Neurochemical Research最新文献

{"title":"DNA Topoisomerase IIβ Suppresses Microglial Inflammatory Cytokine Release: A Potential Regulator of Neuroinflammation","authors":"Rama Şeyhali Abutayeh,&nbsp;Rümeysa Akbayır,&nbsp;Naki Burak Akül,&nbsp;Melike Cansel Eren,&nbsp;Timuçin Avşar,&nbsp;Yeşim Neğiş,&nbsp;Berçem Yeman-Kıyak,&nbsp;Sevim Işık","doi":"10.1007/s11064-026-04899-0","DOIUrl":"10.1007/s11064-026-04899-0","url":null,"abstract":"<div><p>DNA topoisomerase IIβ (topo IIβ) is a nuclear enzyme that regulates DNA topology and gene expression, especially in post-mitotic cells such as neurons. Although its roles in neural development and transcriptional control are well-established, its involvement in neuroinflammatory processes is still to be investigated. This study aims to investigate whether topo IIβ modulates inflammatory responses in human microglial HMC3 cells under immune-stimulated conditions, considering that microglial cells are pivotal mediators of neuroinflammation in the central nervous system (CNS). Inflammation was induced using lipopolysaccharide (LPS), interferon-gamma (IFNγ), Adenosine triphosphate (ATP), whereas topo IIβ expression was modulated by overexpression and siRNA-mediated silencing. Western blot analysis demonstrated that LPS, IFNγ, and ATP stimulation did not alter the endogenous topo IIβ protein levels, indicating that its protein levels are stable under inflammatory conditions. Analysis of cytokine release indicated that topo IIβ overexpression decreased the release of key proinflammatory cytokines, suggesting an anti-inflammatory role. Conversely, the silencing of topo IIβ resulted in increased cytokine release, suggesting that topo IIβ typically functions to mitigate microglial inflammatory responses. Significantly, treatment with Lipofectamine™ 3000 alone increased cytokine release, indicating an intrinsic immunostimulatory impact of the transfection reagent. Collectively, these findings reveal an unacknowledged function of topo IIβ in attenuating neuroinflammatory signaling in microglia and underscore the necessity for careful interpretation of cytokine data when transfection reagents are present. Topo IIβ may represent a novel therapeutic target for modulating microglial activation in neuroinflammatory diseases.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029551","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":"Carbamazepine preserves systemic ionic homeostasis and hippocampal Atp1a1 expression following pentylenetetrazol-induced seizures in rats","authors":"Alfonso Alfaro-Rodríguez,&nbsp;Samuel Reyes-Long,&nbsp;José Luis Cortes-Altamirano,&nbsp;Angélica González-Maciel,&nbsp;Beatriz Pérez-Guille,&nbsp;Rosa Eugenia Soriano-Rosales,&nbsp;Rafael Reynoso-Robles,&nbsp;Francisco Jacob Avila-Camacho","doi":"10.1007/s11064-026-04902-8","DOIUrl":"10.1007/s11064-026-04902-8","url":null,"abstract":"<div><p>Epileptogenesis involves complex neurochemical and neurovascular changes that disrupt the balance between excitatory and inhibitory neurotransmission. Carbamazepine (CBZ) is a standard antiepileptic drug known for blocking voltage-gated sodium channels; however, its potential as a molecular stabilizer of ion transporters such as Na+/K+-ATPase remains largely unexplored. In this study, we investigated the effect of CBZ on systemic ion homeostasis and hippocampal <i>Atp1a1</i> expression in a rat model of PTZ-induced seizures. The male Wistar rats were divided into three groups (<i>n</i> = 6 per group): control, PTZ (70 mg/kg) and CBZ (50 mg/kg) + PTZ. Serial blood sampling revealed that acute PTZ induced severe systemic imbalances (hypernatremia, hypokalemia, and hypocalcemia). RT-qPCR analysis showed a significant and region-specific downregulation (60%) of mRNA <i>Atp1a1</i> in the hippocampus, meanwhile in frontal cortex its levels remained stable. Histopathological examination using cresyl violet staining revealed vascular dilation, endothelial disruption, and neuronal pyknosis in the PTZ group. Pretreatment with CBZ effectively prevented systemic ion shifts, preserving hippocampal <i>Atp1a1</i> mRNA expression at control levels, and preserved neurovascular integrity. Our results suggest that the neuroprotective mechanism of CBZ extends beyond Na+ channel blockade, acting as a multifaceted stabilizer of ionic homeostasis and of Na+/K+-ATPase expression in the hippocampal formation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029542","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":"Lycium Barbarum Polysaccharides