Journal of Neuroscience Research最新文献

{"title":"Effects of Repetitive Transcranial Magnetic Stimulation Combined With Cognitive Training of Response Inhibition on Task-Related Oscillatory Activity","authors":"Xiaomin Xu,&nbsp;Adriano H. Moffa,&nbsp;Mei Xu,&nbsp;Thanh Vinh Cao,&nbsp;Colleen K. Loo,&nbsp;Donel M. Martin,&nbsp;Stevan Nikolin","doi":"10.1002/jnr.70101","DOIUrl":"10.1002/jnr.70101","url":null,"abstract":"<div>\u0000 \u0000 <p>Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) has been explored as a potential novel method to improve response inhibition, but its neural mechanisms remain unclear. This study investigated the effects of rTMS + CT on oscillatory activity across different frequency bands and theta-gamma phase-amplitude coupling during the Stroop task. Sixty healthy participants were randomly assigned to receive four sessions of either active or sham prolonged intermittent theta burst stimulation (iTBS) + CT. Each session involved iTBS over both the right inferior frontal cortex and the pre-supplementary motor area, with participants completing the Stop Signal training task first, followed by the Go/No-Go training task. The Stroop task was administered before and immediately after the intervention while electroencephalography was recorded. There was a significant group effect on the change in beta desynchronization during incongruent trials (<i>t</i> = −2.03, <i>p</i> = 0.048), with a significant decrease observed in the active group (<i>p</i> = 0.03) and no change in the sham group (<i>p</i> = 0.83). Additionally, changes in gamma synchronization differed between groups for congruent trials (<i>t</i> = 2.28, <i>p</i> = 0.03), though neither group showed a significant pre-post change (<i>p</i> &gt; 0.05). Our study suggests that four sessions of iTBS + CT may modulate beta and gamma oscillations during the Stroop task, potentially enhancing motor inhibition and processing speed in response inhibition. These results provide neurophysiological insights into the neural mechanisms through which rTMS + CT may enhance response inhibition.</p>\u0000 </div>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756970","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":"Self-Processing Circuits Among Depressed Youth After Amygdala Neurofeedback Cued to the Self-Face","authors":"Sewon Oh,&nbsp;Niki Hosseini-Kamkar,&nbsp;Carmen Santana-Gonzalez,&nbsp;Janani Ranatunga,&nbsp;Giang-Hoang Nguyen,&nbsp;Matthew Maurice,&nbsp;Kymberly Young,&nbsp;Karina Quevedo","doi":"10.1002/jnr.70097","DOIUrl":"https://doi.org/10.1002/jnr.70097","url":null,"abstract":"<p>Major depressive disorder is a significant health concern among adolescents due to its link to suicide and lifetime impairments. Current treatments yield limited success, but real-time functional magnetic resonance imaging (RT-fMRI) neurofeedback (NF) is a promising intervention. We tested the effects of RT-fMRI neurofeedback on the modulation of neural circuitry underlying self-referential processing and emotion regulation in youth trying to up-regulate the amygdala-hippocampus (AMYHIPP) complex. We examined amygdala functional connectivity during a self-other face recognition task before and after RT-fMRI NF from the AMYHIPP complex. (1) Depressed youth showed higher bilateral amygdala to anterior cingulate cortex (ACC), superior temporal and frontal gyri connectivity compared to controls, who showed lower connectivity before NF. Yet after NF, this pattern reversed, with depressed youth showing lower bilateral amygdala connectivity than controls. (2) Depressed youth showed <i>increased right</i> amygdala-cuneus connectivity while controls showed <i>increased left</i> amygdala-cuneus connectivity during self-other face recognition. (3) Lower right amygdala-cuneus connectivity was linked to improved rumination. Higher left amygdala-cuneus connectivity was linked to improved depression. (4) Shifts of less right versus left amygdala to superior middle temporal gyri connectivity after neurofeedback, and of more right versus left amygdala to middle frontal gyrus after NF, were linked to higher AMYHIPP engagement during training. This is suggestive of NF training effects upon implicit versus explicit emotion circuits. Caution is necessary regarding the meaning of symptoms to circuits associations and putative mechanisms of neurofeedback training given the lack of a placebo group.