Neurochemistry international最新文献

{"title":"Gastrin-releasing peptide in the paraventricular nucleus exerts hypertensive effects in preeclampsia","authors":"Xiaomin Wang ,&nbsp;Md Ahasan Ali ,&nbsp;Xiaoxu Liu ,&nbsp;Ming Zeng ,&nbsp;Zhaoshu Zeng ,&nbsp;Meng Yuan ,&nbsp;Abdoulaye Issotina Zibrila ,&nbsp;Shumin Liu ,&nbsp;Nana Ping ,&nbsp;Yuming Kang ,&nbsp;Xuelan Li ,&nbsp;Jinjun Liu","doi":"10.1016/j.neuint.2025.106004","DOIUrl":"10.1016/j.neuint.2025.106004","url":null,"abstract":"<div><h3>Background</h3><div>Preeclampsia (PE) is a pregnancy complication associated with hypertension, whose central mechanism remains unclear. Gastrin-releasing peptide (GRP) is involved in the regulation of central blood pressure, however, whether GRP and its receptor, GRPR, in the paraventricular nucleus of the hypothalamus (PVN) are involved in blood pressure regulation in PE is unknown.</div></div><div><h3>Methods</h3><div>In this study, we initially assessed GRP/GRPR expression levels and their cellular distribution within the PVN of a PE rat model with reduced uterine perfusion pressure (RUPP). We investigated the effect of five-day antagonism of GRPR with ICI-216140 (1 mM/side/day, PVN microinjection) on PVN activity in this model. On gestational day 19 (GD19), the mean arterial pressure (MAP) was recorded, and samples were collected for analysis. We also investigated the effect of losartan on RUPP-induced changes in MAP and GRP/GRPR expression in the PVN.</div></div><div><h3>Results</h3><div>RUPP rats exhibited increased MAP, and GRP and GRPR expression in the PVN. GRPR antagonism with ICI-216140 attenuated RUPP intervention-increased MAP and expression of oxidative stress markers including NOX2, NOX4, and reactive oxygen species, NF-κB, and tyrosine hydroxylase in the PVN. While ICI-216140 did not affect the expression of angiotensin II receptor type 1 (AT1R), the blockade of AT1R with losartan decreased MAP 2and GRP expression in RUPP rats.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that GRP expression in the PVN mediates placental ischemia-induced hypertension and may depend on AT1R activity, which provides new pharmacological avenues for animal models of PE.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 106004"},"PeriodicalIF":4.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203011","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":"A multiscale atlas of Oprm1-expressing neurons in the central nervous system: Brain-wide distribution, circuit functions, and translational therapeutic implications","authors":"Zixu Zhang ,&nbsp;Shengru Hu ,&nbsp;Shuyan Geng ,&nbsp;Tianxiang Xu ,&nbsp;Xing Liu ,&nbsp;Zixuan Lei ,&nbsp;Chuanyao Sun ,&nbsp;Haoyu Sun ,&nbsp;Wei Xie ,&nbsp;Mingdao Mu","doi":"10.1016/j.neuint.2025.105998","DOIUrl":"10.1016/j.neuint.2025.105998","url":null,"abstract":"<div><div>The mu-opioid receptor (MOR), encoded by the Oprm1 gene, critically modulates diverse physiological processes including pain perception, reward behaviors, emotional regulation, and autonomic control. The genetic complexity and region-specific distribution of Oprm1-expressing neurons underpin both the therapeutic actions and adverse effects of opioid drugs. In this comprehensive review, we systematically construct a multiscale atlas of Oprm1-expressing neurons throughout the central nervous system (CNS) by integrating genetic labeling, neuroanatomical mapping, functional circuit analyses, and translational perspectives. We highlight three interconnected aspects: (1) brain-wide regional distribution patterns, revealing enriched Oprm1 expression across sensory, limbic, and autonomic circuits; (2) functional heterogeneity of Oprm1-expressing neurons, elucidating their distinct roles in nociception, reward processing, emotional and neuroendocrine regulation, with a particular emphasis on sex differences and adaptive plasticity under stress; (3) translational opportunities for therapeutic interventions, focusing on innovative strategies such as circuit-specific opioid modulation and biased agonism, designed to optimize analgesic benefits while minimizing addiction liability and respiratory depression. Furthermore, we critically examine existing challenges and knowledge gaps, including receptor trafficking mechanisms, dynamic changes in Oprm1 expression under conditions such as chronic opioid exposure or stress, interspecies differences, and network-level opioid signaling dynamics. This integrative framework provides essential insights into MOR neurobiology, facilitating the development of next-generation opioid therapeutics that leverage precise modulation of neural circuits and molecular pharmacological advancements. The translational implications of understanding these aspects are emphasized throughout this review, aiming to bridge basic neurobiological findings with clinical applications.