Alleviate Parkinson’s Disease-Induced Neurodegeneration by Up-Regulating USP10 to Modulate Endoplasmic Reticulum Stress","authors":"Yan Zhang,&nbsp;Bonian Ma,&nbsp;Guichao Zuo,&nbsp;Zhengying Jing,&nbsp;Hui Dong,&nbsp;Guisheng Chen","doi":"10.1007/s11064-026-04897-2","DOIUrl":"10.1007/s11064-026-04897-2","url":null,"abstract":"<div><p>Endoplasmic reticulum stress (ERS) is a significant pathological mechanism in Parkinson’s disease (PD), and prolonged ERS can ultimately lead to cellular apoptosis. This study aimed to investigate the neuroprotective effects of <i>Lycium barbarum</i> polysaccharides (LBP) against MPP⁺-induced damage in primary neurons. Mouse primary dopaminergic neurons were treated with MPP⁺ for 24 h to establish PD cell model, and then treated with LBP for another 24 h. Western blot analysis revealed that, compared to the Control group, MPP⁺ treatment induced primary neuron ERS and apoptosis, manifested by upregulating the expression of ERS and apoptotic marker proteins GRP78, p-IRE1α, p-eIF2α, ATF-4, CHOP, Caspase-3 and Bax, repressing mitochondrial transmembrane potential and promoting ROS production, and LBP treatment significantly counteracted MPP⁺-induced ERS and apoptosis. Knockdown of ubiquitin-specific protease 10 (USP10) attenuated the protective effects of LBP in MPP⁺-injured primary neurons. Co-immunoprecipitation (Co-IP) and immunofluorescence co-localization assays confirmed the interaction between USP10 and Yes-associated protein 1 (YAP1). Deubiquitination experiments indicated that USP10 reduced YAP1 ubiquitination and enhanced its protein stability. Additionally, we demonstrated that USP10 suppressed the PERK/eIF2α/ATF-4/CHOP pathway, a key pro-ERS pathway, by inhibiting YAP1 ubiquitination, thereby alleviating MPP⁺-induced ERS and apoptosis. In summary, our findings indicate that LBP attenuates MPP⁺-induced neuronal injury by promoting USP10-mediated deubiquitination of YAP1 and subsequently inhibiting the PERK/eIF2α/ATF-4/CHOP signaling pathway, which proposes a new insight for the pathogenesis research of Parkinson’s disease, as well as a potential pharmacological mechanism and target of <i>Lycium barbarum</i> polysaccharides.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04897-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029521","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":"EGR2 Facilitates LPS-Elicited Microglial Inflammation and Inflammatory Pain by Transcriptionally Activating MRTO4","authors":"Fang Cheng,&nbsp;Olchy Louange Pandy Kaya,&nbsp;Aekraj Shrestha,&nbsp;Dennis Amofah Adjei,&nbsp;Hai-Ying Li,&nbsp;Li-Xue Jiang","doi":"10.1007/s11064-026-04882-9","DOIUrl":"10.1007/s11064-026-04882-9","url":null,"abstract":"<div><p>This study discovers the high expression of EGR2 in neuropathic pain (NP) and further explores the molecular mechanism of EGR2-mediated inflammatory response of spinal microglia. GSE92718 was obtained from the GEO database to screen differentially expressed genes in NP. A chronic constriction injury (CCI) model was established in male C57BL/6J mice. EGR2 shRNA was intrathecally injected into CCI mice, followed by RT-qPCR, Western blot, ELISA, and immunofluorescence to detect inflammatory response and microglial activation. An in vitro inflammatory cell model was established by inducing BV-2 cells with 100 ng/mL LPS. The binding between EGR2 and MRTO4 was predicted through bioinformatics and verified by dual luciferase and ChIP assays. EGR2 was the most significantly differentially expressed gene in NP. EGR2 expression was upregulated in spinal cord tissues of male CCI mice, mainly in microglia and neurons. EGR2 shRNA alleviated CCI-induced mechanical allodynia and thermal hyperalgesia, inhibited pro-inflammatory cytokines and microglial activation. EGR2 transcriptionally activated MRTO4 expression. LPS induced BV-2 cell activation and inflammatory response. Overexpression of EGR2 increased pro-inflammatory cytokines and Iba-1 + positive cells in LPS-stimulated BV2 cells, while the addition of sh-MRTO4 rescued the trend. In conclusion, EGR2 gene is significantly upregulated in the spinal cord tissues of male CCI mice. EGR2 facilitates LPS-induced inflammatory responses in microglia by transcriptionally activating MRTO4 expression, suggesting that this signaling pathway may participate in NP-associated spinal inflammation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015154","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":"Hinokitiol as a Potential GPX4 Allosteric Modulator to