CNS Neuroscience & Therapeutics最新文献

{"title":"SMPD1 as a Potential Prognostic Biomarker in Glioma Is Associated With an Immunosuppressive Microenvironment","authors":"Yanan Xu,&nbsp;Xing Liu,&nbsp;Boya Xu,&nbsp;Qiuling Li,&nbsp;Luofei Zhang,&nbsp;Cao Li,&nbsp;Zhigang Zhao","doi":"10.1002/cns.70813","DOIUrl":"10.1002/cns.70813","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acid sphingomyelinase (ASM), encoded by <i>SMPD1</i>, regulates sphingolipid metabolism and has been implicated in tumor progression and immune modulation. However, its role in glioma remains poorly defined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a comprehensive analysis of <i>SMPD1</i> in gliomas using TCGA and CGGA datasets, evaluating its expression patterns, prognostic significance, immune correlations, pathway enrichment, and copy number variation. Using qRT–PCR, we validated in vitro the effect of SMPD1 expression on macrophage polarization. Immunofluorescence staining was used to assess the levels of ASM of clinical samples and its correlation with tumor-associated macrophages. The functional role of <i>SMPD1</i> was further validated in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>SMPD1</i> expression was significantly elevated in high-grade, IDH-wildtype, and MGMT-unmethylated gliomas. High <i>SMPD1</i> levels were associated with poor prognosis and served as an independent prognostic factor. Tumors with elevated <i>SMPD1</i> showed increased infiltration of regulatory T cells and M0/M2 macrophages. <i>SMPD1</i> expression correlated with multiple immune cell markers and immune checkpoint molecules. Cell-based experiments showed that knocking out or inhibiting ASM drives macrophages toward an M1 phenotype while suppressing M2 polarization. Immunofluorescence analysis confirmed upregulation of ASM protein in high-grade, IDH-wildtype gliomas, with a strong positive correlation with CD163 expression in clinical samples. In vivo, inhibition of <i>SMPD1</i> significantly suppressed glioma growth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p><i>SMPD1</i> is a potential biomarker and therapeutic target in gliomas. Its upregulation may contribute to the formation of an immunosuppressive microenvironment and promote tumor progression, highlighting its potential relevance in glioma immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371959","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":"ShenQi DiHuang Decoction (SQDHD) Ameliorates Neuroinflammation and Neuropsychiatric Manifestations in Pristane Induced Lupus Mice via Blocking JAK1-STAT3 Pathway","authors":"Jie Chen,&nbsp;Chumiao Cui,&nbsp;Fei Xu,&nbsp;Jiayan Feng,&nbsp;Jingyu Chen,&nbsp;Xueru Wang,&nbsp;Hui Yuan,&nbsp;Chenye Jin,&nbsp;Yutian Li,&nbsp;Yang Yun","doi":"10.1002/cns.70814","DOIUrl":"10.1002/cns.70814","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Aims&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Neuroinflammation is widely acknowledged as a crucial pathogenic factor in neuropsychiatric systemic lupus erythematosus (NPSLE). However, specific clinical treatments to mitigate neuroinflammation associated with NPSLE are currently lacking. While ShenQi DiHuang decoction (SQDHD) has demonstrated significant anti-inflammatory effects in lupus nephritis, its efficacy in NPSLE has yet to be investigated. This study aims to explore the neuroprotective effects of SQDHD in NPSLE and to elucidate the underlying mechanisms.&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 vivo, the effects of SQDHD were studied in pristane-induced lupus (PIL) mice using behavioral tests, intravital microscopy, blood–brain barrier (BBB) permeability assessment, cytokine quantification, and brain histopathological analysis. The active compounds and the underlying mechanism of SQDHD action against NPSLE were examined using ultra performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS), network pharmacology, molecular docking, cellular thermal shift assays (CETSAs), and drug affinity responsive target stability (DARTS) assays. In vitro and in vivo experiments were performed to validate the proposed mechanism.