Neurochemistry international最新文献

{"title":"Increased spinal adenosine after subacute cervical injury correlates with sustained upregulation of CD39 and CD73 in microglia","authors":"Mackenzie R. Berschel ,&nbsp;Maria Nikodemova ,&nbsp;Jose R. Oberto,&nbsp;Alexandria B. Marciante,&nbsp;Alysha Michaelson,&nbsp;Gordon S. Mitchell","doi":"10.1016/j.neuint.2025.106030","DOIUrl":"10.1016/j.neuint.2025.106030","url":null,"abstract":"<div><div>Cervical spinal cord injuries (cSCI) are associated with decreased breathing ability. Although no treatment options are currently available, moderate acute intermittent hypoxia (mAIH) is a promising therapeutic modality to improve breathing function after cSCI. Moderate AIH elicits phrenic motor plasticity <em>via</em> distinct, competing serotonin- or adenosine-driven mechanisms that interact <em>via</em> powerful crosstalk inhibition that constrains or even abolishes plasticity. The dominant mechanism driving plasticity depends on the spinal serotonin/adenosine balance. Shortly after cSCI, repeated AIH exposure elicits plasticity <em>via</em> an adenosine-dependent mechanism but reverts to serotonin-dominance with chronic cSCI. In healthy CNS, microglia regulate AIH-induced phrenic motor plasticity <em>via</em> enzymatic activities of ectonucleotidases (CD39, CD73) by converting extracellular ATP to adenosine. We hypothesized that cSCI increases microglial ectonucleotidase expression, elevating adenosine levels that may alter therapeutic responses to mAIH post-cSCI. We assessed microglial CD39 and CD73 expression at the subacute (1 &amp; 2 weeks) and chronic (8 weeks) stages post C2-hemisection, both at the injury site (C1–C3) and in spinal segments containing phrenic motor neurons below the injury (C3–C6). Both enzymes were upregulated (mRNA &amp; protein) 1- and 2-weeks post injury but returned to baseline by 8 weeks. In association, spinal adenosine increased significantly at 2, but not 8 weeks post-injury. Further, microglial CD39 and CD73 expression strongly correlate with P2Y12 receptor expression. Thus, shifting adenosine levels between subacute and early chronic cSCI may impact mechanism regulating mAIH-induced respiratory motor plasticity and breathing recovery at different times post-cSCI.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106030"},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779560","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":"DUSP1-Mediated Suppression of p38 MAPK Signaling Pathway Reduces Ferroptosis in Cerebral Ischemia-Reperfusion Injury.","authors":"Shuyin Ma, Xiaodong Zhang, Jiaxin Fan, Mengying Chen, Qingling Yao, Nan Zhang, Kaili Shi, Minyu Duan, Han Yang, Tiantian Gao, Xiaodong Ma, Jingyi Wang, Weina Li, Chuxiao Zhou, Shuqin Zhan","doi":"10.1016/j.neuint.2025.106024","DOIUrl":"https://doi.org/10.1016/j.neuint.2025.106024","url":null,"abstract":"<p><p>Ferroptosis constitutes a critical pathological mechanism in cerebral ischemia-reperfusion injury (CI/RI), significantly influencing neurological outcomes. While dual specificity phosphatase 1 (DUSP1) demonstrates neuroprotective effects against CI/RI, its regulatory role in ferroptosis remains to be elucidated. This study systematically investigated the therapeutic potential of DUSP1 through ferroptosis modulation in both in vitro and in vivo models. Using oxygen-glucose deprivation/reoxygenation (OGD/R)-treated PC12 cells with either DUSP1 overexpression or knockdown, we comprehensively assessed ferroptosis parameters including cell viability, malondialdehyde content, glutathione levels, intracellular iron concentration, reactive oxygen species accumulation, and expression of key ferroptosis-related proteins. In middle cerebral artery occlusion/reperfusion (MCAO/R) rat models, pharmacological inhibition of DUSP1 was employed to evaluate its impact on cerebral infarction volume, neurological deficits, histopathological changes, and ferroptosis biomarkers. Mechanistic studies incorporated the p38 mitogen-activated protein kinase pathway inhibitor adezmapimod. Our results demonstrated that (1) ferroptosis was significantly induced in both the OGD/R and MCAO/R models, accompanied by upregulated DUSP1 expression; (2) DUSP1 overexpression attenuated ferroptosis and ameliorated CI/RI, whereas genetic knockdown exacerbated these pathological processes; (3) pharmacological inhibition of DUSP1 aggravated cerebral injury and ferroptosis markers in MCAO/R rats; and (4) adezmapimod treatment effectively rescued ferroptosis progression in DUSP1-deficient cells by restoring glutathione peroxidase 4 and ferroportin expression while downregulating transferrin receptor and Ferritin Heavy Chain levels. These findings establish that DUSP1 confers neuroprotection against CI/RI through p38-mediated ferroptosis regulation, suggesting its promise as a novel therapeutic target for ischemic stroke.