Brain Research最新文献

{"title":"Effects of Asiatic acid on brain cancer by altering astrocytes and the AKT1-PRKCB signaling pathway: A genomic and network pharmacology perspective","authors":"Amit Kumar Singh ,&nbsp;Adarsh Kumar Pathak ,&nbsp;Pradeep Kumar ,&nbsp;Anand Kumar Singh ,&nbsp;Manjeet Kumar Sah Gond ,&nbsp;Rohit Singh Negi ,&nbsp;Richa Das ,&nbsp;Shreni Agrawal ,&nbsp;Sunil Kumar Mishra ,&nbsp;Kavindra Nath Tiwari","doi":"10.1016/j.brainres.2025.149652","DOIUrl":"10.1016/j.brainres.2025.149652","url":null,"abstract":"<div><div>The most common primary brain tumor, glioblastoma (GBM), currently has a dismal prognosis because of its fast growth and dissemination. Recent research indicates that Asiatic acid (AA), which is extracted from <em>Trema orientalis</em> L., has potential as a medicinal agent. AA, which was obtained from a methanolic extract of <em>Trema orientalis</em> L. and examined utilizing high-resolution mass spectroscopy (HRMS) analysis, was employed in this investigation. Then, in order to forecast the therapeutic advantages of AA in managing GBM, we conducted an in silico study. Online web servers like SwissADME, pKCSM, and Protox-II were used to assess AA. Then, the major targets of the AA (from Swiss Target Prediction and TargetNet) and GBM (from GeneCards and DisGeNET) were identified. The important genes were then merged into the STRING and ShinyGo databases to examine the protein–protein interaction (PPI) network, gene annotation, and KEGG pathways, with the goal of identifying the core mechanisms involved in GBM management. The top five hub gene targets of the built network (AKT1, SRC, IL-6, TNF, and EGFR) were investigated, along with some contemporaneous additional major targets (PRKCB, GSK3B, ITGB1, BRAF, and PTPN6). These targets were tightly linked to GO activities such as synoviocyte proliferation, cytokine activity, and EGFR tyrosine kinase inhibitor resistance, as well as proteoglycans in cancer-related pathways. Furthermore, a survival study was conducted to assess the chronicity of targets, as well as molecular docking activity between important targets and AA against GBM to determine binding effectiveness. Overall, the study found that AKT1 is the most powerful receptor for AA, having a binding energy of −8.19 kcal/mol, followed by PRKCB (−7.53 kcal/mol). Finally, docking studies suggest that AA has the potential to be an effective treatment for GBM. Furthermore, clinical studies will provide more precise insights into the AA’s efficacy as a medicine in the future.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149652"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma and urinary metabolomic signatures differentiate genetic and idiopathic Parkinson’s disease","authors":"Juliana Cordovil Cotrin ,&nbsp;Gilson Costa dos Santos Junior ,&nbsp;André Simões Cadaxo ,&nbsp;Joao Santos Pereira ,&nbsp;Mariana Spitz ,&nbsp;Ana Lúcia Zuma de Rosso ,&nbsp;Renato Peixoto Veras ,&nbsp;Ana Paula Valente ,&nbsp;Márcia Mattos Gonçalves Pimentel ,&nbsp;Cíntia Barros Santos-Rebouças","doi":"10.1016/j.brainres.2025.149625","DOIUrl":"10.1016/j.brainres.2025.149625","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is marked by alpha-synuclein accumulation and progressive dopaminergic neuron loss. Using Nuclear Magnetic Resonance (NMR)-based metabolomics, we uncovered metabolic disturbances in idiopathic PD (iPD) and PD linked to <em>LRRK2, GBA1</em>, and <em>PRKN</em> variants in a Brazilian ethnically diverse cohort, free of comorbidities, in comparison to healthy, age-matched controls. In plasma, significant PD-associated metabolites included histidine, acetate, acetoacetate, glutamine, glucose, lipids and lipoproteins, N-acetyl-glycoproteins, and sarcosine. Urine samples revealed alterations in creatine, creatinine, L-asparagine, trimethylamine, 3-beta-hydroxybutyrate, isovaleric acid, glutamine, urea, glycine, choline, arginine, and cysteine in association with PD. Notably, creatine, creatinine, acetate, glucose, and histidine showed pathway influences from <em>LRRK2, GBA1</em>, and <em>PRKN</em> variants. Enrichment analyses highlighted disruptions in glyoxylate and dicarboxylate metabolism (plasma) as well as serine, threonine, and glycine metabolism (urine). Additionally, a metabolite-gene-disease interaction network identified 15 genes associated with PD that interact with key metabolites, highlighting <em>MAPT</em>, <em>SNCA</em>, <em>RERE</em>, and <em>KCNN3</em> as key players in both plasma<!