&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;SQDHD significantly ameliorated olfactory dysfunction, anxiety, and depression in PIL mice. Additionally, adhesion molecule upregulation, leukocyte recruitment, BBB leakage, and brain pathophysiological alterations, including cytokine overexpression, immunoglobulin G deposition, and lipofuscin accumulation were markedly reduced. By integrating UPLC-MS/MS, network pharmacology, and molecular docking, we predicted the therapeutic mechanism of SQDHD against NPSLE to involve Janus kinase-signal transducer and activator of transcription (JAK–STAT) signaling. Five primary active compounds of SQDHD, Alisol B acetate, Hederagenin, Ellagic acid, Wogonin, and Quercetin, exhibited strong binding affinities to JAK1 and other JAK–STAT pathway components, surpassing the binding affinities of Upadacitinib, a selective JAK1 inhibitor. CETSAs and DARTS assays confirmed the direct interactions between these compounds and JAK1. Alisol B acetate and Hederagenin inhibited the JAK1-STAT3 pathway and its downstream effectors in cerebrovascular endothelial cells (CVECs). In vitro studies in lupus serum-induced CVECs and in vivo studies in PIL mice further corroborated SQDHD downregulation of elevated levels of adhesion molecules, potentially through inhibition of JAK1-STAT3 signaling.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372069","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":"Glymphatic System Dysfunction in Central Nervous System Diseases","authors":"Anwar Zahran,&nbsp;Omar Abu-Khazneh,&nbsp;Mohammad Bdair,&nbsp;Orabi Hajjeh,&nbsp;Mohammed AbuBaha,&nbsp;Waseem Shehadeh,&nbsp;Ameer Awashra,&nbsp;Ibrahim Alazizi,&nbsp;Raya Fuqha,&nbsp;Sakeena Saife,&nbsp;Hasan Fuqha,&nbsp;Fathi Milhem,&nbsp;Husam Hamshary,&nbsp;Dana Abuzahra,&nbsp;Umar Shuaib","doi":"10.1002/cns.70810","DOIUrl":"10.1002/cns.70810","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The glymphatic system is a perivascular cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange pathway that supports brain homeostasis by clearing metabolic waste and neurotoxic proteins. Across central nervous system diseases, converging evidence indicates that glymphatic dysfunction represents a shared pathophysiological axis linking vascular, astroglial, inflammatory, and sleep-related disturbances to impaired solute clearance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and Conclusion</h3>\u0000 \u0000 <p>In this review, we synthesize mechanistic and clinical evidence for glymphatic impairment in acute brain injury (ischemic and hemorrhagic stroke, traumatic brain injury) and chronic neurological disorders (Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, idiopathic normal pressure hydrocephalus, idiopathic intracranial hypertension, epilepsy, and headache disorders). Major mechanisms include (i) aquaporin-4 (AQP4) depolarization/mislocalization at astrocytic endfeet, reducing perivascular water transport; (ii) perivascular space compression or obstruction from cytotoxic/vasogenic edema, blood-derived products, protein aggregates, or altered extracellular matrix; (iii) loss of arterial pulsatility and vascular stiffening, weakening the driving forces for convective exchange; (iv) blood–brain barrier disruption and neuroinflammation, which remodel perivascular architecture and amplify clearance failure; and (v) sleep and autonomic dysregulation, including altered noradrenergic tone, which suppresses glymphatic activity during periods when clearance is normally maximal. Clinically, glymphatic dysfunction can be probed using diffusion tensor imaging–analysis along the perivascular space (DTI-ALPS), contrast-enhanced MRI approaches, and structural surrogates such as enlarged perivascular spaces, with emerging associations to cognition, mood, and disease severity. Finally, we discuss translational strategies aimed at restoring clearance, including sleep/circadian optimization, vascular risk control, anti-inflammatory approaches, AQP4- and TRPV4-oriented targets, and neuromodulation. Mechanism-guided, standardized imaging and longitudinal interventional studies are needed to establish glymphatic biomarkers as actionable therapeutic and prognostic tools.