapathy,&nbsp;Shin-Yi Tsao,&nbsp;Cheng-Ying Hsieh","doi":"10.1111/cns.70348","DOIUrl":"https://doi.org/10.1111/cns.70348","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The COVID-19 pandemic has left an indelible mark on the world, with mounting evidence suggesting that it not only posed acute challenges to global healthcare systems but has also unveiled a complex array of long-term consequences, particularly cognitive impairment (CI). As the persistence of post-COVID-19 neurological syndrome could evolve into the next public health crisis, it is imperative to gain a better understanding of the intricate pathophysiology of CI in COVID-19 patients and viable treatment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This comprehensive review explores the pathophysiology and management of cognitive impairment across the phases of COVID-19, from acute infection to Long-COVID, by synthesizing findings from clinical, preclinical, and mechanistic studies to identify key contributors to CI, as well as current therapeutic approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Key mechanisms contributing to CI include persistent neuroinflammation, cerebrovascular complications, direct neuronal injury, activation of the kynurenine pathway, and psychological distress. Both pharmacological interventions, such as anti-inflammatory therapies and agents targeting neuroinflammatory pathways, and non-pharmacological strategies, including cognitive rehabilitation, show promise in addressing these challenges. Although much of the current evidence is derived from preclinical and animal studies, these findings provide foundational insights into potential treatment approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>By synthesizing current knowledge, this review highlights the importance of addressing COVID-19-related cognitive impairment and offers actionable insights for mitigation and recovery as the global community continues to grapple with the pandemic's long-term impact.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717193","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":"Comprehensive Analysis of Uric Acid and Myasthenia Gravis: IGF1R as a Protective Factor and Potential Therapeutic Target","authors":"Yu Shen,&nbsp;Lijun Pang,&nbsp;Han Wang,&nbsp;Qili Han,&nbsp;Wang Wan,&nbsp;Si Luo,&nbsp;Ziwei Song,&nbsp;Yaofeng Fang,&nbsp;Hao Chen,&nbsp;Yusen Qiu,&nbsp;Dandan Tan,&nbsp;Meihong Zhou,&nbsp;Daojun Hong","doi":"10.1111/cns.70361","DOIUrl":"https://doi.org/10.1111/cns.70361","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;Previous studies have suggested that oxidative stress can significantly damage acetylcholine receptors (AChRs), which are implicated in the pathogenesis of myasthenia gravis (MG). Uric acid (UA), a scavenger of peroxynitrite and a natural antioxidant, plays a crucial role in eliminating free radicals in the bloodstream. However, the relationship between UA and MG, as well as the underlying mechanisms, remains insufficiently explored.&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 meta-analysis was conducted to evaluate the clinical correlation between UA and MG. Subsequently, Mendelian randomization (MR) and bioinformatics analyses were employed to identify the key protein IGF1R. Public datasets, such as TCGA and GEO, along with patient data from our clinical center, were used for a comprehensive analysis of the relationship between IGF1R and UA in MG patients. Additionally, virtual screening and molecular docking were performed to identify small molecules that target IGF1R as potential therapeutic agents for MG.&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 meta-analysis revealed a significant association between low UA levels and MG (OR −48.46 [95% CI −63.26, −33.65], &lt;i&gt;p&lt;/i&gt; &lt; 0.00001). The two-sample MR analysis indicated a genetic relationship between UA and MG (&lt;i&gt;p&lt;/i&gt; = 0.024; &lt;i&gt;p&lt;/i&gt; = 0.036). The FUMA analysis and enrichment analysis identified IGF1R as a key protein likely involved in this relationship. Using the thymoma dataset from the TCGA database, we analyzed IGF1R expression in the MG and non-MG groups and found that IGF1R expression was lower in MG patients and was associated with a poor prognosis (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Single-cell RNA-seq data from the GEO database further supported the association between low IGF1R expression and MG, as well as the occurrence of crisis (&lt;i&gt;p&lt;/i&gt; &lt; 0.05). Additionally, data from MG patients treated at our center showed that IGF1R expression correlated with UA levels and that higher IGF1R expression was associated with milder clinical phenotypes (ocular phenotypes). Through a virtual screen and molecular docking of small molecules in the DrugBank database, we identified several potential small-molecule drugs that may target IGF1R to treat MG.