--> <!-->and<!--> <!-->urine. NMR in saliva samples did not show significant differences between PD groups and controls. Our findings underscore PD-associated metabolites, particularly related to arginine metabolism, the urea cycle, glutamate metabolism, glucose metabolism, and gut microbiota. These pathways and gene interactions may serve as potential biomarkers for PD diagnosis and precision medicine strategies.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1858 ","pages":"Article 149625"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted structural network resilience in atherosclerosis: A large-scale cohort study","authors":"Hui Tang ,&nbsp;Wanlin Zhu ,&nbsp;Jing Jing ,&nbsp;Yijun Zhou ,&nbsp;Hao Liu ,&nbsp;Shiping Li ,&nbsp;Zixiao Li ,&nbsp;Ziyang Liu ,&nbsp;Chang Liu ,&nbsp;Yuesong Pan ,&nbsp;Xueli Cai ,&nbsp;Xia Meng ,&nbsp;Yilong Wang ,&nbsp;Hao Li ,&nbsp;Yong Jiang ,&nbsp;Suying Wang ,&nbsp;Haijun Niu ,&nbsp;Tiemin Wei ,&nbsp;Yongjun Wang ,&nbsp;Tao Liu","doi":"10.1016/j.brainres.2025.149653","DOIUrl":"10.1016/j.brainres.2025.149653","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis is a major factor in cognitive decline among aging individuals and is frequently linked to the accumulation of white matter hyperintensities. Brain resilience, which represents the brain’s capacity to withstand external disruptions, remains poorly understood in terms of how atherosclerosis impacts it and, in turn, influences cognition. Here, we investigated the relationship between atherosclerosis, white matter hyperintensities, and structural network resilience, along with their combined effects on cognitive performance.</div></div><div><h3>Methods</h3><div>We utilized data from the large-scale community cohort Polyvascular Evaluation for Cognitive Impairment and Vascular Events (n = 2160). Whole-brain structural connections were constructed, and structural disconnections were simulated based on white matter hyperintensities. SNR, serving as a marker to quantify structural network resilience, is defined by the similarity of hub nodes between the original network and its disconnected counterpart.</div></div><div><h3>Results</h3><div>SNR showed higher odds ratios compared to white matter hyperintensities in relation to arterial status. Additionally, chain mediation analysis indicated that cognitive decline associated with atherosclerosis was partially mediated by both white matter hyperintensities and structural network resilience. Atherosclerosis accelerates the degradation of brain structural network resilience as age increases.</div></div><div><h3>Conclusions</h3><div>These findings suggest that SNR could offer complementary insights into cognitive decline caused by atherosclerosis and serve as a potential biomarker of brain health in atherosclerotic conditions. Additionally, SNR may act as an indicator for guiding the selection of future therapies for atherosclerosis.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149653"},"PeriodicalIF":2.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury","authors":"Ji Hyun Park ,&nbsp;Dong Bin Back ,&nbsp;Shuzhen Guo ,&nbsp;Masayoshi Tanaka ,&nbsp;Hajime Takase ,&nbsp;Michael J. Whalen ,&nbsp;Ken Arai ,&nbsp;Kazuhide Hayakawa ,&nbsp;Eng H. Lo","doi":"10.1016/j.brainres.2025.149647","DOIUrl":"10.1016/j.brainres.2025.149647","url":null,"abstract":"<div><div>Damage to vascular cells comprise an important part of traumatic brain injury (TBI) but the underlying pathophysiology remains to be fully elucidated. Here, we investigate the loss of O-Linked β-N-acetylglucosamine<!--> <!