Neurochemical Research最新文献

{"title":"Neuroprotective Effects of lncRNA EPB41L4A-AS1 Against Ischemic Stroke Injury Through Regulating Microglial State Transition and Ferroptosis via miR-214-3p/GPX4 Axis","authors":"Ying Guo,&nbsp;Jinyuan Yi,&nbsp;Haitao Fang,&nbsp;Yu Zhang,&nbsp;Haixiao Zhang","doi":"10.1007/s11064-026-04827-2","DOIUrl":"10.1007/s11064-026-04827-2","url":null,"abstract":"<div><p>Long non-coding RNAs (lncRNAs) regulate microRNAs and their target genes to control key pathological processes after acute ischemic stroke (AIS). To investigate lncRNA EPB41L4A-AS1’s role in microglial function via miR-214-3p/GPX4, and its clinical relevance as a prognostic indicator in AIS. EPB41L4A-AS1 levels were measured by RT-qPCR in 120 AIS patients and OGD/R-treated BV2 microglia. ELISA and western blot were employed to assess microglial state transition and ferroptosis in OGD/R-injured BV2 cells. A combination of RIP, RNA pull-down, and luciferase reporter assays were employed to validate the miRNA and gene targets regulated by EPB41L4A-AS1. Functional rescue assays were conducted by co-transfecting miR-214-3p with GPX4 to validate the regulatory relationship in vitro. EPB41L4A-AS1 was significantly downregulated in the serum of AIS patients, with lower levels predicting worse prognosis. Elevated EPB41L4A-AS1 expression substantially reduced pro-inflammatory markers (iNOS, TL-1β and TNF-α), but enhanced anti-inflammatory markers (Arg1 and IL-10) of OGD/R-injured BV2 cells. Meanwhile, the iron overload and lipid peroxidation in OGD/R cells were also improved. RIP, RNA pull-down, and luciferase reporter assays confirmed the specific binding of miR-214-3p to EPB41L4A-AS1 and GPX4. Upon EPB41L4A-AS1 overexpression, miR-214-3p mimic amplified the iron overload and oxidative stress and led to a pro-inflammatory state of BV2 cells under OGD/R conditions. Restoring GPX4 expression abrogated these observed effects. Lower serum EPB41L4A-AS1 correlates with poor prognosis in AIS patients. The mechanism underlying its neuroprotective effects against microglial state transition and ferroptosis was delineated through the miR-214-3p/GPX4 axis.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417665","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":"Involvement of COX-2 in the Neurovascular Unit Damage Through Up-Regulating Calpain/PARP/NF-κB Inflammatory Signaling During Ischemic Stroke","authors":"Chunyang Wang,&nbsp;Bin Wang,&nbsp;Yumei Zhao,&nbsp;Chen Jin,&nbsp;Ming Sun","doi":"10.1007/s11064-026-04838-z","DOIUrl":"10.1007/s11064-026-04838-z","url":null,"abstract":"<div><p>Cyclooxygenase-2 (COX-2), a key enzyme to catalyzes the formation of prostanoids from arachidonic acid, is involved in inflammatory events. Furthermore, the calpain/PARP/NF-κB inflammatory pathway has been implicated in the damage to the neurovascular unit (NVU) following ischemic stroke. This study investigated the effects of parecoxib, a specific COX-2 inhibitor, on calpain, PARP, NF-κB inflammatory signaling, and NVU damage in the rat model of ischemic stroke. Male Sprague-Dawley rats (<i>n</i> = 107) were subjected to 90 min of ischemia, followed by reperfusion. Parecoxib was administered intraperitoneally 5 min post-ischemia, and the activation of calpain, PARP, and NF-κB-inflammatory signaling, and the NVU damage were evaluated 24 h post-ischemia. It was found that parecoxib alleviated neurological deficits, brain swelling and apoptotic cell death, and decreased infarct volumes 24 h post-ischemia. It decreased the levels of calpain 1 and 2, enhanced the levels of calpastatin, and repressed the activities of calpain in penumbra and core. Meanwhile, it reduced the levels of cytosolic PARP and HMGB1, elevated the level of cytosolic IκBα, lowered the levels of nuclear PARP, poly(ADP-ribose) and NF-κB p65, lessened the levels of cytosolic ICAM-1, IL-1β, MMP-2, and MMP-9, and suppressed the MPO activities in penumbra and core. Additionally, it attenuated the NVU and blood-brain barrier damage in penumbra and core. These data demonstrated that parecoxib exerts its protective effects on the NVU by blocking the over-activation of calpain and PARP, as well as by suppressing NF-κB-mediated inflammatory response during ischemic stroke. Moreover, the findings suggest that COX-2 contributes to NVU damage by up-regulating the calpain/PARP/NF-κB inflammatory pathway during brain ischemia.