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12965907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369097","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":"Restricting Synaptotagmin-3 Internalization Mitigates Cerebral Ischemia/Reperfusion Injury by Curtailed Neuronal Apoptosis and Microglial Re-Programming","authors":"Hua Xu,&nbsp;Hongbo Mi,&nbsp;Rong Cheng,&nbsp;Tiantian Gui,&nbsp;Fangzhou Hu,&nbsp;Yi Yang,&nbsp;Jian Cheng,&nbsp;Qun Xue","doi":"10.1002/cns.70815","DOIUrl":"10.1002/cns.70815","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Ischemic stroke is a major global cause of disability and death. Synaptotagmin-3 (Syt3), a synaptic calcium sensor, exacerbates ischemic injury by promoting pathological glutamate release. This study investigated the potential neuroprotective effect of restriction of Syt3 internalization on neuronal apoptosis and microglial reprogramming following ischemia/reperfusion (I/R).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The effects of Tat-GluA2-3Y (3Y), a cell-permeable peptide inhibitor of Syt3 internalization, were studied in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and in oxygen–glucose deprivation/reperfusion (OGD/R)-induced HT22 and BV2 cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The peptide 3Y treatment significantly reduced infarct volume, brain edema, and improved neurological deficits. Additionally, it reduced neuronal apoptosis and also inhibited neuroinflammation by down-regulating the level of IL-1b, TNF-a, and iNOS but up-regulating the level of TGF-b1 and Arg-1. Single-nucleus RNA sequencing of the peri-infarct region revealed a dual mechanism: 3Y suppressed pro-apoptotic gene programs in neurons and facilitated the transformation between different phenotypes of microglia via the cAMP pathway from a pro-inflammatory to an anti-inflammatory and immune-protective state. In vitro, 3Y attenuated oxygen–glucose deprivation-induced neuronal death and instructed microglia to adopt a protective, TGF-β1-secreting phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Collectively, our findings establish the inhibition of Syt3 internalization as a novel therapeutic strategy that concurrently protects neurons and reprograms the microglial immune response, offering a promising dual-mechanism approach for acute stroke therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147363465","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":"MCC-135 Exerts Antiepileptic and Neuroprotective Effects by Downregulating NCX1 Expression to Decrease Intracellular Calcium Overload in the Hippocampus","authors":"Chaoning Liu,&nbsp;Min He,&nbsp;Rida Li,&nbsp;Shouhuan Zheng,&nbsp;Lanfeng Sun,&nbsp;Chi Gong,&nbsp;Hengchang Qi,&nbsp;Xinran Qin,&nbsp;Xiaohang Gan,&nbsp;Fang Wang,&nbsp;Yuan Wu","doi":"10.1002/cns.70808","DOIUrl":"10.1002/cns.70808","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Approximately 30% of epilepsy patients still develop drug resistance after standard antiepileptic treatment. Therefore, there is an urgent need to identify new drug targets to improve seizure control. Previous studies have shown that NCX1 can regulate the intracellular Ca²⁺ levels in astrocytes and neurons, which are closely associated with epilepsy. MCC-135 has shown potential as an antiseizure medication due to its ability to downregulate NCX and reduce intracellular calcium overload; however, its role and mechanism in epilepsy remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study employed single-cell analysis and molecular docking to identify the potential molecular targets of MCC-135 in treating epilepsy. Additionally, we used a KA-induced epileptic mouse model to validate these molecular levels and the therapeutic effects and mechanisms of MCC-135.