-->(O-GlcNAc) modification (O-GlcNAcylation) and mitochondrial disruption in vascular pericytes as a candidate mechanism. In mouse models in vivo, TBI rapidly induces vascular oxidative stress and down-regulates mitochondrial O-GlcNAcylation. In pericytes but not brain endothelial cultures in vitro, mechanical stretch injury down-regulates mitochondrial O-GlcNAcylation. This is accompanied by disruptions in mitochondrial dynamics, comprising a decrease in mitochondrial fusion and an increase in mitochondrial fission proteins. Pharmacologic rescue of endogenous mitochondrial O-GlcNAcylation with an O-GlcNAcase inhibitor Thiamet-G or addition of exogenous O-GlcNAc-enhanced extracellular mitochondria ameliorates the mitochondrial disruption in pericytes damaged by mechanical injury. Finally, in a pericyte-endothelial co-culture model, mechanical injury increased <em>trans</em>-cellular permeability; adding Thiamet-G or O-GlcNAc-enhanced extracellular mitochondria rescued <em>trans</em>-cellular permeability following mechanical injury. These proof-of-concept findings suggest that mitochondrial O-GlcNAcylation in pericytes may represent a novel therapeutic target for ameliorating oxidative stress and vascular damage after mechanical injury following TBI.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149647"},"PeriodicalIF":2.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menopause triggers microglia-associated neuroinflammation in Parkinson’s disease","authors":"Sehar Usman,&nbsp;Amal Chandra Mondal","doi":"10.1016/j.brainres.2025.149649","DOIUrl":"10.1016/j.brainres.2025.149649","url":null,"abstract":"<div><div>Microglia, the immune cells of brain, can drive neurodegenerative diseases like Parkinson’s disease (PD). The resting microglia can polarize into two extremes, either proinflammatory M1 or anti-inflammatory M2 phenotype under a specific microenvironment. Different transcriptional factors and the release of various cytokines characterize these states. The released proinflammatory markers from M1 microglia lead to neuroinflammation that ultimately causes irreversible loss of dopaminergic neurons in PD patients, on the contrary, the M2 microglia possess neuroprotective activity. PD is caused by aggregation and misfolding of α-synuclein in the affected dopaminergic neurons. The misfolded α-synuclein is cytotoxic and can propagate like a prion from one cell to the other, acting like a template, that can initiate the conversion of normal proteins into abnormal conformation. The extracellular α-synuclein can interact and polarize the microglia into the M1 phenotype resulting in inflammation, thereby driving the progression of PD. The progression of neuroinflammation-mediated neurodegeneration in PD is seen higher in menopausal women; likely due to the low circulating estrogen levels. Estrogen hormones possess neuroprotective activity, and one of the ways is that they can polarize the microglia into M2 phenotype<del>s</del> and reduce α-synuclein-mediated microglial activation. A detailed understanding of the signaling mechanisms underlying microglial polarization between M1 and M2 phenotypes is crucial for identifying druggable targets to reduce PD symptoms, including in menopausal women.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149649"},"PeriodicalIF":2.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plumbagin as a potential therapeutic agent for scopolamine-induced Alzheimer’s disease: Mechanistic insights into GSK-3β inhibition","authors":"Rabiya Ahsan ,&nbsp;Mohd Muazzam Khan ,&nbsp;Anuradha Mishra ,&nbsp;Gazala Noor ,&nbsp;Usama Ahmad","doi":"10.1016/j.brainres.2025.149650","DOIUrl":"10.1016/j.brainres.2025.149650","url":null,"abstract":"<div><h3>Background</h3><div>The study aimed to evaluate Plumbagin’s neuroprotective potential against scopolamine-induced Alzheimer’s disease, proposing that its effects may involve GSK-3β inhibition, a key factor in tau hyperphosphorylation, to promote neuroprotection in Wistar rats.</div></div><div><h3>Methods</h3><div>Alzheimer’s was induced in male Wistar rats. After acclimatization, the rats were subjected to daily intraperitoneal treatment with scopolamine (0.7 mg/kg) and oral administration of Plumbagin (10 mg/kg) for 13 days. The cognitive function of treated rats was evaluated using the Morris water maze test, along with assessments of locomotor activity, acetylcholinesterase activity (AChE), protein levels, antioxidant parameters, cytokines and Brain-Derived Neurotrophic Factor (BDNF) and brain histopathology (hippocampus).