</p>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":" ","pages":"106024"},"PeriodicalIF":4.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768181","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":"Casticin inhibits the release of synaptic vesicular glutamate from rat hippocampal nerve terminals","authors":"Cheng-Wei Lu ,&nbsp;Tzu-Yu Lin ,&nbsp;Wun-Jing Pan ,&nbsp;Ya-Ying Chang ,&nbsp;Kuan-Ming Chiu ,&nbsp;Ming-Yi Lee ,&nbsp;Su-Jane Wang","doi":"10.1016/j.neuint.2025.106025","DOIUrl":"10.1016/j.neuint.2025.106025","url":null,"abstract":"<div><div>The effect of casticin, major polymethoxyflavone extracted from <em>Vitex rotundifolia</em>, on glutamate release and its underlying mechanisms was investigated in rat hippocampal synaptosomes. Casticin inhibited 4-aminopyridine (4-AP)-evoked glutamate release, with an IC₅₀ of approximately 7.2 μM. It reduced the 4-AP-evoked increase in intrasynaptosomal Ca²⁺ concentration without affecting the synaptosomal membrane potential. The inhibitory effect of casticin on glutamate release was markedly prevented by ω-conotoxin GVIA, an N-type Ca²⁺ channel blocker, but not by ω-agatoxin VIA, a P/Q-type Ca²⁺ channel blocker. Further analysis of FM1-43 dye release showed that casticin suppressed glutamate release by decreasing synaptic vesicle exocytosis. Consistently, casticin also reduced 4-AP-induced phosphorylation of synapsin I, a presynaptic protein that regulates synaptic vesicle mobilization. Transmission electron microscopy (TEM) revealed that casticin decreased the proportion of release-competent synaptic vesicles in 4-AP-stimulated hippocampal synaptosomes. Taken together, these findings suggest that casticin inhibits glutamate release from rat hippocampal nerve terminals, potentially by suppression of N-type Ca²⁺ channel and reducing the availability of synaptic vesicles for exocytosis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106025"},"PeriodicalIF":4.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757829","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":"Aerobic exercise rescues synaptic plasticity in early-stage Alzheimer's disease by suppressing miR-3473e to activate EphB2-dependent NMDA/AMPA receptor signaling","authors":"Xiangli Tong ,&nbsp;Zhen Tong ,&nbsp;Weijia Wu ,&nbsp;Jialun Yang ,&nbsp;Juan Wang ,&nbsp;Yang Wang ,&nbsp;Dandan Chen ,&nbsp;Yiyang Wang ,&nbsp;Fanqi Zeng ,&nbsp;Qiyan Du ,&nbsp;Yishan Chen ,&nbsp;Wenfeng Liu","doi":"10.1016/j.neuint.2025.106023","DOIUrl":"10.1016/j.neuint.2025.106023","url":null,"abstract":"<div><div>Cognitive dysfunction in early-stage Alzheimer's disease (AD) involves significant impairments in synaptic plasticity and dendritic spines integrity. Intriguingly, exercise interventions have demonstrated efficacy in enhancing cognitive function. However, the precise molecular mechanisms, particularly the upstream endogenous regulators (such as miRNAs) through which exercise mediates this synaptic improvement, remain unclear. Our findings indicated that 12 weeks of aerobic exercise effectively increased learning and memory, promoted amyloid beta (Aβ) and cerebral amyloid angiopathy (CAA) clearance in early-stage AD. Furthermore, aerobic exercise markedly enhanced dendritic spines density of pyramidal neurons in cortical layers II/III and the hippocampal CA1 region, as well as the expression of synapse-associated proteins such as cAMP response element-binding protein (CREB), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95). Whole genome RNA sequencing (RNA-Seq) and bioinformatics analysis was performed to identify miR-3473e, a target closely related to AD and also a response factor that serves as a key mediator of aerobic exercise benefits. Subsequent findings revealed that miR-3473e was overexpressed in the brains of APP/PS1 mice, whereas aerobic exercise led to a decrease in its expression. Moreover, aerobic exercise enhanced its downstream targets, EPH receptor B2 (EphB2) and solute carrier family 1 member 1 gene (Slc1a1) as well as increased downstream GluN1, GRIA1 and <em>p</em>-GluN2B/GluN2B protein expression levels. In summary, we demonstrate that aerobic exercise can improve synaptic plasticity, and these effects are mediated via suppression of miR-3473e and regulation EphB2-NMDA/AMPA receptor signaling pathway, underscoring the potential of aerobic exercise to enhance cognitive function in early-stage of AD.