BMC Neuroscience最新文献

{"title":"A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models.","authors":"Musaab Abdulrazzaq Qader, Leila Hosseini, Nasrin Abolhasanpour, Farnaz Oghbaei, Leila Maghsoumi-Norouzabad, Hanieh Salehi-Pourmehr, Fatemeh Fattahi, Reza Naghdi Sadeh","doi":"10.1186/s12868-025-00937-9","DOIUrl":"10.1186/s12868-025-00937-9","url":null,"abstract":"<p><p>This systematic review sought to assess the impact of nicotinamide adenine dinucleotide (NAD⁺) precursors on cognitive impairments in several diseases in rat/mouse models. Accumulating evidence suggests that inflammation, apoptosis, oxidative stress responses, and mitochondrial dysfunction are potential factors of cognitive deficits in aging, Alzheimer's disease (AD), diabetes, traumatic brain injury (TBI), vascular dementia (VAD), and schizophrenia. NAD⁺ precursors have received increased interest due to their unique molecular structure targets antioxidant and inflammatory pathways and mitochondrial function. The PubMed, Scopus, Google Scholar, Embase, and Web of Science databases were searched through May 30, 2024. Studies investigating the effect of NAD⁺ precursors on cognitive impairments in rodent models were included. Two reviewers independently extracted and evaluated the data. The PRISMA guidelines for reporting systematic reviews were followed. Thirty preclinical studies were included in the review. Studies have revealed that treatment with NAD⁺ rescues cognitive deficits by inhibiting inflammation, oxidative stress, and apoptosis and improving mitochondrial function. Preclinical evidence has demonstrated that treatment with NAD⁺ precursors may be more effective in learning and memory recovery in AD, TBI, diabetes, aging, VAD, and schizophrenia. The outcomes of this investigation may lead to additional studies on the use of NAD⁺ precursors for treating human cognitive decline.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"17"},"PeriodicalIF":2.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 multisystem exercises on balance, postural stability, mobility, walking speed, and pain in patients with diabetic peripheral neuropathy: a randomized controlled trial.","authors":"Sidra Khurshid, Aruba Saeed, Muhammad Kashif, Aniqa Nasreen, Huma Riaz","doi":"10.1186/s12868-024-00924-6","DOIUrl":"10.1186/s12868-024-00924-6","url":null,"abstract":"<p><strong>Background: </strong>Diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus, is associated with peripheral nerve damage, leading to balance impairments, postural instability, and reduced mobility. Addressing these challenges requires comprehensive interventions that target multiple deficits simultaneously. Evidence suggests that exercise programs combining balance, proprioception, strength, and reaction time training can improve postural stability, enhance mobility, and alleviate pain in individuals with DPN.</p><p><strong>Objective: </strong>The objective of this study was to compare the effects of multisystem exercises and conventional exercises on balance, postural stability, mobility, and walking speed and to reduce pain in patients with diabetic peripheral neuropathy.</p><p><strong>Methods: </strong>This double-blinded, two-arm parallel design randomized controlled trial was conducted at DHQ Hospital, Pakpattan, Pakistan. A total of 50 participants who met the inclusion criteria were recruited using the nonprobability convenience sampling technique. They were randomly assigned to either a multisystem physical exercise (MPE) group (n = 26) and a conventional exercise group (n = 24). The MPE program included balance, proprioception, strength, and reaction time training, while the control group received conventional exercises, consisted of strength, balance, stretching, and range of motion exercises. Both groups underwent 30 min intervention sessions, 3 times per week, for 8 weeks. The outcome measures used for assessing the balance, postural stability, mobility, and pain included the Berg balance scale (BBS), functional reach test (FRT), time up and go test (TUG), 10 min walk test (10-MWT), and numeric pain rating scale (NPRS). The data was analyzed using SPSS version 26.</p><p><strong>Results: </strong>Significant group and time interactions were observed for all outcome measures including BBS, FRT, TUG, 10-MWT, and NPRS (p < 0.001). The between-group analysis also revealed significant differences between the multisystem physical exercise group and the conventional exercise group at both the 4th week and 8th week for BBS, FRT, TUG, 10-MWT, and NPRS (p < 0.05).