Neurotherapeutics最新文献

{"title":"Transcutaneous auricular nerve stimulation modulates the functional connectivity of the descending pain modulation system and reward network in patients with chronic low back pain","authors":"Tingting Li ,&nbsp;Yuefeng Wu ,&nbsp;Yuanyuan Li,&nbsp;Sierra Anne Hodges,&nbsp;Sveta Reddy,&nbsp;Lucy Chen,&nbsp;Valeria Sacca,&nbsp;Jian Kong","doi":"10.1016/j.neurot.2025.e00611","DOIUrl":"10.1016/j.neurot.2025.e00611","url":null,"abstract":"<div><div>This study aims to examine the modulatory effects of transcutaneous auricular vagus nerve stimulation (taVNS) on Chronic low back pain (cLBP). 70 cLBP patients were recruited and randomized into taVNS or transcutaneous greater auricular nerve stimulation (tGANS) group. Both interventions were administered by participants themselves after initial training (five times/week for four weeks). Magnetic resonance imaging (MRI) data were collected at baseline and after 4-week interventions. Seed-based static and dynamic functional connectivity (sFC and dFC) were performed to investigate the modulation effects on descending pain modulation system and reward network using the periaqueductal gray (PAG) and ventral tegmental area (VTA) as seeds. 51 patients (taVNS: n ​= ​25; tGANS: n ​= ​26) completed the study. Within-group comparisons showed a significant improvement in pain-related outcomes for both groups. Between-group comparisons revealed no significant differences. FC analysis showed that both taVNS and tGANS can increase the PAG - postcentral gyrus sFC. The taVNS is associated with increased PAG - amygdala and PAG - paracentral gyrus and decreased PAG – medial frontal cortex sFCs compared to tGANS. The present study suggest that both taVNS and tGANS can alleviate cLBP through distinct yet overlapping pathways. Our findings underscore the potential of auricular nerve stimulation as a telehealth solution for cLBP and other chronic pain conditions.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00611"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel purine derivatives mitigate hypoxia ischemia related brain injury through agrin, zyxin and synaptotagmin proteins","authors":"Aloïse Mabondzo ,&nbsp;Clémence Disdier ,&nbsp;Amal Bouzid ,&nbsp;Khadidja Side Larbi ,&nbsp;Amalia Tsintzou ,&nbsp;Auriane Maïza ,&nbsp;Boram Kim ,&nbsp;Narciso Costa ,&nbsp;Rania Harati ,&nbsp;Anvi Laetitia Nguyen ,&nbsp;Alain Pruvost ,&nbsp;Hervé Galons ,&nbsp;Nassima Oumata ,&nbsp;Jean Armengaud ,&nbsp;Marlou Knijnenburg ,&nbsp;Gaurav Verma ,&nbsp;Henrik Hagberg ,&nbsp;Pierre Gressens ,&nbsp;Xiaodi F. Chen ,&nbsp;Rifat A. Hamoudi ,&nbsp;Barbara S. Stonestreet","doi":"10.1016/j.neurot.2025.e00621","DOIUrl":"10.1016/j.neurot.2025.e00621","url":null,"abstract":"<div><div>Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns resulting in motor and cognitive impairment. Therapeutic hypothermia is the only treatment approved for HIE. Consequently, there is a critical requirement for additional treatments for hypoxic-ischemic (HI) brain injury because hypothermia is only partially protective. Pharmacological therapeutics are as yet not available to treat HIE. Therefore, we developed a novel trisubstituted purine-derivative drug (BRT_002) to attenuate HI related brain injury. The safety of BRT_002 was confirmed by treating adult rats with BRT_002 (100 ​mg/kg) for 7 days. Postnatal day-7 rats exposed to sham surgery or carotid ligation and 8% FiO₂ for 90 ​min were given BRT_002 (30 ​mg/kg) or placebo intraperitoneally (IP) immediately, 24, and 48 ​h after the induction of HI. Pharmacokinetic studies revealed suitable systemic and brain exposure to BRT_002. Treatment with BRT_002 reduced neuropathological infarct volumes in the neonatal rats. Bioinformatics analyses of proteomic data identified upregulation of Agrin, Zyxin and Syt5 (p ​&lt; ​0.05) in both brain hemispheres in the male and female neonatal rats after treatment with BRT_002. BRT_002 also augmented mitochondrial respiration and produced metabolic changes in mouse neurons exposed to oxygen-glucose deprivation <em>in vitro</em>. Protein-protein interactions suggest that Syt5 interacts with major participants required to attenuate injury and/or facilitate parenchymal brain repair through Fblim1 that include Agrin, Zyxin, Vegfa, Vwf and mitochondrial targets. Our study provides preclinical findings that could serve as a foundation for future clinical trials of this novel purine derivative for the treatment of newborns exposed to HIE.