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106023"},"PeriodicalIF":4.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713500","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":"Probing impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and 1H-MRS at 7.0T MRI","authors":"Zhihong Zhao ,&nbsp;Lvhao Wang ,&nbsp;Xiaolei Zhang ,&nbsp;Yue Chen ,&nbsp;Xinhui Zheng ,&nbsp;Renhua Wu","doi":"10.1016/j.neuint.2025.106020","DOIUrl":"10.1016/j.neuint.2025.106020","url":null,"abstract":"<div><h3>Purpose</h3><div>Sleep is a physiological process that plays a crucial role in maintaining cognitive functions. The hippocampus, a key brain region implicated in cognition, is particularly sensitive to sleep deprivation. we aim to investigate impact of sleep deprivation on hippocampal neurochemistry in rats using CEST imaging and ¹H-MRS.</div></div><div><h3>Methods</h3><div>Twelve female Sprague-Dawley rats were randomly divided into sleep deprivation and control groups. All rats experienced Morris water maze training and testing from Day 1 to Day 6 and underwent MRI scans including CEST imaging and ¹H-MRS on Days 1 and Day 3. Lastly, rats were euthanized for Nissl staining.</div></div><div><h3>Results</h3><div>Sleep deprivation led to a significant decrease in CEST signals across various frequency offsets (0.5–3.5 ppm) in the hippocampus (P &lt; 0.05). Meanwhile, sleep deprivation caused an increase in glutamate (P &lt; 0.0001) with no alterations in other metabolites (P &gt; 0.05). Behaviorally, sleep deprivation impaired learning-memory abilities, evidenced by reduced target quadrant distance (P &lt; 0.001) and time (P &lt; 0.01) in the Morris water maze. Histologically, sleep deprivation caused a decline of surviving neurons in the hippocampal CA1 and CA3 regions (P &lt; 0.001). These indicators correlated negatively with the concentrations of glutamate (P &lt; 0.05) and positively with most of the CEST signals (P &lt; 0.05) in the hippocampus.</div></div><div><h3>Conclusion</h3><div>The integration of CEST imaging and ¹H-MRS offers a promising approach for identifying imaging biomarkers that aid in the assessment and management of sleep deprivation's impact on hippocampal neurochemistry.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106020"},"PeriodicalIF":4.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658092","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":"Refinement of TSLP expression mediates chronic allodynia associated with IL22/STAT3 axis","authors":"Chun-Ching Lu ,&nbsp;Ying-Yi Lu ,&nbsp;Hung-Pei Tsai ,&nbsp;Chieh-Hsin Wu","doi":"10.1016/j.neuint.2025.106022","DOIUrl":"10.1016/j.neuint.2025.106022","url":null,"abstract":"<div><div>Chronic allodynia is a painful response to an innocuous stimulus because of maladaptive neuroplasticity within the central nervous system. IL22 is a pleiotropic mediator owing to its proinflammatory and immunosuppressive effects. In this study, we aimed to investigate the potential of modulating TSLP expressions to treat chronic allodynia and elucidate the underlying mechanisms associated with IL22. <em>TSLP</em>^{<em>−/−</em>} mice were generated, and four mouse groups were created as follows: wild-type (WT) + PBS, <em>TSLP</em> knockout (KO) + PBS, WT + bleomycin, and TSLP KO + bleomycin. Repeated bleomycin administration reduced the IL22/STAT3 pathway to trigger chronic allodynia in C57BL/6 mice. The degree of gliosis and neuron loss were significantly greater in the somatosensory cortex and spinal cord dorsal horn of the bleomycin-treated mice compared with those in the PBS-treated mice. Compared with those in WT mice treated with bleomycin, in TSLP-deficient mice, the degree of gliosis and neuron loss were significantly lower in the somatosensory cortex and spinal cord dorsal horn and the mechanical withdrawal threshold was altered. Differentiated human SH-SY5Y cells were created to investigate the neuroprotective effects of TSLP refinement against hydrogen peroxide (H₂O₂)-induced neurotoxicity. The deficiency of TSLP protected