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417608","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":"Role of the miR-340-5p/IRF1/USP18 Axis in Neuroinflammation Associated with Epilepsy","authors":"Jing Liu,&nbsp;Yiting Wang,&nbsp;Bibi Yazgulyyeva,&nbsp;Dandan Sheng,&nbsp;Xinru Li,&nbsp;Luo Zhou,&nbsp;Bo Xiao,&nbsp;Weiping Liu","doi":"10.1007/s11064-026-04836-1","DOIUrl":"10.1007/s11064-026-04836-1","url":null,"abstract":"<div><p>Epilepsy is a prevalent neurological disorder, in which maladaptive neuroinflammation critically contributes to epileptogenesis. In this study, we identified a previously unrecognized signaling axis that regulates inflammatory responses and inflammatory cell death in experimental epilepsy. Integrated bioinformatic analyses of the GSE73878 and GSE18740 datasets, together with transcription factor and microRNA prediction databases, highlighted USP18 and its upstream regulators as key candidates. Functional and mechanistic validations were performed using lipopolysaccharide-stimulated BV2 microglia and pentylenetetrazole-induced mouse seizure models. Seizure severity and epileptic phenotypes were confirmed using the Racine scale assessments and EEG recordings. USP18 was markedly upregulated under epileptic conditions accompanied by increased pro-inflammatory cytokine release, apoptosis, and pyroptosis. Silencing USP18 attenuated neuroinflammation and reduced seizure severity. Mechanistically, interferon regulatory factor 1 (IRF1) was identified as a direct transcriptional activator of USP18, whereas miR-340-5p suppressed USP18 expression by targeting IRF1, thereby mitigating inflammatory signaling and neuronal injury. Collectively, these findings reveal a novel regulatory pathway linking microRNA-mediated control, interferon-responsive transcription, and inflammatory effector mechanisms in epilepsy, and suggest that targeting the miR-340-5p/IRF1/USP18 axis may represent a promising disease-modifying therapeutic strategy.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417600","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":"Regulatory Effects of the PDE8B Inhibitor PF-04957325 on Cognitive Impairment and Neuroinflammation in Aβ-Induced Alzheimer’s Disease Mouse Models","authors":"YaQun Liu,&nbsp;MuYang Li,&nbsp;HongBo Yu,&nbsp;HuiYing Liu,&nbsp;QiuShuang Xu,&nbsp;Fang Li","doi":"10.1007/s11064-026-04830-7","DOIUrl":"10.1007/s11064-026-04830-7","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition, chronic neuroinflammation, and dysregulation of the cAMP/PKA/CREB pathway that impairs synaptic plasticity. PF-04957325 (PF), a selective PDE8B inhibitor, elevates intracellular cAMP; however, its systems-level effects and mechanisms in Aβ-driven AD are unclear. Here, we evaluate PF in an Aβ1–42 mouse model and delineate its modulation of cAMP/PKA/CREB and TLR4/MyD88/NF-κB signaling. An AD model was induced by intracerebroventricular injection of Aβ1–42, followed by oral PF administration (0.1 mg/kg/day). Cognitive performance was evaluated with the Morris water maze. Hippocampal pathology, Aβ burden, and apoptosis were assessed by H&amp;E, immunohistochemistry, and TUNEL assays. IL-1β and IL-6 were measured by ELISA in hippocampal tissue and BV2 supernatants. Western blotting quantified APP, p-tau, and pathway proteins. BV2 cells and si-PDE8B served to validate mechanisms in vitro. PF significantly shortened escape latency (<i>p</i> &lt; 0.01) and increased both platform crossings and target-quadrant dwell time (<i>p</i> &lt; 0.01). It alleviated hippocampal neuronal injury, reduced Aβ burden, and decreased TUNEL-positive cells. Molecularly, PF elevated cAMP and increased p-PKA/PKA and p-CREB/CREB ratios (<i>p</i> &lt; 0.01), while decreasing TLR4, MyD88, and p-NF-κB p65/NF-κB p65 (<i>p</i> &lt; 0.01). PF also lowered IL-1β and IL-6 levels in hippocampal tissue and BV2 supernatants (both <i>p</i> &lt; 0.01). In vitro, 300 nM PF phenocopied PDE8B knockdown, restoring cAMP/PKA/CREB activity and suppressing TLR4/MyD88/NF-κB activation. PF exerts dual protective effects by activating cAMP/PKA/CREB to enhance synaptic plasticity and survival, while inhibiting TLR4/MyD88/NF-κB