ASN NEURO最新文献

{"title":"Proteomic Characterization of Spinal Cord Myelin in the Mouse.","authors":"Oliver Schmitt, Hannes Kaddatz, Stefan Mikkat, Markus Kipp, Antje Schümann, Sarah Joost","doi":"10.1080/17590914.2025.2595945","DOIUrl":"10.1080/17590914.2025.2595945","url":null,"abstract":"<p><p>The myelin proteome is a critical structural and functional component of the central nervous system (CNS), undergoing dynamic remodeling throughout life. Pathological changes, such as those in multiple sclerosis, disrupt myelin integrity and lead to severe neurological deficits. Establishing a reproducible baseline of the CNS myelin proteome is therefore essential for monitoring alterations in disease models. Here, we present a comprehensive proteomic dataset of purified spinal cord myelin from healthy mice. Myelin fractions were isolated by preparative sucrose density centrifugation, followed by gel-free peptide separation and mass spectrometric analysis. Label-free quantification based on at least two tryptic peptides identified 725 proteins across six spinal cord samples. Comparison with previous large-scale datasets confirmed the robustness of our workflow. In particular, our dataset showed a 71% overlap with the 809 proteins identified by Jahn et al. using a highly similar proteomic approach. Importantly, there was near-complete agreement for canonical myelin proteins, validating both the specificity and reproducibility of our method. Beyond this shared core, our dataset contributed additional proteins, including axon- and glia-associated candidates, expanding the baseline repertoire of the spinal cord myelin proteome. In summary, this study establishes and validates a reliable workflow for spinal cord myelin proteomics and provides a reproducible reference dataset. While not yet including diseased tissue, this baseline is directly applicable to experimental models of demyelination and remyelination, offering a critical foundation for detecting and interpreting disease-related proteomic alterations in multiple sclerosis research.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2595945"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720767","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":"Crocetin as a Neuroprotective Agent: Targeting Western Diet-Induced Cognitive Dysfunction Through Antioxidant, Anti-Inflammatory and Gut-Brain Axis Modulation.","authors":"Suresh Babu Kondaveeti, Vrinda Gupta, Aaqib Ahmad Dar, Junaid Ahmad Sheikh, Dinesh Kumar, Neeraj Choudhary, Rajni Tanwar, Sonia Gupta, Pooja Rani, Arunprasad Vk","doi":"10.1080/17590914.2025.2603409","DOIUrl":"10.1080/17590914.2025.2603409","url":null,"abstract":"<p><p>Western diet-induced cognitive dysfunction is a rapidly emerging health challenge driven by excessive intake of high-fat, high-sugar, and ultra-processed foods. These dietary patterns promote neuroinflammation, oxidative stress, insulin resistance, gut dysbiosis, and blood-brain barrier (BBB) disruption, ultimately leading to synaptic dysfunction and cognitive decline. Crocetin, an apocarotenoid derived from saffron and <i>Gardenia jasminoides</i>, exhibits promising neuroprotective effects by scavenging reactive oxygen species, attenuating neuroinflammatory signaling, enhancing mitochondrial bioenergetics, and improving insulin sensitivity. It further upregulates brain-derived neurotrophic factor (BDNF), modulates PI3K/Akt signaling, and restores gut microbiota balance, thereby reinforcing the gut-brain axis and maintaining BBB integrity. This review further aims to critically assess these mechanistic links by distinguishing well-supported findings from speculative associations emphasizing discrepancies between preclinical and human evidence. Preclinical studies strongly support crocetin's role in ameliorating Western diet-induced neurodegeneration, while early clinical evidence highlights improvements in memory, executive function, and cerebral blood flow. However, limitations such as poor bioavailability, rapid metabolism, and limited large-scale human trials constrain its translation into clinical practice. Advanced formulations, including nanoparticles, liposomes, and prodrug derivatives, hold potential to overcome these challenges. This review critically evaluates the pathophysiological mechanisms of Western diet-induced cognitive decline, highlights the pharmacological actions of crocetin, and discusses its therapeutic prospects within the framework of personalized and precision medicine. Future directions include large-scale randomized controlled trials, pharmacokinetic optimization, and AI-driven predictive models to establish crocetin as a clinically viable neuroprotective agent.