</p><p><strong>Conclusion: </strong>The study concluded that multisystem exercises resulted in significant improvement in balance, postural stability, mobility, and walking speed, along with reduction in pain, compared to conventional exercises in patients with diabetic peripheral neuropathy.</p><p><strong>Trial registration: </strong>This randomized controlled study was registered prospectively on November 11th, 2023 with the ClinicalTrials.gov (NCT06130917).</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"16"},"PeriodicalIF":2.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social isolation induces sexually aggressive behaviour in male Wistar rats.","authors":"Mbiydzenyuy Elvis Ngala, Sian Megan Joanna Hemmings, Jacqueline Samantha Womersley, Thando W Shabangu, Lihle Qulu-Appiah","doi":"10.1186/s12868-025-00932-0","DOIUrl":"10.1186/s12868-025-00932-0","url":null,"abstract":"<p><strong>Background: </strong>Sexual violence, a pervasive global issue, significantly impacts individuals and societies, necessitating a deeper understanding of its underlying biological mechanisms. This study aimed to elucidate the role of stress-induced dysregulation of the hypothalamus-pituitary-adrenocortical axis in sexual aggression in male Wistar rats. Employing a sexual aggression paradigm, we investigated the effects of social isolation on aggression, anxiety-like behaviour, and neurochemistry in virgin adult male Wistar rats.</p><p><strong>Results: </strong>The results showed that social isolation significantly escalated aggressive behaviours and induced anxiety-like responses in male rats. The sexual aggression test revealed that socially isolated males exhibited heightened aggression towards non-receptive females. Neurochemical analyses indicated significant alterations in key markers, such as corticotrophin-releasing hormone, oxytocin, and arginine vasopressin, correlating with the observed behavioural changes. Gene expression analyses revealed significant findings, particularly in the expression of the oxytocin receptor (OXTR) and vasopressin receptor 1 A (AVPR1A) genes. Social isolation and the duration of aggressive behaviour prior to the sexual aggression test significantly influenced OXTR expression in the hippocampus and AVPR1A expression in both the prefrontal cortex and hippocampus, highlighting the complex interplay between environmental stressors, neurochemical responses, and gene expression in the manifestation of sexual aggression behaviour.</p><p><strong>Conclusions: </strong>This study underscores the critical impact of stress and social isolation on sexual aggression, providing valuable insights into possible neurobiological underpinnings of sexual violence. Understanding these mechanisms is crucial for developing effective interventions to mitigate the consequences of sexual aggression.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"15"},"PeriodicalIF":2.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ventromedial hypothalamic nucleus neuronal nitric oxide knockdown effects on GABAergic neuron metabolic sensor and transmitter marker gene expression in the male rat.","authors":"Sagor C Roy, Madhu Babu Pasula, Subash Sapkota, Karen P Briski","doi":"10.1186/s12868-025-00940-0","DOIUrl":"10.1186/s12868-025-00940-0","url":null,"abstract":"<p><p>The diffusible gas nitric oxide (NO) and amino acid γ-gamma-aminobutyric acid (GABA) exert contrary effects on glucose counterregulation in the male rat, but how these neurochemical signals integrate within ventromedial hypothalamic nucleus (VMN) neural circuitries remains unclear. Female rat dorsomedial (VMNdm) and ventrolateral (VMNvl) GABAergic neurons express neuronal nitric oxide synthase (nNOS) mRNA; notably these subpopulations exhibit dissimilar nNOS transcriptional responses to insulin-induced hypoglycemia (IIH). Here, nNOS gene knockdown tools were used to examine whether one or both VMN GABA neuron groups may be a target for nitrergic control of basal and hypoglycemic counterregulatory hormone secretion in the male. Data show that VMN nNOS gene knockdown respectively up- or down-regulated counterregulatory hormone profiles in eu- versus hypoglycemic male rats. Single-cell multiplex qPCR analysis of laser-catapult-microdissected GABA neurons showed that IIH elevated nNOS gene expression in GABA neurons from each VMN division, yet nNOS siRNA pretreatment attenuated distinctive IIH-associated transmitter marker gene expression patterns