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00621"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of plasma SEMA3E as the diagnostic biomarker for human epilepsy based on integrated bioinformatics analysis","authors":"Xiaxin Yang ,&nbsp;Jianhang Zhang ,&nbsp;Si Chen ,&nbsp;Zhong Yao ,&nbsp;Shuo Xu","doi":"10.1016/j.neurot.2025.e00630","DOIUrl":"10.1016/j.neurot.2025.e00630","url":null,"abstract":"<div><div>Despite advances in understanding epilepsy, challenges persist in identifying accessible and reliable biomarkers. In this study, an integrative analysis was conducted with transcriptomic data from both brain tissue and blood of epilepsy patients to identify common differentially expressed genes (DEGs). Using weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, and logistic regression, a robust epilepsy gene signature was constructed, and a hub gene associated with seizure frequency was identified. Single-cell RNA analysis, functional investigation, and clinical verification were subsequently conducted. Herein, we reported that the hub gene SEMA3E was significantly upregulated in both peripheral blood and epileptic brain tissue, with a positive correlation to seizure frequency. Subsequent analysis revealed that SEMA3E was enriched in excitatory neurons with NRP1 and VEGFR2, contributing to epileptogenesis by enhancing axonal growth. Clinical validation demonstrated that plasma SEMA3E levels were significantly elevated in epilepsy patients and correlated with specific clinical features. Unlike tissue biomarkers, blood-based SEMA3E exhibits advantages such as non-invasiveness and cost-effectiveness, making it suitable for large-scale screening and monitoring. This study highlights SEMA3E as a promising biomarker and therapeutic target for epilepsy, offering novel insights into its molecular and clinical relevance.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00630"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of cerebellar stimulation on awareness recovery in disorders of consciousness (CARE-DoC): A randomized, sham-controlled, crossover clinical trial","authors":"Rong Chen ,&nbsp;Qiong Gao ,&nbsp;Dian-Wei Wu ,&nbsp;Jianmin Hao ,&nbsp;Jing-Jing Zhao ,&nbsp;Xuan Wang ,&nbsp;Ji-Heng He ,&nbsp;Fang Yuan ,&nbsp;Xiao-Gang Kang ,&nbsp;Ling Wang ,&nbsp;Hai-Bo Di ,&nbsp;Chang-Geng Song ,&nbsp;Wen Jiang","doi":"10.1016/j.neurot.2025.e00635","DOIUrl":"10.1016/j.neurot.2025.e00635","url":null,"abstract":"<div><div>Disorders of consciousness (DoC) are major clinical challenges. We aimed to evaluate the effects of cerebellar intermittent theta-burst stimulation (CRB-iTBS) in the treatment of DoC. We conducted a randomized, sham-controlled, double-blind, cross-over clinical trial. Patients with vegetative state/unresponsive wakefulness syndrome or minimally conscious state within 15 days to 1 year after brain injuries were recruited. The bilateral cerebellum was targeted by iTBS for 5 consecutive days under neuronavigation. The primary outcome was the change in Coma Recovery Scale-Revised (CRS-R) total scores after five sessions. Secondary outcomes included changes in CRS-R scores after the first session, the changes in CRS-R subscales and the alterations in “ABCD” EEG patterns after the first and fifth sessions. Follow-up outcomes included six-month functional outcomes and consciousness recovery. We included 44 patients in the intention-to-treat analysis. No significant difference was observed in the