Neuropeptides最新文献

{"title":"Tauopathies: Emerging discoveries on tau protein, with a special focus on Alzheimer's disease","authors":"Aishwarya Hattiholi ,&nbsp;Harsha Hegde ,&nbsp;Suhas Kumar Shetty","doi":"10.1016/j.npep.2025.102536","DOIUrl":"10.1016/j.npep.2025.102536","url":null,"abstract":"<div><div>Tauopathies encompass a group of neurodegenerative disorders (NDDs) driven by the abnormal accumulation of mutated tau protein, leading to hyperphosphorylation, neuronal damage, and neuroinflammation. The protein plays essential roles in brain function but undergoes hyperphosphorylation and aggregation into toxic oligomers in NDDs. Recent research emphasizes the need to understand tau's post-translational modifications (PTMs) and their role in pathological states. Insights into tau's structure, isoform-specific properties, and aggregation mechanisms are critical for elucidating its propagation in neurodegeneration. Moreover, tau's potential as a biomarker and the development of targeted therapies to mitigate tauopathies, particularly in AD, remain promising avenues. However, many strategies targeted at tau have repeatedly failed, which continues the search for better alternatives. This review focuses on recent advances in tau research, highlighting its structural and functional characteristics, and roles in disease, that may be critical to understanding their implications for new therapeutic strategies. PTMs are important for the stable structure and physiological functions of a protein. However, dysfunctional PTMs are the leading causes of tau protein aggregation. The recent shift on tau hyperphosphorylation has resulted in many discoveries related to their functions in AD. Therapeutic strategies targeting phosphorylated tau are being extensively studied worldwide. This paper gives a comprehensive view on these aspects.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"112 ","pages":"Article 102536"},"PeriodicalIF":2.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571243","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}

{"title":"Dynorphin B induces mitochondrial fragmentation in NSCLC through the PKD/DRP-1 signaling pathway","authors":"Yunxiao Li ,&nbsp;Bin Zhou ,&nbsp;Yuenan Yang ,&nbsp;Kexin Liu ,&nbsp;Shichao Zhou","doi":"10.1016/j.npep.2025.102535","DOIUrl":"10.1016/j.npep.2025.102535","url":null,"abstract":"<div><div>Mitochondrial fragmentation and impairment are essential targets for therapeutic approach for non-small cell lung cancer (NSCLC), given their significant contributions to the persistence and progression of malignant cells. Dynorphin B (Dyn B), an endogenous opioid peptide, has been demonstrated for its involvement in an extensive array of cellular activities; however, its specific functions and mechanisms within the context of cancer remain largely undefined. To address this, we employed NCI-H2087 NSCLC cells treated with Dyn B (0.01–100 μM) and utilized lactate dehydrogenase (LDH) release and γ-glutamyl transpeptidase (GPT) activity assays to evaluate cytotoxicity. Mitochondrial function was assessed via Complex I activity assays, adenosine triphosphate (ATP) production measurements, and MitoSOX Green staining for reactive oxygen species (ROS). MitoTracker Red staining with ImageJ quantification characterized mitochondrial morphology, while Western blot analysis probed phosphorylation of dynamin-related protein 1 (DRP1) and protein kinase D (PKD). Lentiviral shRNA-mediated PKD silencing was used to validate functional rescue of mitochondrial dynamics. This investigation reveals that Dyn B induces cytotoxic effects in NCI-H2087 NSCLC cells by facilitating mitochondrial dysfunction and fragmentation. Treatment with Dyn B resulted in a significant augmentation of LDH and elevated GPT activity, indicating cellular injury. Additionally, Dyn B compromised mitochondrial functionality by reducing Complex I activity, diminishing ATP synthesis, and promoting mitochondrial ROS generation. Mechanistically, Dyn B triggered mitochondrial fragmentation through activation of DRP1 and PKD, without affecting protein kinase C (PKC). Silencing of PKD reversed Dyn B–induced mitochondrial fragmentation and restored mitochondrial functionality. These findings underscore the promising role of Dyn B as a prospective therapeutic agent in NSCLC, targeting mitochondrial dynamics via the PKD-DRP1 signaling pathway.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"112 ","pages":"Article 102535"},"PeriodicalIF":2.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517632","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}