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Relative to controls, NCX1 expression was significantly upregulated in the hippocampus of KA-induced epileptic mice. Immunofluorescence staining revealed that NCX1 was co-localized with both astrocytes and neurons. MCC-135 treatment significantly prolonged the seizure latency in KA-induced epileptic mice and alleviated hippocampal neuronal damage. Furthermore, MCC-135 effectively reduced NCX1 expression, alleviated intracellular calcium overload, and downregulated glutamate levels in the epileptic mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>MCC-135 exerts neuroprotective and antiepileptic effects by downregulating NCX1 expression, thereby alleviating calcium overload and reducing glutamate levels in the hippocampus. We are the first to propose the role and mechanism of MCC-135 in epilepsy treatment, providing novel insights into its potential as a therapeutic agent for epilepsy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147343114","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":"Effects of the STriatal Enriched Tyrosine Phosphatase (STEP) Inhibitor TC-2153 on Hippocampal Long-Term Depression and Synaptic Transmission: Paradoxical Effect on Phosphatase Activity and Role of Adenosine.","authors":"Valentina Chiodi, Rita Pepponi, Lucia Gaddini, Zaira Boussadia, Emilia Marchei, Manuela Pellegrini, Cinzia Mallozzi, Maria Rosaria Domenici","doi":"10.1002/cns.70843","DOIUrl":"10.1002/cns.70843","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to explore the effects of TC-2153, the STriatal Enriched Tyrosine Phosphatase (STEP) inhibitor, on Long-Term Depression (LTD) and basal synaptic transmission in hippocampal slices.</p><p><strong>Methods: </strong>Extracellular field potentials were recorded in the CA1 area of the hippocampal slices. LTD was induced by low-frequency stimulation and by metabotropic glutamate receptor stimulation. The activity of STEP was measured in hippocampal slices and in SH-SY5Y cell culture by a colorimetric assay using p-nitrophenol as a substrate. To evaluate adenosine levels, adenosine was extracted from hippocampal slices homogenates and measured by HPLC.</p><p><strong>Results: </strong>TC-2153 3 μM, applied to the slices one hour before and then along the electrophysiological recordings, blocked both forms of LTD. When hippocampal slices were treated with TC-2153 for shorter periods, 10-20 min, TC-2153 reduced synaptic transmission and increased STEP activity with an adenosine A1 receptor-dependent mechanism. Consistently, we found that TC-2153 increased adenosine levels in hippocampal slices. The increase in STEP activity after brief TC-2153 treatment has been confirmed in SH-SY5Y cells.</p><p><strong>Conclusion: </strong>Our study confirms the role of STEP in LTD and reveals a new mechanism of action for TC-2153. The unexpected adenosine-dependent activation of STEP by TC-2153 has significant implications for both basic research and potential therapeutic applications.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":"e70843"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508233","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":"Dynamic Reconfiguration of Cognitive Networks and Recovery From Microlesion Effects in Parkinson's Disease: Insights From a Longitudinal fNIRS Study.","authors":"Xiang Wei, Yuting Tian, Qiutian Lu, Jingxuan Liu, Guanghan Lu, Jian Sun, Bei Luo, Liang Zhao, Chang Qiu, Wenwen Dong, Wenbin Zhang","doi":"10.1002/cns.70835","DOIUrl":"10.1002/cns.70835","url":null,"abstract":"<p><strong>Background: </strong>Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) significantly improves motor symptoms in advanced Parkinson's disease (PD). However, the perioperative \"microlesion effect\" (MLE) is often associated with cognitive dysfunction, notably declines in verbal fluency (VFT). The dynamic neural mechanisms underlying cognitive network impairment during the MLE phase and functional reorganization following DBS stimulation remain poorly understood.</p><p><strong>Aims and methods: </strong>This study employed longitudinal task-based functional near-infrared spectroscopy (fNIRS) to prospectively track 20 PD patients undergoing bilateral STN-DBS. To effectively disentangle the effects of natural surgical recovery from those specific to electrical stimulation, data were collected at four critical time points: 1 day preoperatively (Pre, T0), 7 days postoperatively (MLE phase, Post, T1), 1 month postoperatively with stimulation off (endpoint of natural recovery, Off, T2), and 1 week after stimulation onset (T3). VFT behavioral performance and global cognitive function (MoCA) were assessed concurrently. Hemodynamic signals from fNIRS were analyzed to examine activation changes in the prefrontal-temporal cortices. Furthermore, graph theory analysis was applied to quantify the dynamic evolution of topological properties within the core cognitive and motor networks.