in VMNdm versus VMNvl GABAergic neurons. nNOS gene silencing had similar effects on glucokinase and glucose transporter gene responses to IIH in each GABA neuron subpopulation but elicited division-specific effects on mRNA encoding 5-AMP-activated protein kinase (AMPK) alpha/catalytic subunits and the lactate membrane receptor GPR81/HCAR1. Current findings provide original evidence that VMN NO may impose bi-directional, glucose status-contingent control of counterregulatory hormone outflow in the male rat. Data moreover imply that during IIH, NO may control distinctive sources of metabolic sensory regulatory stimuli in VMNdm versus VMNvl GABA neurons and may shape unique counterregulation-controlling neurochemical transmission by each cell population.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"14"},"PeriodicalIF":2.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aerobic exercise training improves learning and memory performance in hypoxic-exposed rats by activating the hippocampal PKA-CREB-BDNF signaling pathway.","authors":"Shichen Luo, Lei Shi, Tong Liu, Qiguan Jin","doi":"10.1186/s12868-025-00935-x","DOIUrl":"10.1186/s12868-025-00935-x","url":null,"abstract":"<p><strong>Background: </strong>This study aims to investigate the effects of aerobic exercise training on learning and memory (L&M) performance in rats exposed to altitude hypoxia and its relationship with hippocampal plasticity and the PKA-CREB-BDNF signaling pathway.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats were exposed to 14.2% hypoxia with or without 60 min of non-weight-bearing swimming training for 8 weeks. The L&M performance was evaluated using the Morris water maze, and the mRNA expression of PSD95, SYP, PKA, CREB, CBP, and BDNF in the hippocampus was detected.</p><p><strong>Results: </strong>Chronic hypoxia exposure significantly impaired L&M performance and reduced the mRNA expression of hippocampal PSD95, SYP, PKA, CREB, CBP, and BDNF. Aerobic exercise training effectively reversed these changes by enhancing hippocampal synaptic plasticity through the activation of the PKA-CREB-BDNF signaling pathway.</p><p><strong>Conclusion: </strong>Aerobic exercise training can alleviate the decline in L&M performance caused by altitude hypoxia exposure, possibly through the activation of the hippocampal PKA-CREB-BDNF signaling pathway.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"13"},"PeriodicalIF":2.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of suitable reference genes for gene expression studies in the developing mouse cortex using RT-qPCR.","authors":"Ananya Uppalapati, Timothy Wang, Lena H Nguyen","doi":"10.1186/s12868-025-00934-y","DOIUrl":"10.1186/s12868-025-00934-y","url":null,"abstract":"<p><strong>Background: </strong>Real-time quantitative PCR (RT-qPCR) is a widely used method to investigate gene expression in neuroscience studies. Accurate relative quantification of RT-qPCR requires the selection of reference genes that are stably expressed across the experimental conditions and tissues of interest. While RT-qPCR is often performed to investigate gene expression changes during neurodevelopment, few studies have examined the expression stability of commonly used reference genes in the developing mouse cortex.</p><p><strong>Results: </strong>Here, we evaluated the stability of five housekeeping genes, Actb, Gapdh, B2m, Rpl13a, and Hprt, in cortical tissue from mice at embryonic day 15 to postnatal day 0 to identify optimal reference genes with stable expression during late corticogenesis. The expression stability was assessed using five computational algorithms: BestKeeper, geNorm, NormFinder, DeltaCt, and RefFinder. Our results showed that B2m, Gapdh, and Hprt, or a combination of B2m/Gapdh and B2m/Hprt, were the most stably expressed genes or gene pairs. In contrast, Actb and Rpl13a were the least stably expressed.</p><p><strong>Conclusion: </strong>This study identifies B2m, Gapdh, and Hprt as suitable reference genes for relative quantification in RT-qPCR-based cortical development studies spanning the period of embryonic day 15 to postnatal day 0.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"12"},"PeriodicalIF":2.