{"title":"Neuroprotective effect of Ac-SDKP peptide in SH-SY5Y cells and rat model of Parkinson's disease against 6-OHDA-induced oxidative stress and ER stress","authors":"Maryam Kamarehei ,&nbsp;Hamid Zahednasab","doi":"10.1016/j.npep.2025.102534","DOIUrl":"10.1016/j.npep.2025.102534","url":null,"abstract":"<div><div>Oxidative stress and endoplasmic reticulum (ER) stress are key contributors to the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD), for which no definitive cure currently exists. This study investigated the neuroprotective potential of the <em>N</em>-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) tetrapeptide in both in vitro and in vivo PD models. In cell-based analyses, pre-treatment with 20 nM Ac-SDKP provided significant protection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. In vivo, the neuroprotective potential of the peptide was also supported through daily administration of rats with Ac-SDKP (800 μg/kg) after 6-OHDA lesioning, which unveiled a series of significant observations. Treated animals demonstrated highly preserved dopaminergic neurons through reduced activation of apoptotic markers such as caspase-3 and caspase-12. In addition to cytoprotection, Ac-SDKP also produced striking behavioral improvement. Treated animals exhibited improved motor coordination and ability on spatial memory tasks, as well as the significant attenuation of anxiety-like and depressive-like behaviors. Such behavioral improvement is probable because Ac-SDKP possesses the ability to modulate several pathological features of PD. In fact, the peptide was able to decrease oxidative stress, diminish ER stress, and inhibit neuroinflammatory signaling. Collectively, these findings position Ac-SDKP as a promising neuroprotection candidate, and as a candidate with potential to be developed as a multifactorial treatment for the complex pathophysiology of PD.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"112 ","pages":"Article 102534"},"PeriodicalIF":2.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330967","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}

{"title":"Rapamycin reveals neuropeptide Y as a regulator of senescence and inflammatory pathways in arthritis","authors":"Susana Aideé González-Chávez ,&nbsp;Eduardo Chaparro-Barrera ,&nbsp;Mario Loya-Rivera ,&nbsp;Alejandra Jazmín Rodríguez-Castillo ,&nbsp;Rodrigo Prieto-Carrasco ,&nbsp;Renato J. Aguilera ,&nbsp;Ana P. Betancourt ,&nbsp;Jonathon E. Mohl ,&nbsp;Daniel Alberto Ruizesparza-Hinojos ,&nbsp;Sergio de Jesús Ramírez-Pérez ,&nbsp;Mercedes Bermúdez ,&nbsp;César Pacheco-Tena","doi":"10.1016/j.npep.2025.102533","DOIUrl":"10.1016/j.npep.2025.102533","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune dysregulation and joint destruction. Cellular senescence has been implicated in the progression of RA through the senescence-associated secretory phenotype (SASP), yet its molecular links to inflammation remain unclear. Rapamycin, an mTOR inhibitor with anti-inflammatory and anti-senescence properties, provides a valuable tool for exploring these mechanisms.</div></div><div><h3>Objective</h3><div>To investigate the link between senescence and inflammation in a murine model of RA by comparing the transcriptome of diseased joints in rapamycin-treated and untreated mice.</div></div><div><h3>Methods</h3><div>Collagen-induced arthritis was established in DBA/1 mice, followed by 40 days of rapamycin treatment. RNA sequencing and bioinformatic analyses were performed to identify differentially expressed genes and altered signaling pathways. RT-qPCR and immunohistochemistry validated candidate genes. Functional assays were conducted in fibroblast-like synoviocytes (FLS) following <em>Npy</em> silencing.</div></div><div><h3>Results</h3><div>Rapamycin treatment reduced the incidence and severity of arthritis while modulating senescence- and autophagy-related pathways. Transcriptomic analysis identified neuropeptide Y (<em>Npy</em>) as a differentially expressed gene linking senescence and inflammation, with reduced protein levels following rapamycin treatment, similar to TNF and β-galactosidase. NPY receptor expression (<em>Npy1r</em> and <em>Npy2r</em>) and autophagy-related genes (<em>Sirt1</em>, <em>Sirt6</em>, and <em>Lc3b</em>) were also modulated in vivo. In vitro, <em>Npy</em> silencing in FLS significantly reduced the expression of the SASP cytokines <em>Tnfa</em>, <em>Il1b</em>, and <em>Il6</em>, downregulated <em>Npy1r</em> and <em>Npy2r</em>, and increased <em>Sirt1</em> expression.</div></div><div><h3>Conclusion</h3><div>This study identifies <em>Npy</em> as a modulator of inflammation and senescence-related pathways in arthritis. Its regulation by rapamycin and impact on sirtuins, autophagy, and NPY receptor expression suggest a broader role in RA pathogenesis.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"112 ","pages":"Article 102533"},"PeriodicalIF":2.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308168","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}

