Neurochemical Research最新文献

{"title":"FTO Suppresses Proliferation and Induces Apoptosis of T98G Glioblastoma Cells via N6-methyladenosine Modification of GSTO1","authors":"Jinjiang Dong,&nbsp;Jianhao Mao,&nbsp;Weihua Wu,&nbsp;Xiaoling Qian,&nbsp;Zhenfei Yu","doi":"10.1007/s11064-025-04334-w","DOIUrl":"10.1007/s11064-025-04334-w","url":null,"abstract":"<div><p>Glioblastoma (GBM) is the most malignant type of glioma with a very poor prognosis. N6-methyladenosine (m6A) is well-documented to be involved in GBM progression, and FTO is a demethylase. GSTO1 is also associated with tumor progression. This study aimed to investigate the impact of FTO and GSTO1 on GBM progression and the regulation of FTO on m6A modification of GSTO1. T98G cell phenotypes including proliferation and apoptosis were analyzed by cell counting kit 8, colony formation assay, and flow cytometry. The regulation of m6A methylation mediated by FTO was evaluated by methylated RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assay. The results showed that FTO expression was downregulated in GBM. Overexpression of FTO inhibited cell proliferation and facilitated apoptosis in vitro. Additionally, GSTO1 expression was elevated in GBM, and knockdown of GSTO1 suppressed cell proliferation and promoted apoptosis and oxidative stress. Moreover, FTO inhibited m6A methylation of GSTO1 and reduced the stability of GSTO1. Overexpression of GSTO1 abrogated T98G cellular processes mediated by FTO. The in vivo experiments showed that FTO inhibited tumor growth by downregulating GSTO1 expression. In conclusion, FTO decelerates GBM progression by inducing apoptosis through suppressing m6A methylation of GSTO1.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995673","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":"Methionine Sulfoximine as a Tool for Studying Temporal Lobe Epilepsy: Initiator, Developer, Attenuator","authors":"Jan Albrecht,&nbsp;Stanisław J. Czuczwar,&nbsp;Magdalena Zielińska,&nbsp;Barbara Miziak","doi":"10.1007/s11064-024-04329-z","DOIUrl":"10.1007/s11064-024-04329-z","url":null,"abstract":"<div><p>Methionine sulfoximine (MSO) is a compound originally discovered as a byproduct of agene-based milled flour maturation. MSO irreversibly inhibits the astrocytic enzyme glutamine synthase (GS) but also interferes with the transport of glutamine (Gln) and of glutamate (Glu), and <i>γ</i>-aminobutyric acid (GABA) synthesized within the Glu/Gln-GABA cycle, in this way dysregulating neurotransmission balance in favor of excitation. No wonder that intraperitoneal administration of MSO has long been known to induce behavioral and/or electrographic seizures. Recently, a temporal lobe epilepsy (TLE) model based on local continuous infusion of MSO into the hippocampus has been developed reproducing the main features of human mesial TLE: induction of focal seizures, their spreading, increase in intensity over time, and development of spontaneous recurrent seizures. Fully developed TLE in this model is associated with hippocampal degeneration, hallmarked by reactive astrogliosis, and causally related to the concomitant loss of GS-containing astrocytes. By contrast, short-term pre-exposure of rats to relatively low MSO doses that only moderately inhibited GS, attenuated and delayed the initial seizures in the lithium-pilocarpine model of TLE and in other seizure-associated contexts: in the pentylenetetrazole kindling model in rat, and in spontaneously firing or electrically stimulated brain slices. The anti-initial seizure activity of MSO may partly bypass inhibition of GS: the postulated mechanisms include: (i) decreased release of excitatory neurotransmitter Glu, (ii) prevention or diminution of seizure-associated brain edema, (iii) stimulation of glycogenesis, an energy-sparing process; (iv) central or peripheral hypothermia. Further work is needed to verify either of the above mechanisms.