Prevent Ferroptosis-mediated Neurodegeneration in Parkinson’s Disease","authors":"Devadharuna Mohan,&nbsp;Choudary Soujanya,&nbsp;Raghul Venkatesan,&nbsp;Amritha Chakkittukandiyil,&nbsp;Amarjith Thiyyar Kandy,&nbsp;Ram Kothandan,&nbsp;Shivaramakrishnan Balasubramanian,&nbsp;Divakar Selvaraj","doi":"10.1007/s11064-026-04894-5","DOIUrl":"10.1007/s11064-026-04894-5","url":null,"abstract":"<div><p>Ferroptosis is a form of cell death driven by iron-dependent lipid peroxidation. Recently, it was identified as a key factor in Parkinson’s disease (PD). Through gene network analysis, we identified glutathione peroxidase 4 (GPX4) as a bottleneck node in the ferroptosis pathway. Allosteric activation of GPX4, or increased gene/protein expression of GPX4, was shown to prevent neurodegeneration. Accordingly, we sought to identify novel phytochemicals that could act as allosteric modulators of GPX4. In our study, hinokitiol showed the best ligand efficiency for GPX4’s allosteric pocket. We further validated the binding stability using molecular dynamics (MD) simulations. Hinokitiol showed stable binding throughout the 500ns MD run. Notably, hinokitiol induced conformational changes in residues near the catalytic binding site, which might influence substrate binding to GPX4. We examined the neuroprotective effects of hinokitiol in retinoic acid–differentiated SH-SY5Y cells exposed to rotenone (10 µM). Malondialdehyde (MDA), intracellular iron content, and GPX4 gene expression were quantified in SH-SY5Y cells. Pretreatment with hinokitiol (25 and 50 µM) significantly protected SH-SY5Y cells from rotenone-induced toxicity. Hinokitiol markedly reduced rotenone-induced MDA and iron levels and increased GPX4 gene expression. In <i>Drosophila melanogaster</i>, rotenone reduced mean survival to approximately 19 days, whereas co-treatment with hinokitiol extended lifespan to ~ 23 days (500 ppm) and ~ 27 days (1000 ppm). Similarly, in rotenone-induced PD mice, hinokitiol reduced catalepsy and improved locomotion and motor coordination. Collectively, these findings suggest that hinokitiol could mitigate ferroptosis-mediated neurodegeneration, possibly by modulating GPX4 activity.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987046","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":"Enhanced HCN-Dependent Regulation of Temporoammonic Integration and Entorhinal–Hippocampal Epileptiform Coupling Following Febrile Seizures","authors":"Georgy P. Diespirov,&nbsp;Tatyana Y. Postnikova,&nbsp;Dmitry V. Amakhin,&nbsp;Elena B. Soboleva,&nbsp;Anna A. Kovalenko,&nbsp;Aleksey V. Zaitsev","doi":"10.1007/s11064-026-04896-3","DOIUrl":"10.1007/s11064-026-04896-3","url":null,"abstract":"<div><p>Mechanisms linking early-life developmental pathologies, such as cortical malformations and febrile seizures (FS), to persistent hippocampal circuit alterations remain incompletely understood. We investigated intrinsic excitability, HCN channel function, pathway-specific synaptic integration, and entorhinal–hippocampal network activity using rat models of focal freeze lesion (FFL) at postnatal day (P) 0, experimental FS at P10, and their combination (FFL + FS). Whole-cell recordings at P21–23 showed that FFL predominantly reduced CA1 neuronal excitability, whereas the FS condition was associated with increased hyperpolarization-activated cation current (<i>I</i>_<i>h</i>) amplitude and sag ratio. This functional HCN enhancement was not accompanied by detectable changes in bulk hippocampal <i>Hcn1</i> or <i>Hcn2</i> mRNA levels and remained evident in FFL + FS animals. HCN blockade enhanced synaptic summation in both Schaffer collateral and temporoammonic pathways, with a greater relative effect on temporoammonic inputs after FS. In the 4-aminopyridine model of induced epileptiform activity, HCN blockade increased hippocampal event burden and strengthened EC-leading temporal coupling with CA1, with particularly pronounced effects following FS. Together, these findings suggest that persistent HCN enhancement following prolonged experimental FS is associated with greater HCN-dependent regulation of temporoammonic integration and entorhinal–hippocampal coupling under 4-AP-induced epileptiform conditions.