{"title":"Effects of oxytocin on behavior and neurotrophic factors in the brain of aged female rats exposed to chronic social isolation","authors":"Helin Demirtas ,&nbsp;Burcu Acikgoz ,&nbsp;Ayca Arslankiran ,&nbsp;Bahar Dalkiran ,&nbsp;Amac Kiray ,&nbsp;Muge Kiray ,&nbsp;Ayfer Dayi ,&nbsp;Ilkay Aksu","doi":"10.1016/j.npep.2025.102532","DOIUrl":"10.1016/j.npep.2025.102532","url":null,"abstract":"<div><div>This study aimed to investigate the effects of social isolation stress and intranasally administered oxytocin on physiological and behavioral alterations during aging in rats. A total of 28, aged female Sprague-Dawley rats were allocated into four groups: control (C), social isolation (SI), oxytocin (O), and oxytocin+social isolation (OI). Animals in the SI and OI groups were housed in individual cages for four weeks. Intranasal oxytocin (2 μg/kg/day) was administered to the O and OI groups 14 times during the third and fourth weeks of the study. Behavioral assessments were conducted. Levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were measured. In the Morris water maze test, all groups demonstrated improved learning performance, reflected by a progressive reduction in the time taken to locate the hidden platform. The three-chamber sociability test revealed that sociability was significantly impaired in the SI group but preserved in the O, OI, and C groups. VEGF levels in the prefrontal cortex were significantly reduced in the SI group compared to all other groups. Notably, VEGF levels were higher in the OI group than in the SI group. Hippocampal neuron density was lower in the SI group but was preserved in the OI group, suggesting a neuroprotective effect of oxytocin. These findings highlight the protective roles of oxytocin and sociability against the detrimental effects of chronic social isolation, particularly in preserving hippocampal neuron density and maintaining sociability and learning. Further research is needed to elucidate the molecular and behavioral mechanisms underlying these effects.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"112 ","pages":"Article 102532"},"PeriodicalIF":2.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298115","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}

{"title":"Regulation of the gut-brain-pituitary-gonad axis in tilapia: Evidence for the involvement of orexin","authors":"Mallikarjun Gouda,&nbsp;C.B. Ganesh","doi":"10.1016/j.npep.2025.102525","DOIUrl":"10.1016/j.npep.2025.102525","url":null,"abstract":"<div><div>The neuropeptide orexin is known as the regulator of appetite and is implicated in many physiological functions in vertebrates. Nevertheless, the physiological importance of this peptide within the gut-brain-reproductive axis remains poorly understood in teleosts. This work aimed at assessing the response of orexin to starvation and its impact on food consumption and the reproductive axis in tilapia. In the first experiment, the fish subjected to 21 days of starvation showed a greater increase in the intensity of orexin-A immunoreactivity in the hypothalamus and pituitary gland compared to controls. The administration of either 0.1 or 1 mg orexin antagonist lemborexant (LBX) for 21 days led to a dose-dependent significant reduction in food intake, whereas a significant increase in the numbers of spermatogenic cells was observed in a high-dose LBX-treated group compared to the control fish. Moreover, a high-dose of LBX significantly enhanced the intensity of androgen receptor protein immunolabelling in the testis, percent area of gonadotropin-releasing hormone (GnRH) immunolabelling in the proximal pars distalis of the pituitary gland (PPD), and the serum levels of luteinizing hormone (LH) and 11-ketotestosterone (11-KT). In addition, the <em>in vitro</em> testicular concentration of 11-KT was significantly increased following a high-dose LBX treatment. Overall, these findings suggest that blockade of orexin receptors by LBX promotes the spermatogenesis process. This effect might be mediated <em>via</em> the stimulation of 11-KT and androgen receptors at the testicular level and the GnRH-LH pathway at the hypothalamic-pituitary level in tilapia.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102525"},"PeriodicalIF":2.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134970","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}