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2603409"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12721098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792620","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":"Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction.","authors":"Salaheldeen Elsaid, Muhammad Asad Usmani, Xiangdong Wu, Junkai Hu, Nigus Ambaye, Sui Seng Tee","doi":"10.1080/17590914.2026.2696821","DOIUrl":"10.1080/17590914.2026.2696821","url":null,"abstract":"<p><p>Excess fructose consumption has been implicated in metabolic disease, yet its impact on brain physiology and cellular metabolism remains poorly understood. The hippocampus expresses fructose transporters and fructolytic enzymes, suggesting potential vulnerability to fructose-induced metabolic stress. Here, we investigated fructose uptake mechanisms and downstream functional responses in BV2 microglia and HT22 hippocampal neurons using sodium manipulation, pharmacological inhibition, transporter expression profiling, and live-cell fluorescent sugar uptake assays. Hippocampal neurons exhibited strong sodium-sensitive, phlorizin-responsive fructose uptake, accompanied by reduced expression of facilitated hexose transporters and selective induction of Sglt1. In contrast, microglia demonstrated both sodium-sensitive and sodium-independent components of fructose uptake, associated with coordinated remodeling of GLUT and SGLT family members. Functionally, fructose exposure was associated with membrane hyperpolarization and reduced extracellular vesicle (EV) release in neurons, whereas microglia displayed membrane depolarization, enhanced EV secretion, and induction of pro-inflammatory genes. Knockdown of ketohexokinase (KHK) attenuated inflammatory gene expression and EV release in microglia, while pharmacological inhibition of sodium-dependent transport selectively reduced EV secretion. Complementary secondary analysis of hippocampal RNA-seq data from mice exposed to high-fat/high-fructose feeding revealed coordinated regulation of sodium-coupled transporters, ion channels, and synaptic gene programs, with partial normalization following SGLT inhibition. Together, these findings identify cell-type-specific fructose handling strategies in hippocampal neurons and microglia and suggest that sodium-dependent transport and fructolytic metabolism differentially influence membrane polarization, vesicle signaling, and inflammatory activation under metabolic stress.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2696821"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13360499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148418299","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":"When Powerhouses Fail and Rust Takes Over: Primary Mitochondrial and Lipid Metabolism Failure with Secondary Iron Accumulation and Lipid Peroxidation in Neurodegeneration with Brain Iron Accumulation.","authors":"Aradhika Vijeev, Shaik Basha, Spandana S Nadig, Kripa Agarwal, Vibhuti Meharchandani, Aparna Ramakrishna Pai, Krishna Kishore Mahato","doi":"10.1080/17590914.2026.2717255","DOIUrl":"https://doi.org/10.1080/17590914.2026.2717255","url":null,"abstract":"<p><p>Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically heterogeneous group of rare movement disorders characterized by progressive neurodegeneration and selective basal ganglia iron deposition. Recent discoveries have fundamentally reshaped the understanding of NBIA, indicating that defects in coenzyme A metabolism, mitochondrial bioenergetics, lipid remodeling, autophagy-lysosomal pathways, and ferroptosis precede and promote secondary iron dyshomeostasis rather than resulting from primary abnormalities in iron metabolism. This review integrates recent mechanistic and translational evidence (2020-2026) across both common and underrepresented NBIA subtypes, including pantothenate kinase-associated neurodegeneration, phospholipase A2-associated neurodegeneration, COASY protein-associated neurodegeneration, mitochondrial enoyl-CoA reductase protein-associated neurodegeneration, mitochondrial membrane protein-associated neurodegeneration, β-propeller protein-associated neurodegeneration, fatty acid hydroxylase-associated neurodegeneration, neuroferritinopathy, and mitochondrial DNA-associated forms. Unlike previous reviews, this synthesis consolidates findings from patient-derived induced pluripotent stem cell neuronal and glial models, compartment-specific iron localization, advanced neuroimaging biomarkers, and emerging therapeutic strategies within a unified mechanistic framework. Collectively, the evidence supports a paradigm in which mitochondrial dysfunction and lipid metabolic failure initiate disease progression, whereas iron accumulation amplifies oxidative injury and lipid peroxidation, thereby increasing ferroptotic cell death and neuronal degeneration, providing an updated foundation for biomarker discovery, mechanistically informed therapeutic development, and precision medicine approaches in NBIA.