Journal of Neurochemistry最新文献

{"title":"Fundamentals of Gas-Free Calibrated fMRI for Oxidative Metabolic Neuroimaging","authors":"Fahmeed Hyder,&nbsp;Peter Herman","doi":"10.1111/jnc.70217","DOIUrl":"https://doi.org/10.1111/jnc.70217","url":null,"abstract":"<p>Brain's high energy demands require abundant production of ATP from glucose oxidation, mandating coupling between neural activity and nutrient supply. Understanding how neural activity augments blood flow (CBF) to support metabolism of glucose (CMR_glc) and oxygen (CMR_O2) can help unravel mysteries of neurovascular and neurometabolic couplings underlying functional MRI (fMRI) with blood oxygenation level-dependent (BOLD) contrast. Key to this enigma is oxygen extraction fraction (OEF). Fundamentally, OEF is defined by flow-metabolism (i.e., CBF-CMR_O2) coupling generating mitochondrial ATP to signify limits of hypoxia and ischemia. However, to fully account for observed CBF-CMR_O2 coupling, the OEF must include a term for oxygen diffusivity (D_O2) that is regulated by rheological properties of blood. BOLD contrast depends on intravoxel spin dephasing of tissue water protons due to paramagnetic fields generated by deoxyhemoglobin. During augmented neural activity, if CBF increases more than CMR_O2, then deoxyhemoglobin (paramagnetic) is replaced by perfusing oxyhemoglobin (diamagnetic) to increase BOLD signal. Calibrated fMRI converts BOLD contrast into OEF according to the deoxyhemoglobin dilution model. Agreement across these OEF models (i.e., OEF trifecta) authenticates calibrated fMRI, both gas-based and gas-free methods. CMR_O2 by gas-free calibrated fMRI easily and reproducibly tracks neural activity, while combining it with CMR_glc can also reveal aerobic glycolysis. In summary, there is translational potential of gas-free calibrated fMRI for metabolic imaging in the resting and stimulated brain, from neurodegeneration to neurological disorders.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145223895","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":"Trifluoperazine, an Antipsychotic Drug, Inhibits Viability of Cells Derived From SEGA and Cortical Tubers Cultured In Vitro.","authors":"Malgorzata Urbanska, Krzysztof Sadowski, Aleksandra Stawikowska, Ewa Liszewska, Magdalena Mlostek, Wieslawa Grajkowska, Katarzyna Kotulska","doi":"10.1111/jnc.70247","DOIUrl":"https://doi.org/10.1111/jnc.70247","url":null,"abstract":"<p><p>This study aimed to identify compounds that inhibit the growth of cells with a hyperactive mTOR pathway, offering potential treatment options for Tuberous Sclerosis Complex (TSC). We obtained cells from subependymal giant cell astrocytoma (SEGA) and cortical tuber (CTuber) tissues of TSC patients to establish SEGA and CTuber cell strains. Focusing on these patient-derived cell strains, we screened eight compounds from various drug classes for their effects on cell viability in vitro. Five of these compounds demonstrated significant reductions in cell viability and effectively disrupted mTORC1 signaling and autophagy. Trifluoperazine, which exhibited no adverse effects on normal astrocytes, was selected for further study. Combination studies with rapamycin were conducted to evaluate their joint effects on cell viability and autophagy abnormalities, especially in SEGA-derived cells from rapamycin-resistant patients. Notably, trifluoperazine showed promising properties by maintaining its efficacy in combination with rapamycin and effectively reducing cell viability, even in rapamycin-resistant SEGA-derived cells. Trifluoperazine appears promising as a treatment for TSC. However, further research is crucial to confirm its therapeutic benefits and safety profile in TSC patients, representing a significant direction for future TSC management studies.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":"e70247"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238729","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":"Brain-Derived Neurotrophic Factor (BDNF) and Sex Differences in Metabolic Regulation.","authors":"Ariane M Zanesco, Licio A Velloso","doi":"10.1111/jnc.70245","DOIUrl":"https://doi.org/10.1111/jnc.70245","url":null,"abstract":"<p><p>For decades, most experimental studies were conducted using male rodents as models, and the results obtained in several distinct fields of medical and biological research were regarded as valid for both males and females. However, as evidence progressively challenged this concept by unveiling phenotypes that are regulated according to a pattern of sexual dimorphism, many studies were undertaken to identify the mechanisms driving sex-specific characteristics. In this context, hypothalamic brain-derived neurotrophic factor emerged as an important player regulating metabolism according to a sexual dimorphic pattern. Here, we performed a narrative review that puts together the main pieces of evidence showing how brain-derived neurotrophic factor is involved in metabolic sexual dimorphism. The accumulated data in this field has uncovered important aspects of the physiological and pathological control of metabolic sex-specific functions and has placed hypothalamic brain-derived neurotrophic factor as a potential target for interventions aimed at mitigating metabolic abnormalities that affect differently females and males.