</p><p><strong>Results: </strong>VFT scores dropped during MLE (8.70 ± 2.30 to 5.70 ± 1.78, p < 0.01), partially recovering post-stimulation (8.15 ± 2.48, p < 0.05). MoCA scores also declined in MLE (25.40 ± 1.27 to 21.95 ± 1.10, p < 0.001). Neuroimaging showed activated channels decreased from 8 preoperatively to 2 during MLE (FDR-corrected), followed by reactivation to 12 channels after stimulation, particularly in dorsolateral/ventrolateral prefrontal regions. Between-group comparisons revealed enhanced activation in right DLPFC (Ch6), right SMA (Ch19), and left VLPFC (Ch47) after stimulation versus MLE (all p < 0.05, FDR-corrected).</p><p><strong>Conclusion: </strong>Our findings indicate that MLE-related cognitive decline may stem from acute local network disruption, while DBS can promote functional reorganization of cognitive networks. fNIRS proves to be a valuable tool for monitoring DBS-induced neuroplasticity in PD.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":"e70835"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462396","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":"Intraoperative 40 Hz Visual Light Flicker Attenuates Anesthesia/Surgery-Induced Cognitive Impairments in Elderly Mice With Enhanced Cortical-Hippocampal Coherence.","authors":"Jingyao Jiang, Xin Huang, Jin Liu, Juan Xin, Lanyu Zhang, Zhicheng Yue, Qian Li, Tao Zhu, Peng Liang, Zhiyu Huang, Bhushan Sandeep, Jing Yang, Cheng Zhou","doi":"10.1002/cns.70809","DOIUrl":"10.1002/cns.70809","url":null,"abstract":"<p><strong>Background: </strong>Forty Hz light flicker has shown promise in mitigating cognitive impairments, though its mechanisms remain unclear.</p><p><strong>Aims: </strong>This study aimed to use perioperative neurocognitive dysfunction (PND) as a unique model of neural damage to provide a broader understanding of the neural mechanisms underlying the cognitive improvements associated with 40 Hz visual stimulation and offer new insights into the clinical application of PND treatment.</p><p><strong>Materials and methods: </strong>Postoperative cognitive function was assessed through behavioral tests. Male and female mice received various visual light flicker stimuli, including 40 Hz, random, continuous, or no light. Local field potentials were recorded from the hippocampal dentate gyrus (DG) and primary visual cortex.</p><p><strong>Results: </strong>Our results show that among the stimuli, only the 40 Hz flicker improved cognitive function, impaired by anesthesia or surgery. Intraoperative 40 Hz stimulation activated the primary visual cortex and was correlated with enhanced gamma coherence between this region and the hippocampal DG, a coherence that surgery itself notably reduced. This preserved functional connectivity. Additionally, hippocampal DG activity was enhanced, particularly in the gamma frequency range.</p><p><strong>Conclusion: </strong>Our results suggest that 40 Hz flicker mitigates anesthesia/surgery-induced cognitive deficits, potentially through modulating gamma coherence between the visual cortex and hippocampus. These findings provide insights into PND prevention and the neural mechanisms underlying 40 Hz-induced cognitive benefits.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":"e70809"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372053","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":"SYNGR3 Accelerates α-Synuclein Aggregation and Neurodegeneration in Parkinson's Disease.","authors":"Xin Wang, Jiaolong Yang, Ziku Wang, Zhichao Liu, Wei Tan, Zhentao Zhang","doi":"10.1002/cns.70842","DOIUrl":"10.1002/cns.70842","url":null,"abstract":"<p><strong>Background and aims: </strong>The aggregation of α-synuclein (α-syn) is a central event in Parkinson's disease (PD) pathogenesis. However, the cellular factors that initiate and accelerate the process are not fully understood. Synaptogyrin-3 (SYNGR3) is a synaptic vesicle protein whose role in α-syn pathology remains unexplored. This study investigated whether SYNGR3 is a key factor triggering the pathological process of PD.