differentiated SH-SY5Y cells against H₂O₂-induced neurotoxicity. IL22 stimulator not only rescued the H₂O₂-induced neurotoxicity but augmented the protective effect of si-TSLP on differentiated SH-SY5Y cells. Our data confirmed that a lack of TSLP decreased the expression of TSLPR/STAT5, the bleomycin-induced chronic allodynia and the H₂O₂-induced neurotoxicity. In addition, inhibiting TSLP rescued the IL22/STAT3-mediated effect, which regulated neuroglial interactions to relieve chronic allodynia. Targeting TSLP/TSLPR is a potential therapeutic approach for relieving chronic allodynia by regulating gliosis, neuron loss, and the IL22/STAT3 axis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 106022"},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605605","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":"Combined administration of cocaine and alcohol alters the expression of brain peptide/protein profiles in rats: a MALDI imaging mass spectrometry approach","authors":"Alberto Marcos ,&nbsp;Pilar Alberdi ,&nbsp;Carlos A. Castillo-Sarmiento ,&nbsp;Emilio Ambrosio ,&nbsp;Inmaculada Ballesteros-Yáñez","doi":"10.1016/j.neuint.2025.106015","DOIUrl":"10.1016/j.neuint.2025.106015","url":null,"abstract":"<div><div>While the concurrent use of alcohol and cocaine is common in patterns of polysubstance use, little is known about the combined effects of these substances on the brain. Proteomics approaches enable the identification of potential biomarkers and new pharmacological targets for the diagnosis and treatment of addiction and related psychiatric disorders. The main goal of this study was to explore how the combination of cocaine and alcohol affects brain peptide/protein signatures in the mesolimbic dopaminergic pathway.</div><div>To this end, we used a chronic and simultaneous intravenous administration of these substances in a Wistar rat animal model. Peptide/protein profiles in five brain regions (ventral hippocampus, dorsal hippocampus, amygdala, nucleus accumbens and prefrontal cortex) from individual animals were characterised by means of matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS).</div><div>Our results showed that, compared to exposure to cocaine or alcohol separately, the combination of cocaine and alcohol has a synergistic effect on the number of differentially expressed peptides/proteins (DEPs) detected in all regions, particularly the amygdala. ANOVA reveals 13 DEPs, corresponding to 12 peptides/proteins, that vary significantly between all groups. Gene ontology (GO) analysis indicated that most of the DEPs found for the combined treatment are enriched in neuropeptide receptor binding, neuropeptide signalling and regulation of circadian sleep/wake process pathways.</div><div>Our findings demonstrate that the combination of cocaine and alcohol significantly exacerbates the effects of each substance separately on the expression of peptides and proteins with multiple physiological functions, including the opioid- and GABA-ergic neurotransmission systems. This study therefore provides the basis for future research on biomarkers and substance recovery therapies.</div><div>These insights underscore the importance of examining the interactions between cocaine and alcohol in terms of their effects on neurotransmitter systems in the context of polysubstance use, particularly when addressing issues related to cocaine and alcohol co-use.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 106015"},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614680","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":"Repetitive transcranial magnetic stimulation as a universal modulator of synaptic plasticity: Bridging the gap between functional and structural plasticity","authors":"Danica Popovic ,&nbsp;Milorad Dragic","doi":"10.1016/j.neuint.2025.106021","DOIUrl":"10.1016/j.neuint.2025.106021","url":null,"abstract":"<div><div>Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive technique for neuromodulation that has shown great potential in therapy of several neurodegenerative and neuropsychiatric disorders both in patients and animal models. In addition to its non-invasiveness, the main rationale for using it for these disorders is that the positive effects extend beyond the stimulation period and can last up to several minutes, hours or even days after the last application. While the mechanisms underlying these long-lasting positive effects have not