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987047","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":"Dynamic Remodeling of Dentate Gyrus Microglia Underlies Adult Depression-Like Outcomes Following Adolescent High-Fat Diet Exposure","authors":"Xia Wenbin,&nbsp;Jianbin Su,&nbsp;Minxiu Ye,&nbsp;Chao Huang,&nbsp;Ziwei Cao,&nbsp;Feng Xu,&nbsp;Huijun Liu","doi":"10.1007/s11064-026-04888-3","DOIUrl":"10.1007/s11064-026-04888-3","url":null,"abstract":"<div><p>Adolescent overconsumption of calorie-dense fatty foods is a major public health concern, as its adverse effects on brain function often persist into adulthood. However, the precise cellular and molecular mechanisms by which early-life dietary excess leads to enduring mood disorders remain poorly understood. Previous work from our group and others indicates that loss of dentate gyrus microglia following earlier overactivation is a critical step in depression-like pathology. Because high-fat intake is known to potently stimulate these immune cells, we examined whether such dynamic microglial changes underlie the depression-like behaviors triggered by adolescent high-fat diet (HFD) exposure. Our experimental data clearly show that a sub-chronic 12-day HFD, starting at postnatal day 28, not only induced depression-like behaviors in adult mice but also reduced the microglial population within the dentate gyrus. This marked reduction is associated with early microglial injury, as indicated by a substantial increase in TUNEL-positive cells. Importantly, preventing the initial microglial response with minocycline effectively blocked this damaging cascade, thereby averting both microglial loss and depression-like behaviors in adulthood. Conversely, a low-dose lipopolysaccharide (LPS) injection administered in adulthood, which effectively restored microglial numbers, successfully reversed these established behavioral deficits. Taken together, these findings show that adolescent HFD triggers a detrimental sequence of microglial activation, damage, and eventual depletion within the dentate gyrus. This terminal loss is a key driver of adult depression, strongly suggesting that strategies to reverse microglial decline may represent a viable therapeutic approach for depression associated with early-life nutritional adversity.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987048","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":"SVHRSP Attenuates PTZ-Induced Seizure-Like Behavior in C. elegans: Involvement of HSF-1 and Associated Changes in GABAergic Markers and Mitochondrial Homeostasis","authors":"Muhammad Ibrahim Khalil,&nbsp;Song-Yu Guo,&nbsp;Dan Zhao,&nbsp;Muhammad Khalid Iqbal,&nbsp;Yue Kong,&nbsp;Ao-Ran Sui,&nbsp;Shao Li","doi":"10.1007/s11064-026-04890-9","DOIUrl":"10.1007/s11064-026-04890-9","url":null,"abstract":"<div><p>Epilepsy is a prevalent neurological disorder. Nevertheless, approximately one-third of patients fail to achieve sufficient seizure control through current pharmacological treatments. This unmet need underscores the importance of developing new antiseizure treatments for drug-resistant epilepsy. Scorpion venom heat-resistant synthetic peptide (SVHRSP), which is derived from scorpion venom and chemically synthesized, has demonstrated promising activity against acute PTZ-evoked seizure-like behaviors. In this study, the effects of SVHRSP pretreatment on acute PTZ-evoked seizure-like behavior were evaluated in Caenorhabditis elegans. Our findings indicate that SVHRSP (50 μM) significantly alleviated the seizure-like behavioral symptoms induced by PTZ (30 mg/mL). Specifically, behavioral assessments showed that SVHRSP improved survival and attenuated PTZ-associated deficits in locomotion, food preference, chemotaxis, and pharyngeal pumping in PTZ-exposed nematodes. Furthermore, SVHRSP pretreatment partially reversed PTZ-associated changes in GABAergic and glutamatergic reporter fluorescence and in the transcript abundance of <i>unc-25</i>, <i>gat-1</i>, and <i>eat-4</i>. SVHRSP also ameliorated mitochondrial dysfunction and reduced oxidative stress. SVHRSP pretreatment was also associated with increased <i>ced-9</i> transcript abundance, reduced <i>cep-1</i> transcript abundance, lower intracellular ferrous iron (Fe²⁺) levels, and attenuation of PTZ-associated changes in GABAergic reporter morphology. The attenuation of these SVHRSP-associated changes in <i>hsf-1</i>(sy441) animals supports the involvement of <i>HSF-1</i>-dependent processes; however, direct <i>HSF-1</i> activation and the downstream causal relationships were not established. These findings show that SVHRSP pretreatment attenuated acute PTZ-evoked seizure-like phenotypes in <i>C. elegans</i> and support further evaluation in mammalian seizure and epilepsy models.