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural progenitor cell-derived exosomes in ischemia/reperfusion injury in cardiomyoblasts.","authors":"Oiva Arvola, Virpi Stigzelius, Minna Ampuja, Riikka Kivelä","doi":"10.1186/s12868-025-00931-1","DOIUrl":"10.1186/s12868-025-00931-1","url":null,"abstract":"<p><p>The physiologic relationship between the brain and heart is emerging as a novel therapeutic target for clinical intervention for acute myocardial infarction. In the adult human brain, vestigial neuronal progenitor stem cells contribute to neuronal repair and recovery following cerebral ischemic injury, an effect modulated by secreted exosomes. Ischemia conditioned neuronal cell derived supernatant and experimental stroke has been shown to be injurious to the heart. However, whether unconditioned neuronal progenitor cell derived-exosomes can instead protect myocardium represents a profound research gap. We investigated the effects of unconditioned neural stem cell derived exosomes as post-injury treatment for cardiomyoblasts from three neuronal culture conditions; adherent cultures, neurosphere cultures and bioreactor cultures. Small extracellular vesicles were enriched with serial ultracentrifugation, validated via nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis prior to utilization as post-injury treatment for H9c2 cardiomyoblasts following oxygen and glucose deprivation. LDH assay was used to assess viability and Seahorse XF high-resolution respirometry analyzer to investigate post-injury cardiomyocyte bioenergetics. We found no evidence that unconditioned neural stem cell derived exosomes are cardiotoxic nor cardioprotective to H9c2 cardiomyoblasts following ischemia-reperfusion injury. Based on our findings, utilizing unconditioned neural stem cell derived exosomes as post-injury treatment for other organs should not have adverse effects to the damaged cardiac cells.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"11"},"PeriodicalIF":2.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet-rich fibrin and silver nano-particles loaded chitosan treatment for post- laminectomy epidural scar adhesions: in vivo rats study model.","authors":"Samah Fouad, Awad Rizk, Esam Mosbah, Mostafa M Nabeeh, Walaa Awadin, Ayman S Elmezayyen, Ekramy Elmorsy, Adel Zaghloul","doi":"10.1186/s12868-025-00929-9","DOIUrl":"10.1186/s12868-025-00929-9","url":null,"abstract":"<p><strong>Objective: </strong>Epidural scar fibrosis commonly leads to functional disability and pain following spinal surgery and is a prevalent manifestation of Failed Back Surgery Syndrome (FBSS). This study aimed to evaluate the use of silver nano-articles (AgNPs) loaded on chitosan (Chi/Ag-NPs) with platelets-rich fibrin (PRF) gel for the reduction of post-laminectomy epidural scar adhesions.</p><p><strong>Methods: </strong>A total of 90 male Sprague Dawley rats (255 ± 55gm) were randomized in-to six groups, each group with 15 rats: control group, laminectomy group, PRF group, Chi/Ag-NPs group, combined treatment group (PRF + Chi/Ag-NPs), and a group to prepare PRF. Lumbar laminectomy procedures were performed between L3-L5 in all rats except the control group. After a 30-days follow-up, macroscopic examination, histological studies, and mRNA evaluation for TGFβ-1and IL-6, were conducted.</p><p><strong>Results: </strong>Data revealed that epidural scar adhesion, scaring, arachnoid involvement, dural thickness, as well as inflammation and TGFβ-1and IL-6 coding genes expression were significantly reduced in PRF group, Chi/Ag-NPs group, and combined group compared to the laminectomy group. Combined treatment showed more significant better outcomes.</p><p><strong>Conclusion: </strong>The use of PRF with Chi/Ag-NPs as nano biomaterials could be considered a combination therapy for the reduction of EF post-laminectomy in a rat model.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"10"},"PeriodicalIF":2.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular assessment of NMDAR subunits and neuronal apoptosis in the trigeminal ganglion in a model of male migraine-induced rats following Moringa oleifera alcoholic extract administration.","authors":"Ahmad Vafaeian, Ali Vafaei, Mohammad Reza Parvizi, Mohsen Chamanara, Mojgan Mehriardestani, Yasaman Hosseini","doi":"10.1186/s12868-025-00928-w","DOIUrl":"10.1186/s12868-025-00928-w","url":null,"abstract":"<p><strong>Introduction: </strong>Migraine, a common disorder marked by severe and repetitive headaches, has been linked to the involvement of the NMDA receptor (NMDAR), a receptor responsible for glutamate signaling. Moringa oleifera (M. oleifera), recognized for its anti-inflammatory properties and therapeutic potential in various conditions, has been investigated. This study aims to assess the efficacy and precise mechanisms of M. oleifera for the treatment of migraine, for which evidence is limited.