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 2","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995675","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":"Nanoparticle Interactions with the Blood Brain Barrier: Insights from Drosophila and Implications for Human Astrocyte Targeted Therapies","authors":"Akshata Choudhari Padti,&nbsp;Santosh Mallikarjun Bhavi,&nbsp;Bothe Thokchom,&nbsp;Sapam Riches Singh,&nbsp;Shivanand S. Bhat,&nbsp;B. P. Harini,&nbsp;Mika Sillanpää,&nbsp;Ramesh Babu Yarajarla","doi":"10.1007/s11064-025-04333-x","DOIUrl":"10.1007/s11064-025-04333-x","url":null,"abstract":"<div><p>This review explores the intricate connections between <i>Drosophila</i> models and the human blood-brain barrier (BBB) with nanoparticle-based approaches for neurological treatment. <i>Drosophila</i> serves as a powerful model organism due to its evolutionary conservation of key biological processes, particularly in the context of the BBB, which is formed by glial cells that share structural and functional similarities with mammalian endothelial cells. Recent advancements in nanoparticle technology have highlighted their potential for effective drug delivery across the BBB, utilizing mechanisms such as passive diffusion, receptor-mediated transcytosis, and carrier-mediated transport. The ability to engineer nanoparticles with specific physicochemical properties—such as size, surface charge, and functionalization—enhances their targeting capabilities, particularly towards astrocytes, which play a crucial role in maintaining BBB integrity and responding to neuroinflammation. Insights gained from <i>Drosophila</i> studies have informed the design of personalized nanomedicine strategies aimed at treating neurodegenerative diseases, including Alzheimer’s, Parkinson’s disease etc. As research progresses, the integration of findings from <i>Drosophila</i> models with emerging humanized BBB systems will pave the way for innovative therapeutic approaches that improve drug delivery and patient outcomes in neurological disorders.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995325","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":"Exploring Ubiquitination in Spinal Cord Injury Therapy: Multifaceted Targets and Promising Strategies","authors":"Caizhen Shi,&nbsp;Bingbing Wang,&nbsp;Tianyu Zhai,&nbsp;Can Zhang,&nbsp;Jiarui Ma,&nbsp;Yanjie Guo,&nbsp;Yanling Yang,&nbsp;Chen Chen,&nbsp;Jianzhong Gao,&nbsp;Lin Zhao","doi":"10.1007/s11064-025-04332-y","DOIUrl":"10.1007/s11064-025-04332-y","url":null,"abstract":"<div><p>Spinal cord injury (SCI) is a severely debilitating neurological condition that often results in significant functional impairment and is associated with poor long-term prognosis. Edema, oxidative stress, inflammatory responses, and cell death are the primary factors contributing to secondary injury following spinal cord damage. Ubiquitination is a crucial intracellular mechanism for protein regulation that has garnered significant attention as a therapeutic target in a variety of diseases. Numerous studies have shown that ubiquitination plays a key role in modulating processes such as inflammatory responses, apoptosis, and nerve regeneration following SCI, thereby influencing injury repair. Accordingly, targeting ubiquitination has the potential for mitigating harmful inflammatory responses, inhibiting dysregulated programmed cell death, and protecting the integrity of the blood–spinal cord barrier, thereby providing a novel therapeutic strategy for SCI. In this review, we discuss the role of ubiquitination and its potential as a therapeutic target in SCI, aiming to offer a foundation for developing ubiquitination-targeted therapies for this condition.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995324","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 Fasting Improves Sevoflurane-Induced Cognitive Dysfunction in Rats Through SIRT1-Mediated Autophagy","authors":"Feng-wei Sun,&nbsp;Yue Tian","doi":"10.1007/s11064-025-04335-9","DOIUrl":"10.1007/s11064-025-04335-9","url":null,"abstract":"<div><p>Perioperative neurocognitive disorders (PND) is a common complication affecting the central nervous system, commonly induced by anesthesia and surgical procedures. PND has garnered considerable attention in recent years, not only due to its high morbidity but also its negative impact on patient prognosis, such as increased rates of dementia and