Frontiers in Molecular Neuroscience最新文献

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Retraction: Icariin reduces dopaminergic neuronal loss and microglia-mediated inflammation in vivo and in vitro. 撤回:淫羊藿苷可减轻体内和体外多巴胺能神经元的损失以及小胶质细胞介导的炎症。
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-20 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1441744
{"title":"Retraction: Icariin reduces dopaminergic neuronal loss and microglia-mediated inflammation <i>in vivo</i> and <i>in vitro</i>.","authors":"","doi":"10.3389/fnmol.2024.1441744","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1441744","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.3389/fnmol.2017.00441.].</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1441744"},"PeriodicalIF":3.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The role of Foxo3a in neuron-mediated cognitive impairment. Foxo3a 在神经元介导的认知障碍中的作用
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-19 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1424561
Qin-Qin Liu, Gui-Hua Wu, Xiao-Chun Wang, Xiao-Wen Xiong, Rui-Wang, Bao-Le Yao
{"title":"The role of Foxo3a in neuron-mediated cognitive impairment.","authors":"Qin-Qin Liu, Gui-Hua Wu, Xiao-Chun Wang, Xiao-Wen Xiong, Rui-Wang, Bao-Le Yao","doi":"10.3389/fnmol.2024.1424561","DOIUrl":"10.3389/fnmol.2024.1424561","url":null,"abstract":"<p><p>Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1424561"},"PeriodicalIF":3.5,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia. STIM1 在钙离子进入贮存器中的作用及其对三叉神经痛中 T 细胞介导的炎症的影响的新见解。
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-19 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1391189
Guangyu Cheng, Yu Zhao, Fujia Sun, Qi Zhang
{"title":"Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia.","authors":"Guangyu Cheng, Yu Zhao, Fujia Sun, Qi Zhang","doi":"10.3389/fnmol.2024.1391189","DOIUrl":"10.3389/fnmol.2024.1391189","url":null,"abstract":"<p><p>This investigation aims to elucidate the novel role of Stromal Interaction Molecule 1 (STIM1) in modulating store-operated calcium entry (SOCE) and its subsequent impact on inflammatory cytokine release in T lymphocytes, thereby advancing our understanding of trigeminal neuralgia (TN) pathogenesis. Employing the Gene Expression Omnibus (GEO) database, we extracted microarray data pertinent to TN to identify differentially expressed genes (DEGs). A subsequent comparison with SOCE-related genes from the Genecards database helped pinpoint potential target genes. The STRING database facilitated protein-protein interaction (PPI) analysis to spotlight STIM1 as a gene of interest in TN. Through histological staining, transmission electron microscopy (TEM), and behavioral assessments, we probed STIM1's pathological effects on TN in rat models. Additionally, we examined STIM1's influence on the SOCE pathway in trigeminal ganglion cells using techniques like calcium content measurement, patch clamp electrophysiology, and STIM1- ORAI1 co-localization studies. Changes in the expression of inflammatory markers (TNF-α, IL-1β, IL-6) in T cells were quantified using Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) <i>in vitro</i>, while immunohistochemistry and flow cytometry were applied <i>in vivo</i> to assess these cytokines and T cell count alterations. Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression. Experimental findings from both <i>in vitro</i> and <i>in vivo</i> studies corroborated STIM1's regulatory influence on the SOCE pathway. Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development. Supportive evidence from histological, ultrastructural, and behavioral analyses reinforced the link between STIM1-mediated SOCE and T lymphocyte-driven inflammation in TN pathogenesis. This study presents novel evidence that STIM1 is a key regulator of SOCE and inflammatory cytokine release in T lymphocytes, contributing significantly to the pathogenesis of trigeminal neuralgia. Our findings not only deepen the understanding of TN's molecular underpinnings but also potentially open new avenues for targeted therapeutic strategies.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1391189"},"PeriodicalIF":3.5,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11221526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Editorial: Molecular and cellular mechanisms of sensory functions in insect models, volume II. 社论:昆虫模型感官功能的分子和细胞机制,第二卷。
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-17 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1443041
Takaaki Sokabe, Jia Huang, Youngseok Lee
{"title":"Editorial: Molecular and cellular mechanisms of sensory functions in insect models, volume II.","authors":"Takaaki Sokabe, Jia Huang, Youngseok Lee","doi":"10.3389/fnmol.2024.1443041","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1443041","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1443041"},"PeriodicalIF":3.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Editorial: Restoring neural circuits after spinal cord injury. 社论:恢复脊髓损伤后的神经回路。
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-17 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1428164
Aikeremujiang Muheremu, Jianjun Wu