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2717255"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787707","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":"Endothelin-1 Signaling Mediates Hypoxia-Induced Microglial Activation Through Reactive Oxygen Species and Mitogen-Activated Protein Kinase Pathways.","authors":"Yandy Garcia, Ricardo Vázquez, Yalimar P Pomales-Inostroza, Sebastian Castaño, Francisco Rodriguez, Blake Bailey, Yaritza Inostroza-Nieves","doi":"10.1080/17590914.2026.2698262","DOIUrl":"10.1080/17590914.2026.2698262","url":null,"abstract":"<p><p>Oxidative stress and neuroinflammation are critical contributors to hypoxic-ischemic brain injury. Microglia, the CNS-resident immune cells, undergo rapid activation in response to hypoxic stress. Endothelin-1 (ET-1), a vasoconstrictor implicated in cerebrovascular pathology, is upregulated by hypoxia; however, its role in microglial activation remains poorly understood. HMC3 human microglial cells were exposed to hypoxia (1% O₂) for 4 hours. Reactive oxygen species (ROS) were quantified by flow cytometry. ET-1 and interleukin-6 (IL-6) protein concentrations were measured by ELISA and mRNA levels by qPCR. Mitogen-activated protein kinase (MAPK) activation and ET-1 localization were assessed by flow cytometry and immunofluorescence, respectively. The endothelin B receptor (ET_BR) antagonist BQ788 was used to assess ET-1 signaling in hypoxia-induced responses. Hypoxia significantly upregulated ET-1 gene expression (5.0-fold increase, <i>p</i> < 0.001, <i>n</i> = 4) and elevated ET-1 protein production by 1.4-fold (<i>p</i> < 0.01, <i>n</i> = 4). IL-6 expression and secretion increased 1.5-fold under hypoxic conditions (<i>p</i> < 0.01, <i>n</i> = 4), an effect that was attenuated by BQ788 pretreatment. ROS levels increased 1.9-fold in hypoxic HMC3 cells (<i>p</i> < 0.01, <i>n</i> = 4) but were significantly reduced by ET_BR inhibition. Additionally, hypoxia elevated the percentage of MAPK-activated cells compared to both normoxic and BQ788-treated groups (<i>p</i> < 0.01). These findings demonstrate that hypoxia induces ET-1 overexpression, ROS generation, MAPK activation, and IL-6 production in microglia, establishing a self-perpetuating cycle of neuroinflammation. ET_BR blockade with BQ788 disrupts this cascade, suggesting that ET-1 signaling is a promising therapeutic target to mitigate secondary injury in hypoxic-ischemic brain conditions.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2698262"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677002","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":"Mild Subcortical Stroke Induces Widespread Chronic Reactive Astrogliosis That Is Largely Unaffected by Microglia and Age.","authors":"Teresa L Stackhouse, Bradley D Marxmiller, Steve J Sullivan, Heather L McConnell, Laura M Knittel, Rachel De La Torre, Alexandra Houser, Ozama Ismail, Wenri Zhang, Randall L Woltjer, Anusha Mishra","doi":"10.1080/17590914.2026.2702948","DOIUrl":"10.1080/17590914.2026.2702948","url":null,"abstract":"<p><p>Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimer's disease. The cause of this pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke mostly confined to subcortical regions, similar to many silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, compared to the reactive microglia response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent reactive astrocytes. Aging mice exposed to MSCI exhibited a comparably strong response of reactive astrocytes and microglia as young mice. Lastly, reactive astrocytes persisted for at least nine months after MSCI. We propose that this mild ischemia model is valuable for examining the chronic effects of subcortical stroke. It may be especially useful for investigating the functional impact of reactive astrogliosis in regions distal from the primary injury site.