{"title":"Luteolin ameliorates kainic acid-induced seizure by modulating GADD45B and reducing oxidative stress in hippocampal neurons","authors":"Can Luo,&nbsp;Zhi Wang,&nbsp;Junbao Liao,&nbsp;Chuanyi Fu,&nbsp;Fan Zhang,&nbsp;Jiannong Zhao","doi":"10.1016/j.npep.2025.102524","DOIUrl":"10.1016/j.npep.2025.102524","url":null,"abstract":"<div><div>Epilepsy is a prevalent neurological disorder impacting numerous people. However, existing anti-seizure medications frequently fall short of adequately managing seizures, highlighting the urgent need for the development of novel therapeutic interventions. This study investigates the neuroprotective effects of luteolin, which is a bioactive compound derived from the traditional Chinese medicine Danshen, on kainic acid (KA)-induced seizure in mice. Network pharmacology analysis identified GADD45B as a key target gene involved in acute epileptic seizure, which is modulated by luteolin. In vivo experiments demonstrated that luteolin significantly reduces seizure severity, frequency, and duration dose-dependently. Histological analyses revealed that luteolin preserves neuronal integrity and reduces hippocampal damage. Moreover, luteolin inhibited neuronal apoptosis and inflammation in KA-induced seizure mice by inhibiting MAPK and NF-κB signaling pathways. Furthermore, luteolin was shown to decrease oxidative stress and apoptosis in glutamate-induced HT22 hippocampal neuronal cells. Molecular docking showed that luteolin can bind with its target protein GADD45B in a good bond by intermolecular force. These neuroprotective effects of luteolin are mediated by the upregulation of GADD45B, which was further confirmed through knockdown experiments that GADD45B knockdown attenuated luteolin's protective actions. The findings suggest that luteolin exerts its therapeutic effects by modulating oxidative stress and apoptosis through GADD45B, offering potential as a novel neuroprotective strategy for seizures.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102524"},"PeriodicalIF":2.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166699","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}

{"title":"PQK7: A novel peptide inhibitor targeting alpha-synuclein fibrillogenesis in Parkinson's disease","authors":"Maryam Motamedi ,&nbsp;Dina Morshedi ,&nbsp;Najaf Allahyari Fard","doi":"10.1016/j.npep.2025.102522","DOIUrl":"10.1016/j.npep.2025.102522","url":null,"abstract":"<div><div>The accumulation of alpha-synuclein (⍺-Syn) fibrils plays a central role in the progression of Parkinson's disease (PD) and related neurodegenerative disorders. In this context, the development of peptide inhibitors designed to inhibit ⍺-Syn through computational methods has emerged as a promising area of research. This study focused on developing a peptide inhibitor, PQK7, designed based on the key residues of NAC region of ⍺-Syn fibrils involved in its aggregation. Using molecular docking and dynamics simulations, PQK7 was shown to bind key residues in the NAC region of ⍺-Syn (Val-74, Ala-76, Val-77, Thr-81, Ser-87, Ile-88, and Ala-89), effectively disrupting the formation of fibrils. MD simulations indicated that the PQK7-⍺-Syn complex reaches a stable conformation, which showed increased fluctuations and reduced β-sheet content, suggests that PQK7 interferes with ⍺-Syn fibrillation at the molecular level. In vitro assays like ThT fluorescence assay, AFM imaging, CD specotroscopy, and SDS-PAGE analysis confirmed that PQK7 significantly reduces ⍺-Syn fibril formation, particularly at substoichiometric concentrations, while keeping ⍺-Syn monomers in a soluble state. Additionally, PQK7-⍺-Syn treatment in SH-SY5Y cells reduced the toxicity of ⍺-Syn aggregates, restoring normal cell cycle progression and reducing apoptosis and oxidative stress. Our findings suggest that PQK7 holds potential as a therapeutic agent for PD, acting as an anti-oligomeric inhibitor that targets early ⍺-Syn aggregates without affecting the protein's normal function.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102522"},"PeriodicalIF":2.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916682","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}