</div></div><div><h3>Results</h3><div>The Plumbagin (10 mg/kg, oral) as given orally significantly improved neurobehavioral alterations compared to Alzheimer’s induced group. Scopolamine impaired cognitive function and increased locomotor activity (^#P &lt; 0.05). Treatments improved Morris water maze performance, reducing Escape latency time and increasing Time spent in the target quadrant (*P &lt; 0.05). Biochemically, treatments significantly improved BDNF (*P &lt; 0.05), decreased AChE activity, oxidative stress, reduced Interleukin-6 and Tumor Necrosis Factor Alpha (*P &lt; 0.05) and reversed Scopolamine induced hippocampal neuronal loss (^##P &lt; 0.01). Plumbagin showed significant (*P &lt; 0.05) neuroprotective effects, improving cognitive function, reducing AChE activity, Malondialdehyde, oxidative stress, and neuroinflammatory markers exceeding individual treatments in the scopolamine-induced Alzheimer’s disease model. These improvements suggest a possible mechanism through the inhibition of GSK-3β, which may contribute to the observed neuroprotective effects.</div></div><div><h3>Conclusion</h3><div>This study suggests that Plumbagin’s neuroprotective effects in scopolamine-induced Alzheimer’s disease may involve GSK-3β inhibition. Plumbagin shows significant therapeutic potential for Alzheimer’s treatment, warranting further investigation of its mechanism.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149650"},"PeriodicalIF":2.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of orexin receptor 2 plays anxiolytic effect in male mice","authors":"Lihua Chen ,&nbsp;Rui Tian ,&nbsp;Siqi Wei ,&nbsp;Hongwei Yang ,&nbsp;Chenchen Zhu ,&nbsp;Zicheng Li","doi":"10.1016/j.brainres.2025.149646","DOIUrl":"10.1016/j.brainres.2025.149646","url":null,"abstract":"<div><div>Anxiety disorders are the most common psychiatric illnesses. Present drugs can provide temporary relief for anxiety, however, they also come with side effects and safety concerns such as dependence, suicide, overdose and so on. Therefore, it is critical to discover new anxiolytic targets. An ongoing area of interest in the field of psychiatric diseases is the orexin system. Emerging body of evidences show that orexin receptor 1 (OX1R) has promising potential as novel anxiolytic target. However, little attention has been paid to orexin receptor 2 (OX2R) in anxiety. In this study, by using behavioral test, stereotaxic surgery and microinjection, virus-mediated knockdown of OX2R and pharmacological method, we found that: (1) Intraperitoneal injection of OX2R antagonist Seltorexant induced increased baseline anxiety-like behaviors in male mice. (2) Intraperitoneal injection of OX2R agonist YNT-185 reduced baseline anxiety-like behaviors in male mice. (3) Intraperitoneal injection of YNT-185 alleviated morphine withdrawal-induced anxiety-like behaviors in male mice. (4) Microinjection of YNT-185 into the VTA played anxiolytic effect in male mice. (5) Virus-mediated OX2R knockdown in the VTA induced anxiety-like behaviors in male mice.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149646"},"PeriodicalIF":2.7,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal drug delivery Dynamics: Extracellular and intracellular pathways revealed by Fluoro-Gold tracer in a mouse model","authors":"Meng-Ting Lin ,&nbsp;Tsai-Yun Chan ,&nbsp;Wei-Hao Liao ,&nbsp;Chueh-Hung Wu ,&nbsp;Tai-Horng Young ,&nbsp;Wen-Shiang Chen","doi":"10.1016/j.brainres.2025.149644","DOIUrl":"10.1016/j.brainres.2025.149644","url":null,"abstract":"","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1858 ","pages":"Article 149644"},"PeriodicalIF":2.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Okra-supplemented diet prevents hypothalamic inflammation in early overfeeding-programmed obese rats","authors":"Camila Luiza Rodrigues dos Santos Ricken ,&nbsp;Ginislene Dias ,&nbsp;Ingridys Regina Borkenhagen ,&nbsp;Adriano Nicoli Roecker ,&nbsp;Gisele Facholi Bomfim ,&nbsp;Hercules de Oliveira Costermani ,&nbsp;Aline Milena Dantas Rodrigues ,&nbsp;Nathalia Macedo Sanches ,&nbsp;Ester Vieira Alves ,&nbsp;Ricardo de Oliveira ,&nbsp;Júlio Cezar de Oliveira","doi":"10.1016/j.brainres.2025.149641","DOIUrl":"10.1016/j.brainres.2025.149641","url":null,"abstract":"<div><h3>Background</h3><div>Early overnutrition programs long-term metabolic dysfunctions. Owing to their benefits, functional foods have been used to treat metabolic diseases. We aimed to test the hypothesis that a diet supplemented with okra (<em>Abelmoschus esculentus</em> L.) mitigates energy metabolism impairment and glucose dyshomeostasis in early overfeeding-programmed rat offspring.