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2702948"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583384","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":"IL-4-Primed Microglial Extracellular Vesicles Attenuate Rotenone-Induced Cell Death in SH-SY5Y Cells: A Contributory Role for miR-191-5p.","authors":"Kemal Ugur Tufekci, Burak I Arioz, Aysen Cotuk, Cagla Kiser, Bilgesu Ozturk, Tutku Yaras, Gokhan Karakulah, Pembe Keskinoglu, Alper Bagriyanik, Sermin Genc","doi":"10.1080/17590914.2026.2712448","DOIUrl":"10.1080/17590914.2026.2712448","url":null,"abstract":"<p><p>Microglia contribute to central nervous system homeostasis and neuroprotection partly through the release of small extracellular vesicles (sEVs) carrying regulatory cargoes such as microRNAs. Interleukin-4 (IL-4) alters microglial state and secretory output; however, whether sEVs released from IL-4-treated microglia protect neurons against toxic injury, and which cargoes mediate these effects, remains unclear. Here, we investigated the protective effects of sEVs derived from the IL-4-treated HMC3 human microglial cell line in a rotenone-induced injury model in the SH-SY5Y cell line and examined the contribution of microRNA-191-5p to neuroprotection. Small RNA sequencing revealed a distinct miRNA profile in IL-4-sEVs, with microRNA-191-5p emerging as the most statistically significant upregulated candidate. Its enrichment was confirmed by RT-qPCR. PKH67-labeled sEV-associated fluorescence was detected in SH-SY5Y cells, indicating uptake of microglia-derived sEVs by recipient cells. Functionally, pretreatment with IL-4-sEVs significantly reduced rotenone-induced cell death and preserved cell morphology compared with untreated and control sEV-treated cells. To assess the contribution of microRNA-191-5p, IL-4-sEVs were loaded with a microRNA-191-5p antagomir, which reduced microRNA-191-5p levels and partially attenuated the protective effect of IL-4-sEVs. Together, these findings suggest that sEVs derived from the IL-4-treated HMC3 microglial cell line mitigate rotenone-induced injury in the SH-SY5Y cell line in vitro and that microRNA-191-5p contributes, at least in part, to this effect.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2712448"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688482","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":"Reboxetine Treatment Reduces Hippocampal Gliosis in the P301S Tauopathy Mouse Model.","authors":"Irene L Gutiérrez, Claudia Yanes-Castilla, Karina S MacDowell, Javier R Caso, Borja García-Bueno, Cristina Ulecia-Morón, Juan C Leza, José L M Madrigal","doi":"10.1080/17590914.2026.2630485","DOIUrl":"10.1080/17590914.2026.2630485","url":null,"abstract":"<p><p>The loss of brain noradrenergic neurons is one of the earliest alterations observed in Alzheimer's disease and other neurodegenerative pathologies. The consequent reduction of brain noradrenaline levels facilitates the progression of neuroinflammatory processes that can be fatal for neurons and other brain cells. For this reason, compensating for noradrenaline deficit through different means constitutes an interesting therapeutic strategy. Drugs that inhibit the reuptake of noradrenaline are used to elevate the extracellular concentrations of this neurotransmitter and potentiate this way its effects. These drugs are approved for the treatment of depression or attention deficit hyperactivity disorder, among other indications, but their repurposing and use in Alzheimer's disease could be of interest given the beneficial effects observed for noradrenaline in numerous studies. Based on this, we previously showed the beneficial effects of reboxetine, a noradrenaline reuptake inhibitor, on 5xFAD mice that accumulate amyloid beta in their brains and reproduce some of the typical alterations of Alzheimer's disease. In this study we have analyzed the effects of reboxetine on P301S mice, a different model of Alzheimer's disease based on the expression of mutant forms of human microtubule-associated protein tau. We observed that the administration of reboxetine with osmotic pumps for 28 days to 9-month-old mice reduced the accumulation and activation of microglia and astrocytes in different areas of the hippocampus. These findings indicate that reboxetine treatment prevents the neuroinflammatory response known to cause brain damage in Alzheimer's disease even when the treatment is initiated at an advanced stage of the disease.