</p><p><strong>Methods: </strong>This study investigated the expression of SYNGR3 in the brains of transgenic A53T α-syn mutant mouse line M83 (TgA53T) PD model mice using Western blot. The direct interaction between SYNGR3 and α-syn was assessed by GST pull-down assays. This study examined the effect of SYNGR3 on α-syn aggregation kinetics and fibril stability in vitro through the thioflavin T (Th T) assays and proteinase K (PK) digestion. By overexpressing or knocking down SYNGR3 in HEK-293 cells stably transfected with α-syn, primary neurons, and TgA53T mice, the effects of enhanced or deficient function of SYNGR3 on α-syn pathology, synaptic integrity, mitochondrial function, and motor behavior were evaluated.</p><p><strong>Results: </strong>SYNGR3 levels were significantly elevated in an age-dependent manner in the striatum of TgA53T mice. The study found that SYNGR3 directly interacts with the central region of α-syn and accelerates its aggregation into fibrils that are more resistant to PK digestion. Overexpression of SYNGR3 exacerbated α-syn aggregation, synaptic protein loss, mitochondrial dysfunction, and apoptosis in cellular models. In vivo, SYNGR3 intensified α-syn pathology, dopaminergic neurodegeneration, and PD-like motor deficits. Conversely, knockdown of SYNGR3 effectively alleviated these pathological and behavioral impairments.</p><p><strong>Conclusion: </strong>This study identifies SYNGR3 as a novel and critical promoter of α-syn aggregation and neurotoxicity. These findings establish SYNGR3 as a key contributor to PD pathogenesis and highlight its potential as a therapeutic target for intervention.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":"e70842"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508177","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 PKA/MBD2 Axis Transcriptionally Represses INPP5A to Modulate PI3K/Akt Signaling and Accelerate Pituitary Tumorigenesis.","authors":"Qian Jiang, Yaorui Wang, Zihan Wang, Quanji Wang, Sihan Li, Linpeng Xu, Zhuo Zhang, Zhoubin Tan, Huaqiu Zhang, Kai Shu, Ting Lei, Yimin Huang, Zhuowei Lei","doi":"10.1002/cns.70817","DOIUrl":"10.1002/cns.70817","url":null,"abstract":"<p><strong>Context and objective: </strong>The malignant progression of pituitary neuroendocrine tumors (PitNETs) is closely associated with abnormalities in the phosphoinositide signaling pathway. This study aims to investigate the regulatory role and molecular mechanism of inositol polyphosphate 5-phosphatase A (INPP5A) in the malignant progression of PitNETs, with a focus on its interaction with the PI3K/Akt signaling pathway and the epigenetic regulator MBD2.</p><p><strong>Setting: </strong>Tongji Hospital of Tongji medical college of Huazhong University of Science and Technology.</p><p><strong>Design: </strong>Analyze genes related to IP3 metabolism in single-cell sequencing samples of PitNETs from NCBI, and perform immunofluorescence staining and statistical analysis on samples from 62 patients with PitNETs.</p><p><strong>Result: </strong>INPP5A was significantly downregulated in PitNETs, and its expression was negatively correlated with tumor invasiveness, Ki67 index, and volume, Overexpression of INPP5A inhibited tumor cell proliferation, migration, and hormone secretion, while knockdown of INPP5A promoted these malignant phenotypes, INPP5A negatively regulated the PI3K/Akt pathway by degrading IP3, MBD2 directly bound to the INPP5A promoter region to mediate transcriptional repression, Activation of PKA signaling phosphorylated MBD2 (at S99), recruited 14-3-3σ to stabilize the MBD2 protein, and enhanced the inhibition of INPP5A.</p><p><strong>Conclusion: </strong>INPP5A acts as a tumor suppressor gene in PitNETs, and its downregulation promotes tumor malignant progression by activating the PI3K/Akt pathway. MBD2 and its PKA-mediated phosphorylation are key mechanisms for INPP5A transcriptional repression. Targeting the MBD2-INPP5A-PI3K/Akt axis may provide a new strategy for the treatment of PitNETs.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 3","pages":"e70817"},"PeriodicalIF":5.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484064","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}