mortality. Sevoflurane, a common volatile anesthetic in clinical practice, is increasingly linked to being a potential risk factor for PND with prolonged inhalation, yet effective prevention and treatment methods remain elusive. Autophagy, a crucial regulatory process for maintaining organism function, has been shown to play a key role in sevoflurane-induced cognitive dysfunction. In recent years, intermittent fasting (IF), a unique dietary pattern, has gained significant recognition. IF has been shown in multiple studies to offer neuroprotective advantages in different central nervous system conditions. disorders. This study aims to explore the potential neuroprotective effects of intermittent fasting preconditioning through the autophagic pathway in sevoflurane-induced cognitive impairment in rats and its underlying mechanisms.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995322","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":"Blackcurrant (Ribes nigrum L.) and Its Association with Donepezil Restore Cognitive Impairment, Suppress Oxidative Stress and Pro-inflammatory Responses, and Improve Purinergic Signaling in a Scopolamine-Induced Amnesia Model in Mice","authors":"Pauline da Costa,&nbsp;Maria Rosa Chitolina Schetinger,&nbsp;Jucimara Baldissarelli,&nbsp;Karine Paula Reichert,&nbsp;Naiara Stefanello,&nbsp;Nathieli Bianchin Bottari,&nbsp;Taís Vidal,&nbsp;Ivana Beatrice Mânica da Cruz,&nbsp;Charles Elias Assmann,&nbsp;Vera Maria Melchiors Morsch","doi":"10.1007/s11064-024-04327-1","DOIUrl":"10.1007/s11064-024-04327-1","url":null,"abstract":"<div><p>Purinergic signaling plays a major role in aging and neurodegenerative diseases, which are associated with memory decline. Blackcurrant (BC), an anthocyanin-rich berry, is renowned for its antioxidant and neuroprotective activities. However, evidence on the effects of BC on purinergic signaling is lacking. This study investigated the effects of BC and its association with Donepezil (DNPZ) on learning and memory, on the modulation of purinergic signaling, pro-inflammatory responses, and oxidative markers in a mouse model of cognitive impairment chronically induced by scopolamine (SCO). Animals were divided into twelve groups and treated with BC (50 or 100 mg/kg), and/or DNPZ (5 mg/kg), and/or SCO (1 mg/kg). Results showed that SCO decreased spatial learning and memory as assessed by the Morris Water Maze test, and treatment with BC and/or DNPZ restored these effects. Furthermore, BC and/or DNPZ treatments also prevented changes in ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) and adenosine deaminase (ADA) activities and restored the increased density of P2X7 and A2A receptors in synaptosomes of the cerebral cortex of SCO-induced mice. Moreover, the increased Nod-like receptor protein 3 (NLRP3) and interleukin-1β expression, and the oxidative stress markers levels were reduced by BC and/or DNPZ treatments, compared with the SCO group. Overall, BC and/or DNPZ treatments ameliorated SCO-induced cognitive decline, alleviated oxidative stress and pro-inflammatory responses, and improved purinergic signaling. These findings underscore the potential of BC, especially when in combination with DNPZ, as a therapeutic agent for the prevention of memory deficits associated with aging or neurological diseases.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963167","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":"Trehalose Inhibits ferroptosis Through Activating SIRT3/SOD2 Signaling Axis and Alleviates Brain Injury After Traumatic Brain Injury","authors":"Zhenqian Mu,&nbsp;Zhenlie Sun,&nbsp;Shuai Wu,&nbsp;Jieqiong Yang,&nbsp;Peng Wang,&nbsp;Xudong Zhao","doi":"10.1007/s11064-024-04330-6","DOIUrl":"10.1007/s11064-024-04330-6","url":null,"abstract":"<div><p>Trehalose has neuroprotective effects in neurodegenerative diseases. This study aimed to explore the impact of trehalose on traumatic brain injury (TBI) by investigating its role in neuroprotection. The TBI mice model was established utilizing the cortical impact technique followed by trehalose treatment. Traumatic neuronal injury induced by scratch followed by trehalose treatment was performed to mimic