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2630485"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776133","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":"CD44 Knockout Alters the Cellular Response and Improves Locomotor Outcome After Spinal Cord Injury.","authors":"Dana Creasman, Francisca Benavente, Rebecca Nishi, Aileen Anderson","doi":"10.1080/17590914.2026.2673257","DOIUrl":"10.1080/17590914.2026.2673257","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a devastating condition that results in long-term functional impairments due to loss of tissue and limited regeneration. Investigating the factors that regulate the post-SCI response is critical to understanding the pathophysiology of this condition and developing treatments. One molecule of interest in the post-SCI response is CD44. CD44 is cell-surface protein with a well-established role in regulating cellular functions including cell migration and proliferation. CD44 is expressed in many cells that play a role in the post-SCI microenvironment but the effect of global CD44 KO on SCI outcomes has not previously been tested. Here, we investigate that role in a mouse unilateral cervical contusion SCI model. We predicted that CD44 KO would exert a predominant effect on glial progenitor/cell recruitment, inhibiting astroglial scar formation and thereby increasing lesion expansion and exacerbating locomotor deficits. In contrast, we found that CD44 KO mice exhibited increased numbers of astrocytes at the lesion epicenter, developed a more compact astroglial scar by 28 days after injury, showed improved locomotor function, and exhibited decreased recruitment of acutely activated immune cells vs WT mice. Together, these findings highlight the role of CD44 in diverse cell populations after SCI as a critical point of further investigation to understand the post-SCI response.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2673257"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824285","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":"Intranasal Delivery of Proenkephalin-Expressing Differentiated Mesenchymal Stem Cells Attenuates Morphine Dependence Behaviors and Modulates Neurotrophic Factors in Rats.","authors":"Mohammad Saleh Ranaiy, Hamed Ghazvini, Seyedeh Masoumeh Seyedhosseini Tamijani, Mozhgan Abasi, Seyed Abbas Mousavi, Hamid Kalalian-Moghaddam, Raheleh Rafaiee","doi":"10.1080/17590914.2026.2739826","DOIUrl":"10.1080/17590914.2026.2739826","url":null,"abstract":"<p><p>Substance use disorder is a chronic relapsing condition characterized by persistent drug seeking, cognitive impairment, and neurobiological alterations in brain reward and memory circuits. Emerging evidence suggests that dysfunction of the endogenous opioid system and reduced neurotrophic signaling contribute to the pathophysiology of opioid dependence. Cell based therapeutic strategies may provide a novel approach to modulate these neural pathways. In the present experimental study, morphine dependence was induced in adult male rats using an escalating dose regimen. Animals were randomly allocated into control, morphine-dependent vehicle, and cell-treated groups. Proenkephalin-expressing differentiated mesenchymal stem cells (PENK-MSCs) were delivered via the intranasal route. Behavioral assessments were performed using conditioned place preference, novel object recognition, and the elevated plus maze to evaluate addiction related behaviors, cognitive performance, and anxiety like responses. Hippocampal brain derived neurotrophic factor (BDNF) expression was examined using immunohistochemistry. Morphine dependent rats exhibited significant behavioral alterations, including enhanced drug related preference, impaired recognition memory, and increased anxiety like behavior compared with control animals. In addition, hippocampal BDNF expression was significantly reduced following morphine exposure. Intranasal cell delivery significantly attenuated morphine-induced preference, reversed recognition memory deficits, mitigated anxiety-like behaviors, and upregulated hippocampal BDNF expression compared with the vehicle-treated morphine group. These findings demonstrate that intranasal delivery of PENK-MSCs attenuates behavioral deficits and promotes neurotrophic recovery in morphine-dependent rats. This approach may represent a promising experimental strategy for targeting neural mechanisms involved in substance use disorder, although further studies are required to confirm its long-term efficacy and translational potential.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":"18 1","pages":"2739826"},"PeriodicalIF":4.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103506","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}