{"title":"Interaction of glucocorticoids and interleukins in the control of hypothalamic neurohypophysial system output in salt loaded male rats","authors":"R.R. Ventura ,&nbsp;S.G. Ruginsk ,&nbsp;A. Lopes da Silva ,&nbsp;D. Badauê-Passos Jr ,&nbsp;H.D. Francescato ,&nbsp;T.M. Coimbra ,&nbsp;L.L.K. Elias ,&nbsp;J. Antunes-Rodrigues","doi":"10.1016/j.npep.2025.102523","DOIUrl":"10.1016/j.npep.2025.102523","url":null,"abstract":"<div><div>The present study investigated the effects of a 4-day salt load (0.3 M NaCl, SL) and dexamethasone treatment (DEXA, 1 mg/Kg, subcutaneous) on the mechanisms possibly underlying glucocorticoid-mediated effects on hypothalamic neurohypophyseal system (HNS) activity. As expected, SL animals developed hyperosmolality, reflecting the progressive increase in plasma sodium concentrations. SL also triggered increased hypothalamic expression of vasopressin (AVP) and oxytocin (OT) messenger RNAs (mRNAs), increased magnocellular neuronal activation, and enhanced plasma hormone concentrations. Plasma corticosterone, interleukin (IL) 1β and tumor necrosis factor alfa, but not IL-6 levels, were also elevated in response to SL. Increased salt consumption also significantly decreased hypothalamic mRNA expression for the p65 subunit of the nuclear factor kappa B (NFkB), and increased mRNA expression for type β NFkB inhibitory protein (IκBβ). The protein expression ratio between phosphorylated and total NFκB was also elevated in SL rats. DEXA administration, in turn, prevented SL-induced AVP and OT release, as well as decreased corticosterone/IL plasma levels. Therefore, the present results suggest that increased salt consumption may originate a systemic-driven pro-inflammatory response, which can contribute to the increased secretion of corticosterone observed in SL animals. We therefore hypothesize that elevated systemic IL levels, in parallel with corticosterone secretion, may constitute, besides hyperosmolality, important redundant stimuli triggering SL-induced neuropeptide release. Conversely, high levels of corticosterone would produce, in the long term, inhibition of HNS activity and the termination of the neurosecretory response.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102523"},"PeriodicalIF":2.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928148","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}

{"title":"Netrin-3 enhances recovery and reduces inflammation following spinal cord injury via suppressing NLRP1 inflammasome activation","authors":"Zhe Li ,&nbsp;Xinghua Song ,&nbsp;Jialai Song","doi":"10.1016/j.npep.2025.102521","DOIUrl":"10.1016/j.npep.2025.102521","url":null,"abstract":"<div><div>Spinal cord injury (SCI) represents a significant challenge in the field of neurology due to its complex pathology and the limited efficacy of current treatments. The search for effective therapeutic strategies has led to investigations into molecules that can promote neural repair and functional recovery. Netrin-3, previously known for its roles in axonal guidance and development, emerges as a potential candidate for enhancing recovery post-SCI. Hereby, we used gene therapy to increase Netrin-3 expression in SCI mouse models and evaluated neurological recovery through behavioral tests, histological assessments, and biochemical analyses. Additionally, we examined the activation of the NOD-like receptor family pyrin domain containing 1 (NLRP1) inflammasome and production of interleukin-1β (IL-1β) and IL-18, and confirmed the dependency of Netrin-3's neuroprotective effects on the Adenosine Monophosphate-activated Protein Kinase (AMPK) pathway using an AMPK inhibitor. Our results explores the impact of Netrin-3 on neurological recovery following SCI. It was observed that Netrin-3 expression markedly decreased at both mRNA and protein levels after injury. Enhancing Netrin-3 levels through gene therapy improved neurological outcomes, including locomotor function, reduced lesion size, and normalized spinal cord water content compared to untreated injured mice. Furthermore, Netrin-3 administration mitigated oxidative stress by modulating malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, and inhibited NLRP1 inflammasome activation, resulting in suppressed IL-1β and IL-18 production. The AMPK pathway was activated by Netrin-3 post-injury, suggesting a mechanism underlying its neuroprotective effects. However, these beneficial impacts were abolished by an AMPK inhibitor, indicating the dependency of Netrin-3's protective actions on the AMPK pathway. Collectively, these findings highlight Netrin-3 as a promising target for developing novel therapies aimed at improving restoration from SCI.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102521"},"PeriodicalIF":2.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937226","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}