</p><p><strong>Methods: </strong>Rats were stratified into four distinct groups. The control group did not undergo the migraine-induction protocol. Post-induction, the \"sumatriptan\" group was administered sumatriptan injections, the \"treatment\" group received oral M. oleifera extract, and the \"vehicle\" group was provided with oral solvent treatment. Behavioral evaluations encompassing Von Frey's and hot plate assessments, in addition to qPCR analysis targeting Nr2a, Nr2b, Bax, Bcl-2, and Caspase-3, were conducted.</p><p><strong>Results: </strong>Von Fery's and hot plate tests revealed a notable decrease in triggering pressure and temperature within the vehicle group when compared to the other groups (both ps < 0.001). The Nr2a expression levels in both the vehicle and treatment cohorts exhibited significantly higher values than those observed in the control group (p < 0.001, p = 0.001) and the sumatriptan group (p < 0.001, p = 0.002). Conversely, no substantial alterations in Nr2b or Bcl-2 expression levels were observed across the study groups (p = 0.404, p = 0.976). Notably, heightened expressions of Caspase-3 and Bax were evident in the vehicle group relative to the other groups (p = 0.013, p = 0.010).</p><p><strong>Conclusions: </strong>Moringa oleifera extract appears to mitigate symptoms of migraine by inhibiting apoptosis, suggesting potential efficacy in migraine treatment; however, additional research investigating a wider range of pathways is necessary.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"9"},"PeriodicalIF":2.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson's model.","authors":"Julian E Alecu, Veronika Sigutova, Razvan-Marius Brazdis, Sandra Lörentz, Marios Evangelos Bogiongko, Anara Nursaitova, Martin Regensburger, Laurent Roybon, Kerstin M Galler, Wolfgang Wrasidlo, Beate Winner, Iryna Prots","doi":"10.1186/s12868-025-00926-y","DOIUrl":"10.1186/s12868-025-00926-y","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein aggregates mostly consisting of misfolded alpha-synuclein (αSyn). Progressive degeneration of midbrain dopaminergic neurons (mDANs) and nigrostriatal projections results in severe motor symptoms. While the preferential loss of mDANs has not been fully understood yet, the cell type-specific vulnerability has been linked to a unique intracellular milieu, influenced by dopamine metabolism, high demand for mitochondrial activity, and increased level of oxidative stress (OS). These factors have been shown to adversely impact αSyn aggregation. Reciprocally, αSyn aggregates, in particular oligomers, can impair mitochondrial functions and exacerbate OS. Recent drug-discovery studies have identified a series of small molecules, including NPT100-18A, which reduce αSyn oligomerization by preventing misfolding and dimerization. NPT100-18A and structurally similar compounds (such as NPT200-11/UCB0599, currently being assessed in clinical studies) point towards a promising new approach for disease-modification.</p><p><strong>Methods: </strong>Induced pluripotent stem cell (iPSC)-derived mDANs from PD patients with a monoallelic SNCA locus duplication and unaffected controls were treated with NPT100-18A. αSyn aggregation was evaluated biochemically and reactive oxygen species (ROS) levels were assessed in living mDANs using fluorescent dyes. Adenosine triphosphate (ATP) levels were measured using a luminescence-based assay, and neuronal cell death was evaluated by immunocytochemistry.</p><p><strong>Results: </strong>Compared to controls, patient-derived mDANs exhibited higher cytoplasmic and mitochondrial ROS probe levels, reduced ATP-related signals, and increased activation of caspase-3, reflecting early neuronal cell death. NPT100-18A-treatment rescued cleaved caspase-3 levels to control levels and, importantly, attenuated mitochondrial oxidative stress probe levels in a compartment-specific manner and, at higher concentrations, increased ATP signals.</p><p><strong>Conclusions: </strong>Our findings demonstrate that NPT100-18A limits neuronal degeneration in a human in vitro model of PD. In addition, we provide first mechanistic insights into how a compartment-specific antioxidant effect in mitochondria might contribute to the neuroprotective effects of NPT100-18A.</p>","PeriodicalId":9031,"journal":{"name":"BMC Neuroscience","volume":"26 1","pages":"8"},"PeriodicalIF":2.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}