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 105998"},"PeriodicalIF":4.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184686","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":"Bioactive ROS-responsive nanotherapeutics attenuate intermittent hypoxia-induced cognitive impairment via NRF2/KEAP1/HO-1 signaling","authors":"Yinpei Huang ,&nbsp;Hailun Xie ,&nbsp;Lian Liu ,&nbsp;Heng Zhao ,&nbsp;Bing Li ,&nbsp;Feng Zhang","doi":"10.1016/j.neuint.2025.105997","DOIUrl":"10.1016/j.neuint.2025.105997","url":null,"abstract":"<div><div>Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (IH), which induces oxidative stress and neuronal apoptosis, ultimately leading to progressive cognitive impairment. This study investigated the neuroprotective potential of a reactive oxygen species (ROS)-responsive nanotherapeutic, namely TPCD nanoparticles (TPCD NP), synthesized through the conjugation of Tempol and phenylboronic acid pinacol ester to β-cyclodextrin, in both <em>in vivo</em> and <em>in vitro</em> models. In rats, intravenous administration of TPCD NP improved memory performance as assessed by the Morris water maze test, and preserved hippocampal neuronal morphology. TPCD NP significantly reduced intracellular ROS content and malondialdehyde (MDA) levels while restoring antioxidant capacity, including superoxide dismutase (SOD) and glutathione (GSH). Apoptosis was attenuated, as evidenced by the downregulation of Bax and cleaved caspase-3, and the upregulation of Bcl-2 expression. Mechanistically, TPCD NP enhanced the nuclear translocation of nuclear factor erythroid 2–related factor 2 (NRF2), suppressed Kelch-like ECH-associated protein 1 (KEAP1), and increased heme oxygenase-1 (HO-1) expression. The protective effects were abolished by ML385, a selective NRF2 inhibitor, confirming the essential role of NRF2 activation in mediating the antioxidant and anti-apoptotic effects of TPCD NP. In conclusion, TPCD NP attenuates oxidative stress and apoptosis induced by IH in the hippocampus by activating the NRF2/KEAP1/HO-1 pathway. These findings highlight TPCD NP as a promising therapeutic strategy for OSA-associated neurodegeneration.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 105997"},"PeriodicalIF":4.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172016","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":"Activation or blockade of prelimbic 5-HT4 receptors improves working memory in hemiparkinsonian rats","authors":"Jie Yang ,&nbsp;Li Chen ,&nbsp;Xiaoying Li ,&nbsp;Yuan Guo ,&nbsp;Hao Hu ,&nbsp;Fan Li ,&nbsp;Tao Wang ,&nbsp;Yong Wang ,&nbsp;Lu Yao ,&nbsp;Li Zhang ,&nbsp;Jian Liu","doi":"10.1016/j.neuint.2025.105996","DOIUrl":"10.1016/j.neuint.2025.105996","url":null,"abstract":"<div><div>Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine₄ (5-HT₄) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation and blockade of PrL 5-HT₄ receptors on working memories by T-maze rewarded alternation and Morris water maze tests in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. The lesion induced working memory deficits, decreased dopamine levels in the limbic-related brain regions, changed normalized δ, high θ, α, β, low and high γ power of the PrL, and upregulated expression of PrL 5-HT₄ receptor. Intra-PrL injection of 5-HT₄ receptor agonist BIMU8 or antagonist GR113808 did not impact working memories in sham rats, but improved working memory deficits in the lesioned rats. Intra-PrL injection of BIMU8 or GR113808 had no effect on monoamine levels in the limbic-related brain regions or normalized low and high γ power of the PrL in sham rats. However, in the lesioned rats, intra-PrL injection of BIMU8 significantly increased dopamine and 5-HT levels in the medial prefrontal cortex, amygdala and dorsal hippocampus, while intra-PrL injection of GR113808 significantly increased dopamine levels in these brain regions and increased normalized low and high γ power of the PrL. These results suggest that 6-OHDA lesion in rats induces working memory deficits, while activation or blockade of PrL 5-HT₄ receptors improves the deficits in the lesioned rats, which possibly due to the changes of monoamine levels in the limbic-related brain regions and network activity of neurons in the PrL.