</p>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jnr.70097","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145739810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1","authors":"Oluwademilade Nuga,&nbsp;Masoumeh Pourhadi,&nbsp;Julia P. Rausch,&nbsp;Sokol V. Todi","doi":"10.1002/jnr.70089","DOIUrl":"10.1002/jnr.70089","url":null,"abstract":"<div>\u0000 \u0000 <p>Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a dominant neurodegenerative disease caused by CAG triplet repeat expansion in <i>ATN1</i>, which encodes the transcriptional co-repressor Atrophin-1. DRPLA features motor, cognitive, and epileptic symptoms and shares pathogenic mechanisms with other polyglutamine (polyQ) disorders, including protein misfolding, impaired autophagy, and transcriptional dysregulation. To understand disease mechanisms, we performed RNA-seq on HEK293T cells stably over-expressing wild-type or pathogenic ATN1. Cells expressing pathogenic ATN1 exhibited a distinct transcriptomic profile, including disruptions in synaptic organization, extracellular matrix remodeling, ion channel expression, and neurotransmission. Several genes tied to neurodevelopmental, neurodegenerative, and oncogenic pathways were fully activated or silenced. Dysregulated pathways also included inflammation, chromatin remodeling, stress responses, and redox imbalance. Heat shock protein expression changes suggested proteotoxic stress and impaired protein quality control, with some findings conserved in a previously reported <i>Drosophila melanogaster</i> model of DRPLA. The transcriptomic signatures that we describe here expand understanding of the normal functions of ATN1 and the biology of disease of DRPLA.</p>\u0000 </div>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701289","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":"Male-Specific Ventromedial Hypothalamic Nucleus Glutamate Decarboxylase (GAD)-2/GAD65 Regulation of Counterregulatory Transmitter Marker Gene Expression and Peripheral Hormone Profiles","authors":"Madhu Babu Pasula,&nbsp;Subash Sapkota,&nbsp;Rajesh Yadav,&nbsp;Karen P. Briski","doi":"10.1002/jnr.70094","DOIUrl":"10.1002/jnr.70094","url":null,"abstract":"<div>\u0000 \u0000 <p>The amino acid neurotransmitter gamma-aminobutyric acid (GABA) reportedly acts by unidentified ventromedial hypothalamic mechanisms to suppress hypoglycemia-associated counterregulatory endocrine function in male rats. Present studies addressed the premise that GABAergic transmission of ventromedial hypothalamic nucleus (VMN) origin may regulate dorsomedial VMN (VMNdm) growth hormone-releasing hormone (Ghrh)/steroidogenic factor-1 (SF-1) neuron counterregulatory signaling to control this hormone outflow. VMN glutamate decarboxylase-2 (GAD2/GAD₆₅) gene knockdown increased basal but inhibited insulin-induced hypoglycemia (IIH)-associated augmentation of corticosterone and glucagon secretion, while suppressing growth hormone secretion regardless of glucose status. Multiplex qPCR analysis of laser-catapult-microdissected VMNdm Ghrh-immunoreactive neurons showed that GAD2 siRNA pretreatment intensified IIH-associated upregulation of mRNAs that encode the counterregulatory-enhancing neurochemicals nitric oxide and glutamate, and exacerbated hypoglycemic downregulation of GAD1, GAD2, and SF-1 transcription. VMN GAD2 gene silencing augmented hypoglycemic enhancement of Ghrh neuron 5′-AMP-activated protein kinase alpha-1 and alpha-2 gene expression. VMN GAD2 gene knockdown exacerbated both positive lactate receptor and negative estrogen receptor transcriptional reactivity to IIH. Study outcomes provide novel evidence for bidirectional, glucose status-specific VMN GABAergic control of corticosterone and glucagon secretion in male rats, which is not documented in the other sex. Data verify GABA regulation of VMN dorsomedial Ghrh neuron metabolic and hormonal signal reception, energy screening, and counterregulatory neurochemical release. Further effort is needed to characterize the impact of GABA-dependent neurotransmission by this discrete VMN neuron population on neural circuitries that govern glucose homeostasis.