{"title":"Editorial: Restoring neural circuits after spinal cord injury.","authors":"Aikeremujiang Muheremu, Jianjun Wu","doi":"10.3389/fnmol.2024.1428164","DOIUrl":"10.3389/fnmol.2024.1428164","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1428164"},"PeriodicalIF":3.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs. 利用 omics 解决体外神经变性问题:通往新目标和新药物之路。
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-17 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1414886
Caterina Carraro, Jessica V Montgomery, Julien Klimmt, Dominik Paquet, Joachim L Schultze, Marc D Beyer
{"title":"Tackling neurodegeneration <i>in vitro</i> with omics: a path towards new targets and drugs.","authors":"Caterina Carraro, Jessica V Montgomery, Julien Klimmt, Dominik Paquet, Joachim L Schultze, Marc D Beyer","doi":"10.3389/fnmol.2024.1414886","DOIUrl":"10.3389/fnmol.2024.1414886","url":null,"abstract":"<p><p>Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly urgent considering the long list of late-stage drug candidate failures. Although our knowledge on the pathogenic mechanisms driving neurodegeneration is growing, additional efforts are required to achieve a better and ultimately complete understanding of the pathophysiological underpinnings of NDDs. Beyond the etiology of NDDs being heterogeneous and multifactorial, this process is further complicated by the fact that current experimental models only partially recapitulate the major phenotypes observed in humans. In such a scenario, multi-omic approaches have the potential to accelerate the identification of new or repurposed drugs against a multitude of the underlying mechanisms driving NDDs. One major advantage for the implementation of multi-omic approaches in the drug discovery process is that these overarching tools are able to disentangle disease states and model perturbations through the comprehensive characterization of distinct molecular layers (i.e., genome, transcriptome, proteome) up to a single-cell resolution. Because of recent advances increasing their affordability and scalability, the use of omics technologies to drive drug discovery is nascent, but rapidly expanding in the neuroscience field. Combined with increasingly advanced <i>in vitro</i> models, which particularly benefited from the introduction of human iPSCs, multi-omics are shaping a new paradigm in drug discovery for NDDs, from disease characterization to therapeutics prediction and experimental screening. In this review, we discuss examples, main advantages and open challenges in the use of multi-omic approaches for the <i>in vitro</i> discovery of targets and therapies against NDDs.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1414886"},"PeriodicalIF":3.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Recovery kinetics of dual AAV-mediated human otoferlin expression. 双 AAV 介导的人类奥托费林表达的恢复动力学。
IF 3.5 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-17 eCollection Date: 2024-01-01 DOI: 10.3389/fnmol.2024.1376128
Jonathan B Sellon, Kathy S So, Andrew D'Arcangelo, Sarah Cancelarich, Meghan C Drummond, Peter G Slade, Ning Pan, Tyler M Gibson, Tian Yang, Joseph C Burns, Adam T Palermo, Lars Becker
{"title":"Recovery kinetics of dual AAV-mediated human otoferlin expression.","authors":"Jonathan B Sellon, Kathy S So, Andrew D'Arcangelo, Sarah Cancelarich, Meghan C Drummond, Peter G Slade, Ning Pan, Tyler M Gibson, Tian Yang, Joseph C Burns, Adam T Palermo, Lars Becker","doi":"10.3389/fnmol.2024.1376128","DOIUrl":"10.3389/fnmol.2024.1376128","url":null,"abstract":"<p><p>Deafness-causing deficiencies in <i>otoferlin</i> (<i>OTOF</i>) have been addressed preclinically using dual adeno-associated virus (AAV)-based approaches. However, timing of transduction, recombination of mRNA, and protein expression with dual hybrid AAV methods methods have not previously been characterized. Here, we have established an <i>ex vivo</i> assay to determine the kinetics of dual-AAV mediated expression of <i>OTOF</i> in hair cells of the mouse utricle. We utilized two different recombinant vectors that comprise DB-OTO, one containing the 5' portion of <i>OTOF</i> under the control of the hair cell-specific <i>Myo15</i> promoter, and the other the 3' portion of <i>OTOF</i>. We explored specificity of the <i>Myo15</i> promoter in hair cells of the mouse utricle, established dose response characteristics of DB-OTO <i>ex vivo</i> in an OTOF-deficient mouse model, and demonstrated tolerability of AAV1 in utricular hair cells. Furthermore, we established deviations from a one-to-one ratio of 5' to 3' vectors with little impact on recombined <i>OTOF</i>. Finally, we established a plateau in quantity of recombined <i>OTOF</i> mRNA and protein expression by 14 to 21 days <i>ex vivo</i> with comparable recovery timing to that <i>in vivo</i> model. These findings demonstrate the utility of an <i>ex vivo</i> model system for exploring expression kinetics and establish <i>in vivo</i> and <i>ex vivo</i> recovery timing of dual AAV-mediated <i>OTOF</i> expression.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1376128"},"PeriodicalIF":3.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Frontiers | hnRNPs: roles in neurodevelopment and implication for brain disorders hnRNPs前沿:在神经发育中的作用及对脑部疾病的影响
IF 4.8 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-17 DOI: 10.3389/fnmol.2024.1411639
Pierre Tilliole, Simon Fix, Juliette D. GODIN