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 105996"},"PeriodicalIF":4.4,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140954","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":"Impact of NLRP6 inflammasome on neuroinflammation in temporal lobe epilepsy","authors":"Yiming Guo ,&nbsp;Jiaqi Song ,&nbsp;Yingxi Chen ,&nbsp;Yang Lü ,&nbsp;Weihua Yu","doi":"10.1016/j.neuint.2025.105994","DOIUrl":"10.1016/j.neuint.2025.105994","url":null,"abstract":"<div><div>Epilepsy is one of the most common and severe chronic brain diseases, affecting up to 70 million people worldwide. Neuroinflammation plays a central role in the progression of the disease. The Nod-Like Receptor Protein 6 (NLRP6) inflammasome assembles with apoptosis-associated speck-like protein (ASC) to cleave pro-caspase-1 into caspase-1, thus forming the NLRP6 inflammasome. This process promotes the maturation and release of downstream interleukins (IL)-18 and IL-1β, exacerbating pathological processes in various diseases. In this study, we demonstrated significantly enhanced NLRP6 expression in the cortex and hippocampus of epileptic mice, suggesting a role for the inflammasome in epilepsy. Immunofluorescence staining further revealed that NLRP6 was predominantly expressed in hippocampal neurons of these mice. Additionally, knockdown of NLRP6 reduced susceptibility to epilepsy, alleviated post-seizure neuronal damage, and decreased levels of pro-inflammatory cytokines, including IL-18, IL-1β, and IL-6. Conversely, NLRP6 overexpression produced opposite effects, which were effectively reversed by treatment with the caspase-1 inhibitor VX765. To the best of our knowledge, this is the first study to demonstrate a link between NLRP6 and the activation of the caspase-1/IL-1β/IL-18 signaling pathway in a kainic acid (KA)-induced epilepsy mouse model. Administration of VX765 alleviated pathological alterations and exerted neuroprotective effects. These findings suggest that NLRP6 plays a critical role in the initiation and progression of epilepsy.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 105994"},"PeriodicalIF":4.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144106394","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":"Intermittent theta burst stimulation is superior to 10 Hz-repetitive transcranial magnetic stimulation in promoting episodic-like memory in healthy male rats by enhancing low γ oscillation and glutamate neuronal activities of the anterior cingulate cortex","authors":"Yixuan Wang,&nbsp;Yanping Hui,&nbsp;Ling Wang,&nbsp;Hongfei Qiao,&nbsp;Xiang Wu,&nbsp;Yihua Bai,&nbsp;Qingfeng Sun,&nbsp;Qiaojun Zhang,&nbsp;Libo Li","doi":"10.1016/j.neuint.2025.105995","DOIUrl":"10.1016/j.neuint.2025.105995","url":null,"abstract":"<div><div>Intermittent theta-burst stimulation (iTBS) and high-frequency repetitive transcranial magnetic stimulation (rTMS) produce beneficial after-effects on memory performance. The two modalities have modulatory after-effects on the prefrontal neuronal oscillations and neurotransmitters, which are critically involved in episodic memory processing. However, whether iTBS exerts better cognitive effects than high-frequency rTMS through modulating neuronal oscillations and neurotransmitter levels in the prefrontal cortex has not been determined. Thus, iTBS and 10 Hz-rTMS modalities were applied to healthy male rats respectively, and behavior tests, electrophysiological experiments and microdialysis and neurochemistry were performed. We found that iTBS and 10 Hz-rTMS promoted episodic memory in healthy male rats, and iTBS exerted better cognitive effects than 10 Hz-rTMS. Intriguingly, iTBS induced greater effects than 10 Hz-rTMS in enhancing low γ oscillation in the anterior cingulate cortex (ACC) which is a subregion of the prefrontal cortex. Further, compared to sham stimuli, iTBS suppressed δ oscillation and enhanced θ oscillation, while 10 Hz-rTMS did not, suggesting that iTBS induces higher cortical excitability in the ACC than 10 Hz-rTMS. This is supported by a higher increase in glutamate neuronal activities in the ACC following iTBS than 10 Hz-rTMS. Finally, we found that iTBS and 10 Hz-rTMS decreased extracellular gamma-aminobutyric acid levels and increased extracellular glutamate levels in the ACC, thus leading to the activation of ACC glutamate neurons after the two modalities. These findings suggest that iTBS produces better cognitive effects in healthy male rats, which may be attributed to enhanced low γ oscillation and activated glutamatergic neurons in the ACC.