change of CRS-R total scores between active and sham groups after five sessions (difference ​= ​0.428, 95 ​% CI ​= ​−0.202 - 1.057, <em>P</em> ​= ​0.180). However, active stimulation induced greater CRS-R improvements after the first session (difference ​= ​1.048, 95 ​% CI ​= ​0.480–1.615, <em>P</em> ​&lt; ​0.001), especially in auditory, visual, oromotor/verbal, and arousal subscales. Active stimulation increased the prevalence of EEG patterns “C” and “D” after both the first and fifth sessions. Favorable six-month functional outcomes and consciousness recovery were associated with an elevation in “ABCD” EEG patterns during active treatment periods. These findings demonstrate that CRB-iTBS exhibits potential as a neuromodulation strategy to promote consciousness recovery in DoC.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00635"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Symptom specific deep brain stimulation for depression","authors":"Martijn Figee ,&nbsp;Patricio Riva Posse ,&nbsp;Helen Mayberg","doi":"10.1016/j.neurot.2025.e00637","DOIUrl":"10.1016/j.neurot.2025.e00637","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00637"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Montelukast alleviates neuroinflammation and improves motor functions in the line 61 model of Parkinson's disease: An exploratory study","authors":"Katharina Strempfl ,&nbsp;Marco Zattoni ,&nbsp;Heike Mrowetz ,&nbsp;Michael S. Unger ,&nbsp;Nikolaos Schörghofer ,&nbsp;Barbara Altendorfer ,&nbsp;Jörg Neddens ,&nbsp;Stefanie Flunkert ,&nbsp;Birgit Hutter-Paier ,&nbsp;Yachao He ,&nbsp;Johan Wallin ,&nbsp;Rodolphe W. Poupardin ,&nbsp;Frank Pietrantonio ,&nbsp;Nadine Paiement ,&nbsp;Horst Zerbe ,&nbsp;Thomas Felder ,&nbsp;Per Svenningsson ,&nbsp;Ludwig Aigner","doi":"10.1016/j.neurot.2025.e00690","DOIUrl":"10.1016/j.neurot.2025.e00690","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative movement disorder of high global burden. Uncertainties regarding its exact etiology have been hindering the development of curative therapies. As microglia, the brain's immune cells, are suspected to contribute to neurodegeneration by instigating neuroinflammation, existing anti-inflammatory agents could potentially serve as disease-modifying treatments for PD. Here we evaluated the impact of montelukast, a leukotriene receptor antagonist and anti-inflammatory drug, on motor symptoms and neuropathology in an α-synuclein transgenic mouse model (Line 61) for early onset/genetic PD. Two -weeks -old male Line 61 mice and non-transgenic littermates received daily 10 ​mg/kg montelukast or vehicle orally for 10 weeks. Motor functions were assessed through behavioral tests. Brain tissue was analyzed via unbiased transcriptomics, biochemically, and histologically for various parameters, including microglial and inflammation mediators. Upon montelukast treatment, Line 61 mice significantly improved their beam walk performance compared to vehicle -treated mice. The striatum and cerebellum of the montelukast -treated group showed microglial changes toward a smaller but more ramified appearance. Transcriptomics analysis revealed <em>SGK1</em>, a serine/threonine kinase upstream of NFκB and known target in PD, as the most downregulated gene in the striatum of montelukast -treated animals. This downregulation correlated with reduced striatal protein levels of activated IκB kinase, suggesting a reduced NFκB pathway activity upon montelukast treatment. Thus, oral montelukast administration might be promising for the management of PD, with specific effects on motor coordination and balance.