yet been fully deciphered, current literature supports hypothesis of modulation of both functional and structural plasticity. Dendritic spines are structures on dendritic branches that regulate synaptic transmission at the level of postsynapse and represent one of the structural and functional carriers of synaptic plasticity. Since rTMS has been proposed to induce long-term potentiation/long-term depression-like effects, based on the existing literature in animal studies, we suggest several molecular mechanisms which could underpin rTMS-induced structural plasticity manifested at the level of dendritic spines that include processes starting from spinogenesis to gradual spine maturation and eventual spine shrinkage and loss. The results gathered in this review postulate rTMS as a universal modulator of synaptic plasticity, which could guide future research and help in optimizing appropriate protocols of transcranial magnetic stimulation for adequate disorders and pathologies.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 106021"},"PeriodicalIF":4.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597494","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":"Circular RNAs from the MAPT and TARDBP genes: Novel players in neurodegeneration?","authors":"Naghme Bagheri ,&nbsp;Giorgi Margvelani ,&nbsp;Tai-Wei Chiang ,&nbsp;Peter T. Nelson ,&nbsp;Trees-Juen Chuang ,&nbsp;Stefan Stamm","doi":"10.1016/j.neuint.2025.106019","DOIUrl":"10.1016/j.neuint.2025.106019","url":null,"abstract":"<div><div>The microtubule associated protein tau (<em>MAPT</em>) and TAR DNA binding protein (<em>TARDBP</em>) genes play crucial roles in neurodegeneration. The tau protein encoded by <em>MAPT</em> is the main component of tau tangles, a pathologic hallmark of “tauopathies” such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by <em>TARDBP</em> are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both <em>MAPT</em> and <em>TARDBP</em> express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and to date all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the <em>MAPT</em> and <em>TARDBP</em> genes should be considered in molecular analysis of AD, LATE and other neurological diseases.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"189 ","pages":"Article 106019"},"PeriodicalIF":4.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599022","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 potentiating activity of benzodiazepine site of the GABA(A) receptor is inhibited by competitive antagonists of orthosteric site","authors":"Elena I. Solntseva,&nbsp;Julia V. Bukanova,&nbsp;Rodion V. Kondratenko","doi":"10.1016/j.neuint.2025.106018","DOIUrl":"10.1016/j.neuint.2025.106018","url":null,"abstract":"<div><div>Benzodiazepines (BDZs) are widely-prescribed drugs that act as positive allosteric modulators of GABA_A receptor, enhancing the GABA-elicited chloride current (<em>I</em>_GABA). In this work, we studied the influence of competitive antagonists of the GABA_A receptor gabazine (GBZ), bicuculline (Bic), and amiloride (Ami) on the potentiating effect of the agonist of BDZ site zolpidem (Zolp). These antagonists bind to their own sites, which partially overlap with the orthosteric site. The experiments were carried out on native GABA_A receptors in isolated Purkinje cells of the rat cerebellum. The <em>I</em>_GABA was measured using the patch-clamp technique and a system of fast application. The effects of the drugs on <em>I</em>_GABA were assessed by the change in the EC₅₀ value for GABA dose-effect curve constructed in the ranges of 0.5–100 μM GABA. Changes in EC₅₀ values as a percentage relative to the control were calculated. 0.5 μM Zolp shifted the GABA curve to the left and decreased the EC₅₀ by 54 % (from 4.8 μM to 2.2 μM). Competitive antagonists shifted the GABA curve to the right and increased the EC₅₀ to 72.6 μM (0.5 μM GBZ), 25.5 μM (500 μM Ami) and 28.8 μM (5 μM Bic). With the addition of Zolp, these EC₅₀ values decreased by 21–25 % and were 56.8 μM (GBZ), 19.2 μM (Ami), and 22.7 μM (Bic), respectively. The results show that the potentiating effect of Zolp is reduced by half in the presence of competitive GABA_A receptor antagonists (p &lt; 0. 001).</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"188 ","pages":"Article 106018"},"PeriodicalIF":4.4,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581127","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}