&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;Our study revealed an association between low UA levels and MG and subsequently showed that low IGF1R expression is associated with the onset, severity, and poor prognosis of MG. We also explored the molecular mechanisms underlying the protective role of IGF1","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717192","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":"Electroacupuncture Regulates Sympathetic Nerve Through the NTSGlu-RVLM Circuit to Relieve Spontaneous Pain in SNI Rats","authors":"Wen Chen,&nbsp;Xin Ma,&nbsp;Yi-Ming Fu,&nbsp;Cun-Zhi Liu,&nbsp;Hong-Ping Li,&nbsp;Guang-Xia Shi","doi":"10.1111/cns.70327","DOIUrl":"https://doi.org/10.1111/cns.70327","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Patients suffering from neuropathic pain often experience sympathetic dysfunction. Acupuncture has shown promise in alleviating pain and modulating the activity of the autonomic nervous system. This study aims to explore the potential mechanism through which electroacupuncture (EA) modulates sympathetic nerves to alleviate neuropathic pain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Spared nerve injury (SNI) was utilized to induce neuropathic pain. EA was administered at acupoints Huantiao and Yanglingquan for 30 min every other day after SNI. Pain behavior was evaluated using paw withdrawal thresholds (PWTs) and spontaneous pain scores. Various techniques including immunofluorescence, viral tracing, electrophysiology, and chemogenetic manipulations were employed to investigate the impact of EA on the sympathetic nerves and pain behaviors, specifically through the nucleus tractus solitarii (NTS)^Glu-rostral ventrolateral medulla (RVLM) circuit.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In SNI rats, EA alleviated both mechanical and spontaneous pain, diminished sympathetic nerve excitability, and inhibited sympathetic nerve sprouting within the dorsal root ganglia (DRG), reduced the excitability of glutamatergic neurons in the NTS which project to the RVLM. Chemogenetic inhibition of the NTS^Glu-RVLM circuit produced the same effect as EA in spontaneous pain, sympathetic nerve excitability, extracellular discharge frequency in RVLM, but not in mechanical pain. Similarly, chemogenetic activation of the NTS^Glu-RVLM circuit negated the analgesic effects of EA on spontaneous pain while not affecting mechanical pain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study suggested that EA alleviates spontaneous pain rather than mechanical pain by regulating the sympathetic nerve activity via the NTS^Glu-RVLM circuit.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70327","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717256","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 Association of Serum Biomarkers With Symptomatic Hemorrhagic Transformation in Acute Ischemic Stroke Patients: A Combined Retrospective and Prospective Study","authors":"Shuhua Yuan,&nbsp;Daiquan Gao,&nbsp;Wenjuan Shi,&nbsp;Yue Zhao,&nbsp;Zhengran Guo,&nbsp;Xiaodong Chen,&nbsp;Weili Li,&nbsp;Ke Jian Liu,&nbsp;Jing Yang,&nbsp;Yunzhou Zhang,&nbsp;Xunming Ji,&nbsp;Zhifeng Qi","doi":"10.1111/cns.70321","DOIUrl":"https://doi.org/10.1111/cns.70321","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background and Purpose&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Symptomatic intracranial hemorrhage transformation (s-HT) is a serious complication of ischemic stroke, leading to early neurological deterioration and poor prognosis. It is an urgent problem to timely and effectively identify high-risk patients with s-HT at the early stage of stroke. However, so far, there are no effective clinical detection methods or measures. Therefore, the present study aimed to explore novel blood biomarkers related to s-HT.&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 includes two parts: a retrospective study and a prospective cohort study. In the first part, s-HT patients were screened (&lt;i&gt;n&lt;/i&gt; = 18), and non-s-HTs (&lt;i&gt;n&lt;/i&gt; = 128) were selected from the same period of case patients in the retrospective study cohort. The baseline blood samples were obtained within 30 min of admission, and the levels of 92 proteins related to cerebrovascular diseases were detected using the Olink proteomics technology. Multivariate logistic regression and receiver operating characteristic curves were used to analyze the relationship between serum biomarker levels and s-HT. In the second part, s-HT patients (&lt;i&gt;n&lt;/i&gt; = 28) and non-s-HTs (&lt;i&gt;n&lt;/i&gt; = 130) were selected from a prospective study cohort, which met the same criteria for inclusion and exclusion. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of potential biomarker(s) in serum screened from the first part to confirm its/their association(s) with s-HT.