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00690"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response","authors":"Hui Sun ,&nbsp;Shenrui Guo ,&nbsp;Hongfu Jin ,&nbsp;Lin Ding ,&nbsp;Yuanyuan Chen ,&nbsp;Yu Zhang ,&nbsp;Kun He ,&nbsp;Qi Huang ,&nbsp;Jinyuan Gu ,&nbsp;Suyun Chen ,&nbsp;Hui Wang ,&nbsp;Chenglai Fu ,&nbsp;Yafu Yin ,&nbsp;Weiwei Cheng","doi":"10.1016/j.neurot.2025.e00618","DOIUrl":"10.1016/j.neurot.2025.e00618","url":null,"abstract":"<div><div>Cerebral glucose hypometabolism has been consistently associated with Alzheimer's disease (AD). With extensive efforts to eliminate AD pathologies, including the removal of amyloid-β ​(Aβ) plaques and hyperphosphorylated Tau, strategies aimed at restoring glucose metabolism in the brain regions most affected by AD are believed to have significant clinical implications. In this study, we demonstrated that glucose hypometabolism preceded neuronal death in triple-transgenic AD (3xTg-AD) mice, likely attributable to reduced expression of glucose transporter type 1 (GLUT1) or glucose transporter type 3 (GLUT3). Furthermore, we observed aberrant activation of the integrated stress response (ISR) pathway in AD models, with Aβ and Tau phosphorylation contributing to the activation of the ISR and subsequent reduction in GLUT1/3 expression. Inhibiting ISR activation by utilizing the ISR inhibitor ISRIB can effectively restore GLUT1/3 expression in both <em>in vitro</em> and <em>in vivo</em> models. Importantly, ISRIB treatment improved cognitive function and brain glucose metabolism in 3xTg-AD mice. Our findings suggest that targeting the ISR pathway to restore GLUTs expression may be a potential therapeutic strategy for AD.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00618"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vibration stimulation to the lower limbs improves freezing of gait and modifies cortical electrical activities in Parkinson's disease","authors":"Puyuan Wen ,&nbsp;Hong Zhu ,&nbsp;Amin Chang ,&nbsp;Xianwen Chen","doi":"10.1016/j.neurot.2025.e00626","DOIUrl":"10.1016/j.neurot.2025.e00626","url":null,"abstract":"<div><div>Muscle vibration, a form of proprioceptive stimulation, is a promising therapeutic method for alleviating freezing of gait in Parkinson's disease. This study aimed to investigate whether vibration stimulation enhances freezing of gait in Parkinson's Disease by modifying sensory-motor integration and cortical excitability. Sixty patients with Parkinson's Disease patients with freezing of gait were enrolled to participate in 10-m Timed Up and Go test with/without lower limbs vibration stimulation during single, cognitive-load, and motor-load task walking. Spatiotemporal gait data were collected from 36 patients during timed up and go tests with unilateral vibration to the less affected or more affected side and bilateral stimulation. Additionally, 22 and 28 patients with and without freezing of gait, respectively, underwent neuroelectrophysiological evaluations with/without vibration stimulation. Spatiotemporal gait and neuroelectrophysiological relative changes in patients with freezing of gait were compared between “ON” and “OFF” vibration. Our results showed both unilateral and bilateral vibration stimulation improved gait and reduced freezing of gait, with more pronounced effects on the less affected side. Patients with freezing of gait revealed decreased latency afferent inhibition and short interval intracortical inhibition in comparison to patients without freezing of gait and healthy controls. Bilateral vibration stimulation improved latency afferent inhibition and short interval intracortical inhibition, which could be attributed to improvements in gait. Overall, our findings suggested that vibration stimulation improved gait and freezing of gait in Parkinson's disease, potentially by enhancing sensory-motor integration and modifying cortical excitability.