TBI in vitro. Memory function was assessed using the Water maze test. Brain damage was evaluated through various methods including brain water content analysis, Nissl staining, Evans blue exudation, and TUNEL staining. Biochemical and morphological changes related to ferroptosis post-TBI were also examined. The results showed that trehalose was found to enhance spatial memory, reduce brain injury, and inhibit ferroptosis in TBI mice, similar to ferroptosis inhibitors. The influence of trehalose on TBI was reversed by the SIRT3 inhibitor. Trehalose upregulated SIRT3 to increase SOD activity in TBI, which could also be counteracted by the SIRT3 inhibitor. Combining trehalose with a ferroptosis inhibitor had a more significant effect on reducing brain injury and inhibiting ferroptosis. Furthermore, in TBI mice treated with trehalose and SIRT3 inhibitors, the effect of trehalose was reversed by SIRT3 inhibitors, but the addition of ferroptosis inhibitors reversed the effect of SIRT3 inhibitors, as shown by decreased ferroptosis and neuronal apoptosis in damaged brain tissue. In summary, this study provides initial evidence that trehalose plays a crucial role in neuroprotection post-TBI through the SIRT3/SOD2 pathway-mediated ferroptosis.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941048","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":"Glycyrrhizic Acid Mitigates Haloperidol-Induced Neurotoxicity in SHSY-5Y Cells and Rats Via Activation of PI3k/Akt/Nrf2 Pathways","authors":"Mohammad Aqeel,&nbsp;Shubham Upadhayay,&nbsp;Ritika Devi,&nbsp;Kailash Jangid,&nbsp;Vinod Kumar,&nbsp;Puneet Kumar","doi":"10.1007/s11064-024-04319-1","DOIUrl":"10.1007/s11064-024-04319-1","url":null,"abstract":"<div><p>Antipsychotic medications are used to treat a psychological condition called ‘Schizophrenia’. However, its long-term administration causes irregular involuntary motor movements, targeting the orofacial regions. Glycyrrhizic acid (GA) is a naturally occurring triterpene saponin glycoside obtained from the roots of the <i>Glycyrrhiza glabra</i> (liquorice) plant and well known for its antioxidant, antiapoptotic and neuroprotective abilities. The present study investigated the neuroprotective potential of GA against haloperidol (Halo) induced neurotoxicity in SHSY-5Y cells and Wistar rats. Schrodinger software was utilized to estimate the target binding affinity of GA with various targets. To assess cell viability, SHSY-5Y cells were pretreated with GA (25, 50, and 100 µM) 1 h before halo (100 µM) treatment. In an in-vivo study, Wistar rats were divided into five groups: control (saline), halo (1 mg/kg), GA (25 mg/kg), and GA (50 mg/kg). The GA was injected for 21 days, 1 h before halo. All behavior changes were recorded on the 14th and 21st days. Results indicate that pretreatment with GA improves cell viability and reduces ROS formation in halo-treated SHSY-5Y cells, showing its antioxidant ability. Furthermore, GA administration reduced vacuous chewing movements, tongue protrusion, facial jerking, and locomotor abnormalities in halo-treated rats. Moreover, GA treatment improves antioxidant levels, including GSH, and SOD, in halo-injected rats. Additionally, GA treatment upregulates the striatal expression of p-PI3k, p-Akt, and Nrf2 in rats injected with halo. Findings indicate that GA can be a therapeutic agent for tardive dyskinesia and other neurological disorders.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142938928","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":"Identification of a Subpopulation of Astrocyte Progenitor Cells in the Neonatal Subventricular Zone: Evidence that Migration is Regulated by Glutamate Signaling","authors":"Zila Martinez-Lozada,&nbsp;Alain M. Guillem,&nbsp;Isabella Song,&nbsp;Michael V. Gonzalez,&nbsp;Hajime Takano,&nbsp;Esha Parikh,&nbsp;Jeffrey D. Rothstein,&nbsp;Mary E. Putt,&nbsp;Michael B. Robinson","doi":"10.1007/s11064-024-04326-2","DOIUrl":"10.1007/s11064-024-04326-2","url":null,"abstract":"<div><p>In mice engineered to express enhanced green fluorescent protein (eGFP) under the control of the entire glutamate transporter 1 (GLT1) gene, eGFP is found in all ‘adult’ cortical astrocytes. However, when 8.3 kilobases of the human GLT1/EAAT2 promoter is used to control expression of tdTomato (tdT), tdT is only found in a subpopulation of these eGFP-expressing astrocytes. The eGFP mice have been used to define mechanisms of transcriptional regulation using astrocytes cultured from cortex of 1–3 day old mice. Using the same cultures, we were never able to induce tdT⁺ expression. We hypothesized that these cells might not have migrated into the cortex by this age. In this study, we characterized the ontogeny of tdT⁺ cells, performed single-cell RNA sequencing (scRNA-seq), and tracked their migration in organotypic slice cultures. At postnatal day (PND) 1, tdT⁺ cells were observed in the subventricular zone and striatum but not in the cortex, and they did not express eGFP. At PND7, tdT⁺ cells begin to appear in the cortex with their numbers increasing with age. At PND1, scRNA-seq demonstrates that the tdT⁺ cells are molecularly heterogeneous, with a subpopulation expressing astrocytic markers, subsequently validated with immunofluorescence. In organotypic slices, tdT⁺ cells migrate into the cortex, and after 7 days they express GLT1, NF1A, and eGFP. An ionotropic glutamate receptor (iGluR) antagonist reduced by 50% the distance tdT⁺ cells migrate from the subventricular zone into the cortex. The pan-glutamate transport inhibitor, TFB-TBOA, increased, by sixfold, the number of tdT⁺ cells in the cortex. In conclusion, although tdT is expressed by non-glial cells at PND1, it is also expressed by glial progenitors that migrate into the cortex postnatally. Using this fluorescent labeling, we provide novel evidence that glutamate signaling contributes to the control of glial precursor migration.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-024-04326-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142938922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition","authors":"Ângela Beatris Zemniaçak,&nbsp;Rafael Teixeira Ribeiro,&nbsp;Gustavo Machado das Neves,&nbsp;Sâmela de Azevedo Cunha,&nbsp;Tailine Quevedo Tavares,&nbsp;Andrey Vinícios Soares Carvalho,&nbsp;Carlos Alexandre Netto,&nbsp;Roger Frigério Castilho,&nbsp;Moacir Wajner,&nbsp;Alexandre Umpierrez Amaral","doi":"10.1007/s11064-024-04328-0","DOIUrl":"10.1007/s11064-024-04328-0","url":null,"abstract":"<div><p>Brain accumulation of the branched-chain α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) occurs in maple syrup urine disease (MSUD), an inherited intoxicating metabolic disorder caused by defects of the branched-chain α-keto acid dehydrogenase complex. Patients commonly suffer life-threatening acute encephalopathy in the newborn period and develop chronic neurological sequelae of still undefined pathogenesis. Therefore, this work investigated the in vitro influence of pathological concentrations of KIC (5 mM), KMV (1 mM), and KIV (1 mM) on mitochondrial bioenergetics in the cerebral cortex of neonate (one-day-old) rats. KIC, but not KMV and KIV, decreased phosphorylating (stimulated by ADP) and uncoupled (induced by CCCP) mitochondrial respiration supported by pyruvate, malate, and glutamate, indicating metabolic inhibition. These effects were less evident after supplementing the medium with succinate. KIC also mildly increased non-phosphorylating respiration (in the presence of oligomycin) using pyruvate plus malate or glutamate plus malate as substrates, suggesting an uncoupling effect. Moreover, KIC markedly inhibited the activity of α-ketoglutarate dehydrogenase noncompetitively and decreased ATP synthesis. Finally, docking simulations demonstrated that KIC preferentially interacts with E2 and E3 subunits of α-ketoglutarate dehydrogenase at the dihydrolipoamide binding site and into an allosteric site of E1. The present data strongly indicate that KIC compromises mitochondrial bioenergetics in the neonatal rat brain, supporting the hypothesis that disruption of energy homeostasis caused by brain KIC accumulation in the first days of life may be implicated in the neuropathology of MSUD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142938923","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}