&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;Olink assay showed that patients with s-HT had lower von Willebrand factor (vWF) levels and higher osteoprotegerin, phospholipase C, human insulin-like growth factor binding protein-7, matrix metalloproteinase-2, galectin-4, spondin-1 than non-s-HTs (&lt;i&gt;n&lt;/i&gt; = 128) (&lt;i&gt;p&lt;/i&gt; &lt; 0.005) in a retrospective study cohort. Principal component (PC) and factor analysis showed that the seven biomarkers could explain 62.76% of the variance in the Olink biomarker set, and vWF was a main loading factor in PC2. Multivariate regression analysis showed that a low level of vWF was an independent risk factor (&lt;i&gt;p&lt;/i&gt; &lt; 0.05) for s-HT after adjusting for potential confounders. ELISA test results showed that s-HT patients had a significantly lower vWF levels than the non-s-HT group (26.57 [13.64–37.18] vs. 42.00 [26.02–55.52] ng/mL, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) in the prospective study cohort. Incorporating vWF into the clinical risk factors significantly improved the accuracy of predicting s-HT (area under the curve [AUC, 0.731 vs. 0.641, &lt;i&gt;p&lt;/i&gt; &lt; 0.001], [AUC, 0.747 vs. 0.560, &lt;i&gt;p&lt;/i&gt; &lt; 0.001]) compared to a mo","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698719","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":"Inhibition of Salt-Inducible Kinase 2 Protects Motor Neurons From Degeneration in ALS by Activating Autophagic Flux and Enhancing mTORC1 Activity","authors":"Weiwei Liang,&nbsp;Chunting Zhang,&nbsp;Di Wang,&nbsp;Xiaoli Su,&nbsp;Xingli Tan,&nbsp;Yueqing Yang,&nbsp;Chaohua Cong,&nbsp;Ying Wang,&nbsp;Di Huo,&nbsp;Hongyong Wang,&nbsp;Shuyu Wang,&nbsp;Xudong Wang,&nbsp;Honglin Feng","doi":"10.1111/cns.70341","DOIUrl":"https://doi.org/10.1111/cns.70341","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Autophagic impairment has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Salt-inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK) family widely expressed in the central nervous system, plays critical roles in neuronal survival, neurogenesis, and the regulation of autophagy. This study aims to investigate the effects and underlying mechanisms of SIK2 in the pathogenesis of ALS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In our work, we used both in vivo and in vitro models of ALS to study the effect of SIK2. Protein and RNA levels were assessed by Western blot, RT-qPCR, immunofluorescence, and immunohistochemistry. Cell viability and apoptosis were evaluated using CCK-8 assay and flow cytometry. Transmission electron microscopy was employed to examine autophagic vacuoles. Additionally, lentivirus particles carrying shRNA targeting SIK2 (sh-SIK2) were injected into the lateral ventricle of ALS mice at 60 days of age. Motor performance was evaluated by the rotarod test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed that increased expression of SIK2 significantly contributed to the degeneration of motor neurons in both the cellular model and the hSOD1^G93A transgenic mice model of ALS. SIK2 knockdown enhanced neuronal survival and restored mTORC1 activity. Furthermore, SIK2 suppression facilitated the clearance of mutant SOD1 accumulation by activating autophagic flux and enhancing lysosomal acidification. Conversely, SIK2 overexpression impaired mTORC1 activity, exacerbating autophagy dysfunction by inhibiting lysosomal function, and ultimately led to motor neuron degeneration. In vivo, SIK2 deficiency delayed disease onset and extended the lifespan of ALS mice by enhancing autophagy-mediated clearance of mutant SOD1 aggregates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings reveal that SIK2 regulates autophagic flux by modulating lysosomal acidification, thereby influencing the degradation of mutant SOD1 aggregates. SIK2 suppression enhances autophagy-mediated clearance of toxic protein aggregates and protects motor neurons, highlighting its potential as a therapeutic target for ALS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698720","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":"Differences Between Patients With Multiple System Atrophy With Predominant Parkinsonism and Parkinson's Disease Based on fNIRS and Gait Analysis","authors":"Mengxi Gao,&nbsp;Heng Zhang,&nbsp;Aidi Shan,&nbsp;Yongsheng Yuan,&nbsp;Xingyue Cao,&nbsp;Lina Wang,&nbsp;Caiting Gan,&nbsp;Huimin Sun,&nbsp;Shiyi Ye,&nbsp;Chenghui Wan,&nbsp;Youyong Kong,&nbsp;Kezhong Zhang","doi":"10.1111/cns.70342","DOIUrl":"https://doi.org/10.1111/cns.70342","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate the differences in gait parameters and cortical activity during a single-task walking (STW) and cognitive dual-task walking (DTW) between multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson's disease (PD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>24 MSA-P patients, 20 PD patients, and 22 healthy controls (HCs) were enrolled. Gait parameters were collected using a portable inertial measurement unit system, and the relative change of oxyhemoglobin (ΔHbO₂) in the bilateral frontal and sensorimotor cortex was obtained by functional near-infrared spectroscopy during walking with and without cognitive tasks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MSA-P patients had increased step length variability and higher ΔHbO₂ in the right dorsolateral prefrontal cortex (DLPFC), relative to PD patients and HCs during the DTW condition. Meanwhile, MSA-P patients exhibited higher step length variability and ΔHbO₂ in the right DLPFC during DTW compared to STW. Furthermore, mild negative correlations were found between the ΔHbO₂ in the right DLPFC and step length, while there was a mild positive correlation between ΔHbO₂ and step length variability during the DTW condition. Notably, receiver operating characteristic (ROC) curve analysis uncovered that the areas under the curve (AUCs) of the ΔHbO₂ of the right DLPFC and step length variability