</p>\u0000 </div>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654648","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":"Propofol Alleviates Depression-Like Behavior and Cognitive Disorder in Learned Helplessness Model Mice via Regulating Synaptic Function","authors":"Jiarong Wang,&nbsp;Jinchen Xiang,&nbsp;Xuemei Han,&nbsp;Jing Liang,&nbsp;Xueliang Shang","doi":"10.1002/jnr.70096","DOIUrl":"10.1002/jnr.70096","url":null,"abstract":"<div>\u0000 \u0000 <p>Propofol, an anesthetic known for its safety, efficacy and neuroprotective properties, has potential novel antidepressant effects. However, its specific mechanisms still require further elucidation. Presently, we established a learned helplessness (LH) depression model to investigate the effects of propofol treatment on depression-like impairment. Thirty adult male C57BL/6j mice were randomly divided into three groups: control group (CON), model group (LH), and propofol group (PRO), with 10 mice per group. Behavioral analyses were conducted using weight measurement, sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and Morris water maze test (MWM). Subsequently, HE staining was performed to examine pathological changes in the hippocampal region. Western blotting was conducted to assess changes in Notch signaling pathway components, synaptic plasticity-related proteins, and proteins in the glutamate system. Immunofluorescence was used to detect expression changes of NICD, SYP, and DCX. Hippocampal glutamate concentration was determined using a glutamate assay kit. Consequently, stressed mice exhibited pronounced depressive behaviors and decreased spatial learning and memory, accompanied by significant neuronal death in the dentate gyrus of the hippocampal region and reduced levels of neuronal regeneration as well as synaptic plasticity. Additionally, glutamate reuptake function was impaired in depression, manifested specifically as increased glutamate concentrations in the hippocampal region and neuronal glutamate transmission levels. Meaningfully, propofol upregulated Notch signaling pathway activity and improved glutamate reuptake function significantly resulting in enhanced adult hippocampal neurogenesis and synaptic plasticity. These findings demonstrated the effectiveness of propofol as a potential antidepressant and contributed to discovering novel antidepressant drugs.</p>\u0000 </div>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654659","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":"Serum miR-598-3p as a Diagnostic and Prognostic Biomarker for Traumatic Brain Injury: Involvement in Modulating Microglial Inflammation","authors":"Yuxuan Lei,&nbsp;Guoan Shen,&nbsp;Zhengrui Wang,&nbsp;Yingying Pan,&nbsp;Zhi Zhang,&nbsp;Yang Liu,&nbsp;Hang Sui,&nbsp;Congcong Yuan","doi":"10.1002/jnr.70095","DOIUrl":"https://doi.org/10.1002/jnr.70095","url":null,"abstract":"<div>\u0000 \u0000 <p>Traumatic brain injury (TBI) results from external mechanical forces causing brain dysfunction. Dysregulated microRNAs (miRNAs) have been implicated in TBI pathophysiology, but the role of miR-598-3p remains unclear. This study aimed to evaluate the diagnostic and prognostic value of miR-598-3p in TBI and explore its regulatory effects on inflammation in an LPS-induced microglial injury model. Serum miR-598-3p levels were measured via RT-qPCR in 137 TBI patients and 120 controls. ROC curves assessed its diagnostic and prognostic utility. TBI severity was classified by Glasgow Coma Scale (GCS) scores, and outcomes were evaluated using the Glasgow Outcome Scale (GOS). In vitro, LPS-treated BV2 microglia were transfected with a miR-598-3p inhibitor to analyze inflammatory cytokine levels. miR-598-3p expression was significantly elevated in TBI patients versus controls (<i>p</i> &lt; 0.001) and increased progressively with injury severity. ROC analysis demonstrated high diagnostic accuracy for distinguishing TBI severity (AUC = 0.892/0.905) and predicting poor prognosis (AUC = 0.891, sensitivity = 83.33%, specificity = 90.36%). High miR-598-3p expression correlated with elevated Marshall grades, neural injury markers (S100B, GFAP), and pro-inflammatory cytokines (IL-6, TNF-<i>α</i>). Multivariate analysis identified miR-598-3p as an independent risk factor for poor outcomes (OR = 5.03, <i>p</i> &lt; 0.01). miR-598-3p inhibition attenuated LPS-induced IL-6/TNF-<i>α</i> secretion (<i>p</i> &lt; 0.01). Serum miR-598-3p demonstrates clinical utility as a biomarker for TBI diagnosis, severity grading, and prognostic evaluation. Its observed association with amplified microglial inflammatory responses suggests a potential mechanism involving regulation of neuroinflammation pathways.