to mitigate neuroinflammation. These findings highlight PDE8B inhibition as a promising therapeutic strategy for AD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410111","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 Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice","authors":"Xinyuan Suo,&nbsp;Peifeng Wan,&nbsp;Jie Yu,&nbsp;Xinyu Zhu,&nbsp;Chenggang Tian,&nbsp;Shuyu Li,&nbsp;Guangqiang Sun,&nbsp;Hongchun Liu,&nbsp;Simin Liu,&nbsp;Meiyu Geng,&nbsp;Jingwei Tian,&nbsp;Weibo Yang,&nbsp;Yu Zhang","doi":"10.1007/s11064-026-04834-3","DOIUrl":"10.1007/s11064-026-04834-3","url":null,"abstract":"<div><p>Neuroinflammation and tau pathology are central drivers of Alzheimer’s disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.</p><h3>Graphical abstract</h3><p>Created with BioGDP.com [1]</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395232","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":"Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism","authors":"Hao Wu,&nbsp;Juntao Xia,&nbsp;Zhidan Shi,&nbsp;Chu Zhang,&nbsp;Shuting Chen,&nbsp;Li Dai,&nbsp;Ling He","doi":"10.1007/s11064-026-04831-6","DOIUrl":"10.1007/s11064-026-04831-6","url":null,"abstract":"<div><p>With the acceleration of global aging, Alzheimer’s disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA’s anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389814","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":"MST4 Regulates Microglia Neuroinflammation via Targeting PKM2 Nuclear Translocation in Epilepsy: An In Vivo and In Vitro Study","authors":"Jie Fu,&nbsp;Shaotao Zhang,&nbsp;Yifei Chu,&nbsp;Jinglun Li,&nbsp;Xiu Chen","doi":"10.1007/s11064-026-04824-5","DOIUrl":"10.1007/s11064-026-04824-5","url":null,"abstract":"<div><p>Microglia-mediated neuroinflammation is closely associated with the pathogenesis of epilepsy. Mammalian sterile-20-like kinase 4 (MST4) has been suggested a regulator of inflammation. However, the effect of MST4 on microglia neuroinflammation in epilepsy remains unclear. A pilocarpine-induced rat epilepsy model was constructed and a lipopolysaccharide (LPS)-stimulated microglia cell model was applied in the current research. Knockdown or overexpression of MST4 was established using lentivirus transfection. Electroencephalograph (EEG) was employed to measure brain activities of rats. The protein and mRNA expressions were detected using western blot and qRT-PCR, respectively. Immunofluorescent staining was conducted to detect the distribution of the proteins. TUNEL staining was performed to evaluate cell apoptosis. The protein interaction was evaluated with Co-IP assay. Our results showed that MST4 and nuclear PKM2 expressions were increased in epileptic rats compared to control and colocalized with microglia. MST4 overexpression inhibited microglia activation, the release of TNF-α and IL-1β, and improved neuronal apoptosis in epileptic rats. Furthermore, MST4 interacted with PKM2 and regulated PKM2 nuclear translocation. Inhibiting PKM2 nuclear translocation by TEPP-46 reversed the promoting effect of MST4 knockdown on microglia neuroinflammation. In summary, our study demonstrated that MST4 alleviated microglia-mediated neuroinflammation in epilepsy, and the mechanism of MST4-mediated anti-neuroinflammatory effects may be associated with the inhibition of PKM2 nuclear translocation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148380662","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":"Correction to: Dual Antioxidant DH-217 Mitigated Cerebral Ischemia-Reperfusion Injury by Targeting IKKβ/Nrf2/HO-1 Signal Axis","authors":"Mengya Shen,&nbsp;Yuantie Zheng,&nbsp;Ge Li,&nbsp;Yinqi Chen,&nbsp;Lili Huang,&nbsp;Jianzhang Wu,&nbsp;Chenglv Hong","doi":"10.1007/s11064-026-04832-5","DOIUrl":"10.1007/s11064-026-04832-5","url":null,"abstract":"","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148358963","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":"Microglia-Dependent BDNF Signaling in the Dentate Gyrus Underlies the Antidepressant Effects of Gardiquimod, a Toll-Like Receptor 7 Agonist, in Chronically Stressed Mice","authors":"Jing Gu,&nbsp;Jin Hong,&nbsp;Xu Lu,&nbsp;Nan Liu,&nbsp;Hao Lu,&nbsp;Lijuan Tong,&nbsp;Huijun Liu,&nbsp;Yi Zhang,&nbsp;Chao