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 105995"},"PeriodicalIF":4.4,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118462","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":"Overexpression of TAFA4 in the dorsal root ganglion ameliorates neuropathic pain in male rats through promoting macrophage M2-Skewing","authors":"Zhangran Ai ,&nbsp;Huili Li ,&nbsp;Songchao Xu ,&nbsp;Chenghui Cai ,&nbsp;Xuejuan Wang ,&nbsp;Yun Guan ,&nbsp;Ruijuan Guo ,&nbsp;Yun Wang","doi":"10.1016/j.neuint.2025.105993","DOIUrl":"10.1016/j.neuint.2025.105993","url":null,"abstract":"<div><div>Neuro-immune interactions between macrophages and primary sensory neurons have been implicated in nerve injury and associated pain. This study aims to explore the function of the TAFA4 as a crucial neuroimmune regulator in modulating macrophage states within the context of neuropathic pain. To elucidate the role of TAFA4 in dorsal root ganglia (DRG) following a chronic constriction injury (CCI) model in male rats, immunofluorescent staining, western blot, flow cytometry analysis and enzyme-linked immunosorbent assay were performed. Microinjection of self-complementary adeno-associated virus expressing TAFA4 mRNA into the L4 and L5 DRGs was conducted to overexpress TAFA4 in the DRGs. Following peripheral nerve injury, we observed a downregulation of TAFA4 in ipsilateral DRG neurons. Restoring this downregulation effectively alleviated the mechanical and thermal nociceptive hypersensitivity by inhibiting pro-inflammatory mediators while promoting the secretion of anti-inflammatory cytokines on day 14 post-CCI. Notably, scAAV-TAFA4 microinjection also facilitated the polarization of macrophages in the DRGs towards the M2 phenotype. Mechanistically, TAFA4 modulates the functions of macrophages in a lipoprotein receptor-related protein 1-dependent manner. Our findings revealed the role of TAFA4 in shifting macrophages in favor of an anti-inflammatory phenotype and enhancing interleukin 10 concentrations in the DRG, suggesting it is a potential analgesic target for alleviating neuropathic pain.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"187 ","pages":"Article 105993"},"PeriodicalIF":4.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092459","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":"Proteostasis and autophagy disruption by the aging-related VGVAPG hexapeptide - preliminary insights into a potential novel elastin-induced neurodegeneration pathway in an in vitro human cellular neuron model","authors":"Bartosz Skóra,&nbsp;Konrad A. Szychowski","doi":"10.1016/j.neuint.2025.105992","DOIUrl":"10.1016/j.neuint.2025.105992","url":null,"abstract":"<div><div>The hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is the most readily released product of elastin degradation, a process closely associated with aging. Recent studies have demonstrated the ability of this peptide to upregulate Sirtuin 2 (SIRT2) mRNA and protein expression. The correlation between HRD1 ligase (Synoviolin 1) and the degradation of SIRT2 has been previously reported in the literature. This study aimed to explore the impact of VGVAPG-induced interaction between HRD1 and SIRT2 and its effects on autophagy in differentiated SH-SY5Y cells <em>in vitro</em> (a simplified model of neurons). The results revealed that VGVAPG decreases HRD1 mRNA and protein expression while correlating with SIRT2 overexpression. Further analysis showed reduced SEL1L protein levels and an increase in p97/VCP protein expression. Additionally, enhanced phosphorylation of IRE1α indicated induction of ER stress in the tested cell model without affecting mTOR. Decreased proteasome activity and accumulation of ubiquitin were also noted. This phenomenon triggered VGVAPG-induced autophagy, as evidenced by increased expression of autophagy-related proteins ATG16L1, ATG5, ATG18, and FIP200. However, autophagy was suppressed probably as a result of VGVAPG-induced phosphorylation of ERK1/2. These findings demonstrate that the aging-related hexapeptide VGVAPG downregulates the function of the SEL1L-HRD1 complex, leading to SIRT2 accumulation and subsequent ER stress due to ERAD and UPS. This cascade, in turn, activates autophagy as an alternative clearance pathway aimed at restoring proteostasis; however, the process becomes dysregulated, leading to persistent ER stress. This dual effect may have significant implications in neurobiology, given the well-established correlation between autophagy impairment and aging-related neurodegenerative disorders.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"187 ","pages":"Article 105992"},"PeriodicalIF":4.