</p>\u0000 </div>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 12","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626839","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":"Fiber Distribution and Myelination of Dopaminergic Neurons in the Medial Forebrain Bundle of a Rodent Depression Model","authors":"Zhuo Duan,&nbsp;Yixin Tong,&nbsp;Xiongpeng Weng,&nbsp;Volker A. Coenen,&nbsp;Máté D. Döbrössy","doi":"10.1002/jnr.70093","DOIUrl":"10.1002/jnr.70093","url":null,"abstract":"<p>It has been hypothesized that the rapid/long-lasting antidepressant action observed following medial forebrain bundle DBS in clinical trials of Treatment-Resistant Depression patients could partially be driven by modulation of the midbrain-to-forebrain dopaminergic fibers. The study investigated the spatial distribution and myelination status of dopaminergic fibers within the rodent equivalent structure in a preclinical depression model, the Flinders Sensitive Line (FSL). Fixed, sliced brain sections were double stained with anti-tyrosine hydroxylase/anti-dopamine-β-hydroxylase antibodies to distinguish dopaminergic from noradrenergic fibers, and with anti-tyrosine hydroxylase/anti-myelin antibodies to specifically investigate myelination. Quantification was done at six predefined segments. The dopaminergic fibers coursing through the medial forebrain bundle were small diameter, unmyelinated and mainly restricted to the dorsolateral quadrant on the AP axis. Analyses across six predefined planes revealed significantly fewer dopaminergic fibers in FSL males (vs control males, and vs. FSL females) at AP −2.8 mm, the segment corresponding to the medial forebrain bundle DBS target in the rat. No differences were observed elsewhere along the medial forebrain bundle. Previously reported differences in stimulation-evoked dopamine release in the FSLs could be due to differences in the numbers of recruited dopaminergic fibers.</p>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12619984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of Glial Gap Junction Protein Innexin2 Mediates Seizures and Disrupted Sleep in a Drosophila Model for North Sea Progressive Myoclonus Epilepsy","authors":"Nicola A. Grzeschik,&nbsp;Roald A. Lambrechts,&nbsp;Marianne van der Zwaag,&nbsp;Ellie Eggens-Meijer,&nbsp;Ody C. M. Sibon,&nbsp;Jenke A. Gorter","doi":"10.1002/jnr.70087","DOIUrl":"10.1002/jnr.70087","url":null,"abstract":"<p>North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disease that presents at an early age with progressive ataxia, myoclonus, and epilepsy. The disease is caused by a mutation in the Golgi SNAP receptor 2 gene (GOSR2). However, the consequences of this genetic defect at the cellular level are still unknown. Using a NS-PME <i>Drosophila melanogaster</i> model, it was previously found that knockdown of <i>membrin</i>, the fruit fly GOSR2 ortholog, in glial cells leads to progressive heat-induced seizure-like behavior in adult flies. Upon close inspection, we found NS-PME flies not only show progressive heat-induced seizures but also disrupted sleep architecture (higher number of shorter sleep bouts). Here we asked what glial cellular consequences could be underlying these phenotypes of <i>membrin</i> knockdown. First, we investigate whether these phenotypes are attributed to specific glial types; we found that these phenotypes were partly reproduced with specific knockdown of <i>membrin</i> in perineurial glia only. Next, we show that Innexin2, a gap junction protein specifically expressed in glia, is affected upon <i>membrin</i> knockdown, with an altered expression pattern and reduced protein levels. Finally, glial overexpression of Innexin2 in the background of glial <i>membrin</i> knockdown strongly ameliorates the heat-induced seizure phenotype, disrupted sleep architecture, as well as Innexin2 expression pattern, corroborating the importance of Innexin2 in maintaining neuronal homeostasis in NS-PME. These findings show that dysregulation of Innexin2 at least partially underlies the phenotypes of <i>membrin</i> knockdown in <i>Drosophila melanogaster</i> and could suggest a similar role of Innexin2-like proteins in the human disease NS-PME.