Huang","doi":"10.1007/s11064-026-04813-8","DOIUrl":"10.1007/s11064-026-04813-8","url":null,"abstract":"<div><p>Accumulating evidence suggests that pharmacological restoration of microglial homeostasis in the hippocampus may be a promising strategy for treating depression. In this study, we evaluated whether gardiquimod (GDQ), a selective Toll-like receptor 7 (TLR7) agonist, produces antidepressant effects in mice subjected to chronic unpredictable stress (CUS). A single intraperitoneal injection of GDQ at 1 or 1.5 mg/kg, but not 0.5 mg/kg, improved depression-related behaviors within 5 h of administration. Time-course analyses showed that the antidepressant efficacy of GDQ (1.5 mg/kg) appeared between 5 and 8 h, persisted for up to 7 days, and diminished by 14 days after a single dose. Notably, a second GDQ injection at 14 days restored the behavioral improvements, indicating sustained responsiveness to the drug. Mechanistically, the antidepressant effects of GDQ were abolished by both pharmacological inhibition (minocycline) and genetic depletion (PLX3397) of microglia, highlighting the necessity of these cells. Furthermore, GDQ reversed the CUS-induced reduction in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus in a microglia-dependent manner. The critical role of BDNF signaling was confirmed by three complementary approaches: intra-hippocampal infusion of a BDNF-neutralizing antibody, genetic disruption of activity-dependent BDNF release via the Val68Met knock-in mutation, and pharmacological blockade of the TrkB receptor with K252a. Each intervention abolished the behavioral effects of GDQ. Together, these findings identify GDQ as a promising candidate for antidepressant development and highlight the restoration of microglia-supported BDNF signaling in the dentate gyrus as a key mechanism underlying TLR7-mediated mood regulation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343691","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":"Long-Term Impact of Early-Life Stress on Hippocampal Apoptotic Gene Expression in BALB/c Mice","authors":"Aida Nurul Barokah,&nbsp;İhsan Kıvanç Gürsoy,&nbsp;Merve Hilal Dönmez,&nbsp;Juliette Fitremann,&nbsp;Arslan Bayram,&nbsp;Keziban Korkmaz Bayram","doi":"10.1007/s11064-026-04822-7","DOIUrl":"10.1007/s11064-026-04822-7","url":null,"abstract":"<div><p>Early-life stress (ELS), such as maternal separation, has been associated with neuronal apoptosis and impaired hippocampal function in rodent models. This study investigated the long-term effects of two ELS paradigms—unpredictable maternal separation (MS) and MS combined with unpredictable maternal stress (MSUS)—on the hippocampal mRNA expression of proapoptotic (<i>Bax</i>,<i> Tp53</i> and <i>Casp3</i>) and prosurvival (<i>Bcl2</i>) genes in offspring, both in vivo and in a complementary in vitro neuronal culture model. The study included three groups (Control, MS and MSUS groups), with ELS applied from postnatal days 1 to 14 to <i>BALB/c</i> mice. For the in vitro experiments, total RNA from the MSUS hippocampus was nucleofected at different concentrations into healthy mouse hippocampal cells, followed by 3D neuronal cell culture using N-heptyl-D-galactonamide (GalC7) hydrogels. Quantitative real-time PCR was used to assess gene expression, which was analyzed via the comparative Ct method (2^−ΔΔCt). This study revealed that <i>Bax</i> mRNA expression was significantly lower in the MS group than in the control group, whereas both the MS and MSUS groups presented significant increases in <i>Bcl2</i> mRNA expression. In addition, the expression ratio of <i>Bcl2/Bax</i> was significantly greater in the MS and MSUS groups. No significant differences in <i>Tp53</i> or <i>Casp3</i> mRNA expression levels were detected between the groups. Although the in vitro mRNA expression levels were not significantly different, the mRNA expression ratio of <i>Bcl2/Bax</i> reached equilibrium as the concentration of total RNA nucleofected increased. Our results suggested that, in response to ELS, hippocampal cells adapt to prioritize survival over apoptosis.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"51 4","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-026-04822-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315355","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}