</div></div><div><h3>Methods</h3><div>At postnatal Day 3, the litters were adjusted to 3 (small litter, SL) or 8 (normal litter, NL) pups. During lactation, milk collection and milk intake were performed. At 22 days-old, the pups were weaned and fed a standard diet (NL-SD and SL-SD groups) or an okra-supplemented diet (1.5 % <em>A. esculentus</em>; NL-AE and SL-AE groups). Body weight and food and water intake were measured every two days. Intraperitoneal glucose tolerance and intracerebroventricular insulin (10^-3 mmol/L) tests were performed, and then the offspring were euthanized. Blood, hypothalamus, and visceral fat pads were collected and lean body mass was measured.</div></div><div><h3>Results</h3><div>Milk from SL mothers had higher triglyceride and energy contents (P &lt; 0.05), and milk consumption by SL offspring was greater than that by NL rats. SL-SD rats were obese, hyperphagic, hypertriglyceridemic, hyperglycemic and glucose intolerant (P &lt; 0.05) and presented central insulin resistance and increased levels of hypothalamic proinflammatory [tumor necrosis factor alpha (TNF-α), 43.5 %; interleukin 6 (IL-6), 78.5 %; and interleukin 1 beta (IL-1β), 50.1 %, P &lt; 0.05] cytokines. On the other hand, the consumption of an okra-supplemented diet prevented all metabolic impairments.</div></div><div><h3>Conclusion</h3><div>In summary, dietary supplementation with okra prevents obesity and glucose deregulation in early-overfeeding rats, which is associated with improved hypothalamic inflammation and insulin resistance.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1858 ","pages":"Article 149641"},"PeriodicalIF":2.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term treatment with haloperidol modulates angiotensin I-converting enzyme (ACE) activity in transgenic animal model with construct validity for schizophrenia studies","authors":"William Y. Oyadomari ,&nbsp;Thays C. Santiago ,&nbsp;Leonardo Basso ,&nbsp;Vitor Oliveira ,&nbsp;Fábio C. Cruz ,&nbsp;João V. Nani ,&nbsp;Mirian A.F. Hayashi","doi":"10.1016/j.brainres.2025.149640","DOIUrl":"10.1016/j.brainres.2025.149640","url":null,"abstract":"<div><div>Elevated angiotensin I-converting enzyme (ACE) activity has been correlated with worse cognitive performance in patients with first-episode psychosis (FEP) and chronic schizophrenia (SZ). In this study, we investigated ACE activity in drug-naïve transgenic rats overexpressing the full-length non-mutated human <em>Disrupted-in-Schizophrenia 1</em> (<em>tg</em>DISC1) compared to wild-type (WT) controls, while we also assessed the effects of long-term treatment with typical antipsychotic haloperidol. Our findings indicated that untreated <em>tg</em>DISC1 rats show elevated serum ACE activity compared to WT animals, which is consistent with clinical observations in drug-naïve FEP patients. In contrast, baseline ACE activity in the brain of <em>tg</em>DISC1 was generally lower than in WT rats, with the exception of no difference in ACE activity observed in brain regions associated with learning, memory, and reward, such as the hippocampus and nucleus accumbens. Consistent with clinical observations in FEP patients following treatment with antipsychotics, 30-days of daily haloperidol-treatment significantly increased serum ACE activity in blood serum of both <em>tg</em>DISC1 and WT rats. However, ACE responses in brain were markedly different, as haloperidol treatment reduced ACE activity in most brain regions of both rat strains. These results support the existence of a central renin-angiotensin system (RAS) distinct from the peripheral RAS, suggesting that the treatment with a dopamine blocker exerts brain-specific effects on ACE activity, which was essentially opposite to that observed in the periphery. This region-specific alterations observed in cognition-related brain areas (notably with a relative stronger effect size in hippocampus and nucleus accumbens of <em>tg</em>DISC1 compared to WT rats) also suggest a critical interplay among dopamine homeostasis, ACE activity, and cognitive deficits in SZ. Understanding this interplay could help identifying novel biomarkers and/or therapeutic strategies for improving cognitive outcomes in SZ patients.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1859 ","pages":"Article 149640"},"PeriodicalIF":2.7,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}