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148927401","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":"The Senescent Phenotype of Cultured Hypothalamic Astrocytes from Rats with Streptozotocin-Induced Dementia","authors":"Vanessa-Fernanda Da Silva,&nbsp;Daniele Schauren da Costa,&nbsp;Vitor Gayger-Dias,&nbsp;Thomas Michel Sobottka,&nbsp;Ana Carolina Ribeiro Da Silva,&nbsp;Bruna Cristiana R. Biolchi,&nbsp;Laíse Freese da Silva,&nbsp;Nikoli Zasso,&nbsp;Fernanda Becker Weber,&nbsp;Izaviany Schimitz,&nbsp;Diorlon Nunes Machado,&nbsp;Carlos Alexandre Netto,&nbsp;Marina Concli Leite,&nbsp;Larissa Daniele Bobermin,&nbsp;André Quincozes-Santos,&nbsp;Carlos-Alberto Gonçalves","doi":"10.1007/s11064-026-04884-7","DOIUrl":"10.1007/s11064-026-04884-7","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is the most prevalent form of dementia, with aging as its primary risk factor. Among experimental models of sporadic AD, intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents is widely used. We hypothesized that STZ accelerates the process of cellular senescence, which in astrocytes can be assessed using classic markers, including p16, β-galactosidase, Lamin B1, and the senescence-associated secretory phenotype (SASP). To explore this, we cultured hypothalamic astrocytes from adult male Wistar rats at four weeks after STZ-ICV model induction to investigate whether the astroglial changes observed in vivo were maintained under in vitro conditions, and whether markers of senescence were more evident in astrocytes from STZ animals. As in the STZ dementia model, astrocyte cultures exhibited reduced levels of glutamine synthetase and glutathione. Furthermore, elevations in the transcription factors, FOXO3a, Nrf2, and NF-κB, were observed. Markers of unfolded protein response (CHOP and sorcin) were also increased in astrocytes from STZ animals. When evaluating senescence parameters, increases in p53, p21, and p16 were observed, while Lamin B1 levels remained unchanged. With regard to SASP, modulations in TNFα and extracellular HMGB1 and S100B levels also suggested the induction of a senescent profile. Taken together, these findings demonstrate that cultured astrocytes retain key alterations observed in the in vivo model of STZ-induced dementia, highlighting its usefulness for studying AD and therapeutic strategies. Observations in cultures suggest that STZ indeed induces astrocyte senescence and that S100B may be included as a component of the astroglial SASP.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04884-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148927400","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":"Pathophysiological Role of Perivascular Macrophages in Blood–Brain Barrier Dysfunction Induced by Cerebral Hypoperfusion in Mice","authors":"Sayaka Matsumura,&nbsp;Yoshiyuki Moriyama,&nbsp;Ayumi Ochiai,&nbsp;Yui Iwatani,&nbsp;Hideki Hayashi,&nbsp;Norio Takagi","doi":"10.1007/s11064-026-04881-w","DOIUrl":"10.1007/s11064-026-04881-w","url":null,"abstract":"<div><p>This study investigated the role of perivascular macrophages (PVMs), localized alongside the brain vasculature, in blood-brain barrier (BBB) dysfunction induced by reduced cerebral blood flow (CBF). Using a mouse model of bilateral carotid artery stenosis (BCAS) to examine cerebral hypoperfusion, the effects of pharmacological depletion of PVM-enriched macrophage populations were examined using clodronate liposomes. The results demonstrated that while cerebral hypoperfusion significantly increased BBB permeability, depletion of PVM-enriched macrophage populations attenuated this leakage. Mechanistic analyses suggested that PVM-associated responses may be linked to reduced pericyte marker expression, astrocyte activation, and increased MMP-2/9 expression. Furthermore, depletion of PVM-enriched macrophage populations inhibited the upregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. These findings suggest that PVM-enriched macrophage populations are involved in early BBB dysfunction following cerebral hypoperfusion, possibly through changes in pericyte-associated vascular integrity, astrocyte activation, and MMP-2/9-related tight junction remodeling. These results provide insight into vascular inflammatory mechanisms that may contribute to hypoperfusion-associated BBB dysfunction and later small vessel pathology.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 5","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04881-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148927856","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}