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00626"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preoperative network activity predicts the response to subthalamic DBS for Parkinson's disease","authors":"Prashin Unadkat ,&nbsp;An Vo ,&nbsp;Yilong Ma ,&nbsp;Chris C. Tang ,&nbsp;Vijay Dhawan ,&nbsp;Martin Niethammer ,&nbsp;Nha Nguyen ,&nbsp;Shichun Peng ,&nbsp;Akash Mishra ,&nbsp;Ritesh Ramdhani ,&nbsp;Albert Fenoy ,&nbsp;Silvia Paola Caminiti ,&nbsp;Daniela Perani ,&nbsp;David Eidelberg","doi":"10.1016/j.neurot.2025.e00699","DOIUrl":"10.1016/j.neurot.2025.e00699","url":null,"abstract":"<div><div>Quantitative imaging markers to aid in the selection of Parkinson's disease (PD) patients for surgical interventions such as subthalamic nucleus deep brain stimulation (STN-DBS) are currently lacking. Using metabolic PET and network analysis we identified and validated a treatment-induced topography, termed STN StimNet. Stimulation-mediated changes in network expression correlated with concurrent motor improvement in independent STN-DBS cohorts scanned on and off stimulation. Moreover, STN StimNet measurements off stimulation correlated with local field potentials recorded from the STN, whereas intraoperative modulation of cortical activity by STN stimulation correlated with contributions to the network from corresponding brain regions. These findings suggested that stimulation-mediated clinical responses are influenced by baseline StimNet expression. Indeed, we found that motor outcomes following STN-DBS were predicted by preoperative network expression measured using metabolic PET or resting-state fMRI. To illustrate the potential utility of these measures in selecting optimal candidates for DBS surgery, STN StimNet expression was computed in scans from 175 PD patients (0–21 years from diagnosis). The resulting values were used to identify those individuals likely to derive meaningful benefit from a potential STN-DBS procedure. This approach suggests that preoperative network quantification provides unique information regarding baseline brain circuitry, which may be useful in surgical decision making.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00699"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysophosphatidic acid receptor 5 in insular cortex as a potential analgesic target in neuropathic pain","authors":"Bing Wang ,&nbsp;Xiaozhou Feng ,&nbsp;Kristen Woodhouse ,&nbsp;Dilip Sharma ,&nbsp;Xianglei Meng ,&nbsp;Huijie Shang ,&nbsp;Huijuan Hu ,&nbsp;Dehui Zhang ,&nbsp;Yanan Zhang ,&nbsp;Jun-Xu Li ,&nbsp;Yuan-Xiang Tao","doi":"10.1016/j.neurot.2025.e00609","DOIUrl":"10.1016/j.neurot.2025.e00609","url":null,"abstract":"<div><div>Neuropathic pain remains a significant clinical challenge and existing treatments have limited efficacy and often over rely on opioids. Pharmacological inhibition and genetic knockout of lysophosphatidic acid receptor 5 (LPA5) lead to an analgesic effect on nerve injury-induced nociceptive hypersensitivity in rodents. However, the specific pain-associated regions where LPA5 is required for neuropathic pain remain unidentified. Here, we demonstrate a site-specific increase in the levels of <em>Lpa5</em> mRNA and LPA5 protein in the contralateral insular cortex and hippocampus 3–14 days after chronic constriction injury (CCI) of the unilateral sciatic nerve in mice. Blocking this time-dependent increase through microinjection of adeno-associated virus 5 (AAV5) expressing <em>Lpa5</em> shRNA (AAV5-LPA5 shRNA) into insular cortex mitigated CCI-induced development of nociceptive hypersensitivities. This effect was not seen after microinjection of AAV5-LPA5 shRNA into the hippocampus. Mimicking this increase through microinjection of AAV5 expressing full-length <em>Lpa5</em> mRNA into the insular cortex augmented responses to mechanical, heat and cold stimuli and induced ongoing pain in naïve mice. Moreover, systemic administration of selective LPA5 antagonist RLPA-76 alleviated CCI-induced mechanical allodynia and heat hyperalgesia. All treated mice displayed normal locomotor activities. Altogether, these findings suggest that LPA5 in the insular cortex plays a critical role in neuropathic pain genesis and support LPA5 as a potential target for neuropathic pain treatment.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 5","pages":"Article e00609"},"PeriodicalIF":6.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}