during DTW were 0.798 (95% confidence interval [CI]: 0.651–0.945, sensitivity = 0.650, specificity = 0.958) and 0.721 (95% CI: 0.570–0.871, sensitivity = 0.625, specificity = 0.800), respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>MSA-P patients demonstrate more severe gait disturbance and increased DLPFC activity compared with PD patients and HCs. Gait parameters and cortical activity could be a potential features discerning MSA-P patients and PD patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70342","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698721","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":"Long-Term Minocycline Treatment Exhibits Enhanced Therapeutic Effects on Ischemic Stroke by Suppressing Inflammatory Phenotype of Microglia Through the EMB/MCT4/STING Pathway","authors":"Bo Cheng,&nbsp;Shangqi Liu,&nbsp;Ling Gao,&nbsp;Ning Xin,&nbsp;Zhenying Shang,&nbsp;Ziwen Zhu,&nbsp;Yang Yang,&nbsp;Rui Ma,&nbsp;Zixiang Xu,&nbsp;Jing Liu,&nbsp;Dunjing Wang","doi":"10.1111/cns.70328","DOIUrl":"https://doi.org/10.1111/cns.70328","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Neuroinflammation caused by excessive activation of microglia is a significant cause of poor prognosis in ischemic stroke patients. Minocycline, a microglial cell inhibitor, has neuroprotective effects in stroke, but its optimal treatment duration and specific mechanisms of action remain unclear. This study aimed to compare the efficacy of different minocycline treatment durations on stroke and explore their mechanisms of action.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated the effects of various durations of minocycline treatment on microglial polarization using cellular and animal models. The mechanisms of long-term minocycline therapy for neuroprotective effects were explored through in vitro and in vivo experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In stroke models, long-term minocycline treatment showed a stronger inhibitory effect on neuroinflammation and improved neuron viability compared with short-term treatment. Further in vitro and in vivo results indicated that long-term minocycline treatment downregulated microglial glycolysis levels through the EMB/MCT4 axis, promoting the transformation of microglia to an anti-inflammatory phenotype by inhibiting the activation of the STING pathway, thereby improving post-stroke neuroinflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Long-term minocycline therapy exerts neuroprotective effects in ischemic stroke by regulating the EMB/MCT4/STING axis and inhibiting the inflammatory phenotype of microglia through downregulating cellular glycolysis levels. Extending the treatment duration of minocycline appropriately may further improve ischemic stroke outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70328","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698718","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":"TSG-6 Protects Against Cerebral Ischemia–Reperfusion Injury via Upregulating Hsp70-1B in Astrocytes","authors":"Yewei Qu,&nbsp;Lian Yi,&nbsp;Yushi Tang,&nbsp;Fan Yang,&nbsp;Byron Fei Pan,&nbsp;Shanshan Shi,&nbsp;Changda Qu,&nbsp;Fangqin Li,&nbsp;Shirong Wen,&nbsp;Yujun Pan","doi":"10.1111/cns.70354","DOIUrl":"https://doi.org/10.1111/cns.70354","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This study aimed to investigate the relationship between tumor necrosis factor alpha-induced protein (TNFAIP6/TSG-6) and astrocytes in cerebral ischemia/reperfusion (I/R) injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Utilizing in vivo and in vitro cerebral I/R models, cerebral infarct volumes, neurobehavioral outcomes, blood–brain barrier (BBB) permeability, as well as indicators of astrocyte apoptosis, reactivity, and A1 phenotype were assessed to evaluate the effects of recombinant rattus TSG-6 (rrTSG-6) on astrocytes in acute cerebral I/R injury. Following mRNA sequencing of all astrocyte groups, astrocyte apoptosis and reactivity were analyzed through a combined intervention of rrTSG-6 and Apoptozole, a heat shock protein 70-1B (Hsp70-1B) inhibitor, in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The findings demonstrated that rrTSG-6 significantly reduced cerebral infarct volumes by nearly half, improved neurobehavioral outcomes, mitigated BBB damage, and suppressed the expressions of astrocyte apoptosis markers, reactivity indicators, and A1 phenotype markers. mRNA sequencing revealed that the Hsp70-1B protein level increased to approximately 1.6 times that of the rrTSG-6 non-intervention group. Furthermore, Apoptozole impeded the expressions of astrocyte apoptosis markers, reactivity indicators, and A1 phenotype markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>TSG-6 inhibited nuclear factor kappa-B (NF-κB) phosphorylation by upregulating Hsp70-1B in oxygen–glucose deprivation/reoxygenation (OGD/R)-induced astrocytes, thereby exerting a protective effect through anti-apoptotic mechanisms and the suppression of astrocyte reactivity and A1 transformation following cerebral I/R injury.</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.70354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690054","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}