{"title":"Frontiers | hnRNPs: roles in neurodevelopment and implication for brain disorders","authors":"Pierre Tilliole, Simon Fix, Juliette D. GODIN","doi":"10.3389/fnmol.2024.1411639","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1411639","url":null,"abstract":"Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a family of multifunctional RNA-binding proteins able to process nuclear pre-mRNAs into mature mRNAs and regulate gene expression in multiple ways. They comprise at least 20 different members in mammals, named from A (HNRNP A1) to U (HNRNP U). Many of these proteins are components of the spliceosome complex and can modulate alternative splicing in a tissue-specific manner. Notably, while genes encoding hnRNPs exhibit ubiquitous expression, increasing evidence associate these proteins to various neurodevelopmental and neurodegenerative disorders, such as intellectual disability, epilepsy, microcephaly, amyotrophic lateral sclerosis, or dementias, highlighting their crucial role in the central nervous system. This review explores the evolution of the hnRNPs family, highlighting the emergence of numerous new members within this family, and sheds light on their implications for brain development.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"26 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141721582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Frontiers | Copper Toxicity and Deficiency: The Vicious Cycle at the Core of Protein Aggregation in ALS 铜的毒性和缺乏:ALS蛋白聚集核心的恶性循环
IF 4.8 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-14 DOI: 10.3389/fnmol.2024.1408159
Jin-Hong Min, Robert A. Harris, Heela Sarlus
{"title":"Frontiers | Copper Toxicity and Deficiency: The Vicious Cycle at the Core of Protein Aggregation in ALS","authors":"Jin-Hong Min, Robert A. Harris, Heela Sarlus","doi":"10.3389/fnmol.2024.1408159","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1408159","url":null,"abstract":"The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"60 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141576867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Frontiers | Disease-Modifying rdHSV-CA8* Non-Opioid Analgesic Gene Therapy Treats Chronic Osteoarthritis Pain by Activating Kv7 Voltage-Gated Potassium Channels 疾病修饰rdHSV-CA8*非阿片类镇痛剂基因疗法通过激活Kv7电压门控钾通道治疗慢性骨关节炎疼痛
IF 4.8 3区 医学
Frontiers in Molecular Neuroscience Pub Date : 2024-06-13 DOI: 10.3389/fnmol.2024.1416148
Gerald Z. Zhuang, William F. Goins, Munal Kandel, Marco Marzulli, Mingdi Zhang, Joseph C. Glorioso, Yuan Kang, Alexandra E. Levitt, Konstantinos D. Sarantopoulos, Roy C. Levitt
{"title":"Frontiers | Disease-Modifying rdHSV-CA8* Non-Opioid Analgesic Gene Therapy Treats Chronic Osteoarthritis Pain by Activating Kv7 Voltage-Gated Potassium Channels","authors":"Gerald Z. Zhuang, William F. Goins, Munal Kandel, Marco Marzulli, Mingdi Zhang, Joseph C. Glorioso, Yuan Kang, Alexandra E. Levitt, Konstantinos D. Sarantopoulos, Roy C. Levitt","doi":"10.3389/fnmol.2024.1416148","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1416148","url":null,"abstract":"Chronic pain is common in our population, and most of these patients are inadequately treated, making the development of safer analgesics a high priority. Knee osteoarthritis (OA) is a primary cause of chronic pain and disability worldwide, and lower extremity OA is a major contributor to loss of quality-adjusted life-years. In this study we tested the hypothesis that a novel JDNI8 replication-defective herpes simplex-1 viral vector (rdHSV) incorporating a modified carbonic anhydrase-8 transgene (CA8*) produces analgesia and treats monoiodoacetate-induced (MIA) chronic knee pain due to OA. We observed transduction of lumbar DRG sensory neurons with these viral constructs (vHCA8*) (~40% of advillin-positive cells and ~ 50% of TrkA-positive cells colocalized with V5-positive cells) using the intra-articular (IA) knee joint (KJ) route of administration. vHCA8* inhibited chronic mechanical OA knee pain induced by MIA was dose- and time-dependent. Mechanical thresholds returned to Baseline by D17 after IA KJ vHCA8* treatment, and exceeded Baseline (analgesia) through D65, whereas negative controls failed to reach Baseline responses. Weight-bearing and automated voluntary wheel running were improved by vHCA8*, but not negative controls. Kv7 voltage-gated potassium channel-specific inhibitor XE-991 reversed vHCA8*-induced analgesia. Using IHC, IA KJ of vHCA8* activated DRG Kv7 channels via dephosphorylation, but negative controls failed to impact Kv7 channels. XE-991 stimulated Kv7.2–7.5 and Kv7.3 phosphorylation using western blotting of differentiated SH-SY5Y cells, which was inhibited by vHCA8* but not by negative controls. The observed prolonged dose-dependent therapeutic effects of IA KJ administration of vHCA8* on MIA-induced chronic KJ pain due to OA is consistent with the specific activation of Kv7 channels in small DRG sensory neurons. Together, these data demonstrate for the first-time local IA KJ administration of vHCA8* produces opioid-independent analgesia in this MIA-induced OA chronic pain model, supporting further therapeutic development.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"32 1","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141721581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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