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958519","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":"Eslicarbazepine, a third-generation anti-seizure medication, inhibits INa but stimulates IK(M)","authors":"Te-Yu Hung ,&nbsp;Sheng-Nan Wu ,&nbsp;Chin-Wei Huang","doi":"10.1016/j.neuint.2025.105990","DOIUrl":"10.1016/j.neuint.2025.105990","url":null,"abstract":"<div><div>Eslicarbazepine (ESL) is a new antiseizure medication used to treat focal epilepsy. It is not entirely clear how ESL affects the magnitude and gating kinetics of membrane ionic currents, although a few reports have demonstrated its ability to suppress voltage-gated Na⁺ currents (<em>I</em>_Na). With the aid of patch clamp technology, docking prediction, and simulation modeling, this study was conducted to investigate the potential modifications through which ESL may induce on ionic currents, including <em>I</em>_Na, M-type K⁺ current (<em>I</em>_K(M)), and <em>erg</em>-mediated K⁺ current (<em>I</em>_K(erg)), in hippocampal neurons. ESL distinctly inhibited transient <em>I</em>_Na (<em>I</em>_Na(T)) and late <em>I</em>_Na (<em>I</em>_Na(L)), demonstrating greater potency against <em>I</em>_Na(L). ESL shifted the steady-state inactivation curve of <em>I</em>_Na(T) leftward without altering its steepness or activation curve. Additionally, ESL attenuated the tefluthrin-induced enhancement of voltage-dependent hysteresis (Hys_(V)) of persistent <em>I</em>_Na (<em>I</em>_Na(P)).</div><div>ESL increased <em>I</em>_K(M) in a concentration-dependent manner, shifting its steady-state activation curve toward more depolarized potentials and enhancing Hys(V) strength. It also increased the activity and mean open time of <em>I</em>_K(M) without affecting single-channel conductance. Minimal changes were observed in the magnitude of <em>I</em>_K(erg). Predicted docking analysis revealed that ESL binds to the hNa_V1.7 channel via hydrogen bonds and hydrophobic contacts. Simulation modeling using hippocampal CA1 pyramidal neurons demonstrated that ESL's inhibition of <em>I</em>_Na and stimulation of <em>I</em>_K(M), along with changes in their Hys(V), modulate neuronal action potential firing. Overall, these findings highlight ESL's dual effects on <em>I</em>_Na and <em>I</em>_K(M), revealing mechanisms that likely contribute to its efficacy in treatment of epilepsy.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"187 ","pages":"Article 105990"},"PeriodicalIF":4.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935376","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":"Therapeutic potential of cell-permeable PEP-1-Srxn1 in mitigating oxidative and ischemic damage in the hippocampus","authors":"Kyu Ri Hahn ,&nbsp;Hyun Jung Kwon ,&nbsp;Seung Myung Moon ,&nbsp;Woosuk Kim ,&nbsp;In Koo Hwang ,&nbsp;Dae Won Kim ,&nbsp;Dae Young Yoo","doi":"10.1016/j.neuint.2025.105988","DOIUrl":"10.1016/j.neuint.2025.105988","url":null,"abstract":"<div><div>In the present study, we validated the neuroprotective effects of sulfiredoxin 1 (Srxn1) against oxidative damage in HT22 cells and ischemic damage in gerbil hippocampus. To efficiently deliver Srxn1 protein into cells or the hippocampus, a PEP-1-Srxn1 fusion protein was synthesized, and efficient delivery was visualized in HT22 mouse hippocampal neuronal cells. PEP-1-Srxn1 was delivered to HT22 cells in a concentration- and incubation time-dependent manner and showed significantly higher levels at 36 h after incubation for 1 h. Morphologically, the delivered protein was localized in the cytoplasm of HT22 cells. In addition, PEP-1-Srxn1 treatment significantly ameliorated formation of reactive oxygen species, DNA fragmentation, and cell death in HT22 cells induced by treatment with 100 μM H₂O₂. In gerbils, PEP-1-Srxn1 treatment significantly alleviated transient ischemia-induced forebrain hyperactivity 1 d after ischemia and memory deficits 4 d after ischemia. Neuroprotective effects were confirmed by morphological analysis of the hippocampal CA1 region 4 or 10 d after ischemia. Treatment with PEP-1-Srxn1 significantly ameliorated the formation of reactive oxygen species and lipid peroxidation in the hippocampus during the early stages (3–12 h) of ischemia. In addition, treatment with PEP-1-Srxn1 alleviated the ischemia-induced reduction of glutathione levels in the hippocampus. PEP-1-Srxn1 also decreased ischemia-induced microglial activation and pro-inflammatory cytokine release in the hippocampus. These results suggest that PEP-1-Srxn1 is a potential therapeutic agent for reducing neuronal damage induced by oxidative or ischemic damage.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"187 ","pages":"Article 105988"},"PeriodicalIF":4.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941282","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}