</p>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12598673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble Epoxide Hydrolase Inhibition Confers Neuroprotection via PPAR-α Activation During Intracerebral Hemorrhage","authors":"Ari Misael Martínez-Torres,&nbsp;Cynthia Navarro-Mabarak,&nbsp;Julio Morán","doi":"10.1002/jnr.70092","DOIUrl":"10.1002/jnr.70092","url":null,"abstract":"<p>Epoxyeicosatrienoic acids (EETs), are known to possess potent anti-inflammatory and antioxidant neuroprotective properties. However, the molecular mechanisms responsible for these effects are not well understood. In this work, we aimed to evaluate the neuroprotective role of EETs in a hemorrhagic stroke model and the possible involvement of PPAR-α activation in this neuroprotection. Hemorrhagic damage was induced in mice through the intracerebral administration of collagenase VII in the striatum. The neuroprotective effect of EETs was tested in mice by pre-treatments of 2 h with TPPU, an inhibitor of the EETs metabolism. TPPU was administered intraperitoneally at a dose of 0.5, 1.0, or 2 mg/kg. Brain damage was evaluated based on measurements of motor activity, hematoma volume, brain water content, and blood–brain barrier (BBB) permeability. Additionally, the levels of enzymes involved in the oxidative stress balance, such as NADPH oxidase 2 (NOX-2) and superoxide dismutase (SOD), were determined by Western blot analysis. Our results showed that EETs exert neuroprotective effects by significantly decreasing all parameters related to brain damage, improving motor function and promoting an antioxidant state, as evidenced by increased levels of SOD and reduced levels of NOX enzymes. Subsequently, PPAR-α involvement was evaluated through the administration of GW6471, a PPAR-α antagonist. Pre-treating mice with GW6471 for 30 min, reverted all neuroprotective effects, including the observed changes in SOD and NOX levels. Our results demonstrate that EETs confer neuroprotection in hemorrhagic brain injury, and this effect is dependent on PPAR-α activation.</p>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jnr.70092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rolipram-Loaded PgP Nanotherapeutics via Intrathecal Administration Reduces Secondary Injury in a Rat Acute Moderate Contusion SCI Model","authors":"Zhen Liao,&nbsp;Jun Gao,&nbsp;Min Kyung Khang,&nbsp;Ken Webb,&nbsp;Megan Ryan Detloff,&nbsp;Jeoung Soo Lee","doi":"10.1002/jnr.70091","DOIUrl":"10.1002/jnr.70091","url":null,"abstract":"<p>Spinal cord injury (SCI) triggers complex secondary injury mechanisms, resulting in long-term impacts on sensory and motor function. Rolipram, a phosphodiesterase-4 inhibitor, has shown promise in preserving/restoring cyclic adenosine monophosphate (cAMP) to reduce secondary injury responses, but its clinical application is hindered by poor solubility and systemic side effects. To overcome these challenges, we developed rolipram-loaded poly(lactide-co-glycolide)-graft-polyethylenimine (PgP) nanoparticles (Rm-PgP) to enable localized and sustained drug delivery. In our previous findings, Rm-PgP administered via intraspinal injection restored cAMP levels at the lesion site, and reduced secondary injury after moderate, contusive SCI. In this study, we investigated the effect of single and repeat administration of Rm-PgP by the clinically relevant intrathecal route immediately after injury. We observed that the hydrophobic dye, DiR-loaded PgP (DiR-PgP) was retained in the CNS over 7 days post-injury (DPI). In addition, we observed that both single and repeat Rm-PgP treatment groups showed higher cAMP levels compared to those in the untreated SCI group and only the single treatment group showed a significant difference compared to the untreated SCI group. Lastly, we observed that cAMP restoration in both single and repeat Rm-PgP treatment groups showed higher levels of activated cAMP-response element-binding protein (pCREB) relative to the untreated control. We also observed that both Rm-PgP treatment groups showed reduced inflammatory response, reduced astrogliosis and apoptosis, and increased neuronal survival and spared tissue volume. These findings highlight the neuroprotective efficacy of Rm-PgP by intrathecal administration in mitigating secondary injury during the critical early phase of recovery after SCI.</p>","PeriodicalId":16490,"journal":{"name":"Journal of Neuroscience Research","volume":"103 11","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jnr.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}