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":"e70245"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238821","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":"Lactate Transport via Glial MCT1 and Neuronal MCT2 Is Not Required for Synchronized Synaptic Transmission in Hippocampal Slices Supplied With Glucose.","authors":"Lennart Söder, Felipe Baeza-Lehnert, Babak Khodaie, Amr Elgez, Lena Noack, Andrea Lewen, Stefan Hallermann, Gernot Poschet, Karin Borges, Oliver Kann","doi":"10.1111/jnc.70251","DOIUrl":"10.1111/jnc.70251","url":null,"abstract":"<p><p>The metabolite lactate (L-lactate) has been hypothesized to represent an important energy source during brain activation. The contribution of lactate in fueling synchronized synaptic transmission during fast neural network oscillations underlying complex cortex function such as visual perception, memory formation, and motor activity is less clear, however. We explored the role of cellular lactate production and lactate transport (uptake and release) via the monocarboxylate transporters 1 and 2 (glial MCT1 and neuronal MCT2) during persistent gamma oscillations (frequency at around 40 Hz) and recurrent rhythmic events called sharp wave-ripples (with \"ripples\" at around 250 Hz) in cultured rat and acute mouse hippocampal slices (ex vivo) that received energy substrate supply with glucose (D-glucose) only. In addition, we assessed neuronal lactate dynamics during spontaneous activity (\"resting state\") and during electrical stimulation (10 Hz) in mouse primary neuron-astrocyte cultures (in vitro) receiving glucose only. We combined electrophysiology (local field potential recordings), tissue lactate analysis [ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)], and live-cell fluorescence imaging [Förster resonance energy transfer (FRET) sensor Laconic]. We report that (1) lactate is produced during gamma oscillations when glucose is supplied and oxygen availability is unlimited (high oxygenation) for mitochondrial respiration. (2) The properties of gamma oscillations remain regular in the presence of the MCT1/2 blocker AR-C155858. (3) By contrast, MCT1/2 blockade fully suppresses gamma oscillations when mainly lactate is supplied. (4) The properties of sharp wave-ripples remain regular during MCT1/2 inhibition. (5) Lactate is produced in primary hippocampal neurons during spontaneous activity and electric stimulus-induced excitation, and it accumulates in the neuronal cytosol during MCT1/2 inhibition. In conclusion, lactate is produced in cortical tissue, including neurons fueled by glucose only. Moreover, lactate transport and lactate exchange (\"shuttling\") via glial MCT1 and neuronal MCT2 are not required to sustain synchronized synaptic transmission during fast neural network oscillations.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":"e70251"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232846","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":"Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.","authors":"Leyre Sánchez de Muniain, Paula Escalada, María J Ramírez, Maite Solas","doi":"10.1111/jnc.70252","DOIUrl":"https://doi.org/10.1111/jnc.70252","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":"e70252"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238760","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":"Tiny Messengers, Huge Consequences: Extracellular Vesicles and mTOR Signaling in Neuroinflammation.","authors":"P Garcia-Segura, A Chicote-González, A Espasa-Marco, M Garcia-Alcaraz, L Mora-Bernabé, M Abelló-Fernández, C Malagelada","doi":"10.1111/jnc.70256","DOIUrl":"10.1111/jnc.70256","url":null,"abstract":"<p><p>Neuroinflammation plays a fundamental role in the pathogenesis of neurodegenerative disorders. Among the central regulators of this process are the mechanistic target of rapamycin (mTOR) signaling pathway and extracellular vesicles (EVs). This review discusses the bidirectional interaction between mTOR and EVs, describing their interconnection in the regulation of cellular communication and inflammatory responses in the central nervous system (CNS). On one hand, mTOR controls EV biogenesis and cargo composition, and, on the other hand, EVs also modulate mTOR activity in target cells with effects in neuronal survival, glial activation, and immune signaling. This bidirectional communication creates a feedback loop that, depending on cell context and molecular cues, may either promote neuroprotection or exacerbate neurotoxicity and inflammation.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":"e70256"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232911","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":"Nitrergic Signaling Mediation of Neurobehavioral Responses to Stress in Zebrafish.","authors":"João Alphonse Apóstolo Heymbeeck, Eveline Bezerra de Sousa, Monica Lima-Maximino, Antonio Pereira, Caio Maximino","doi":"10.1111/jnc.70254","DOIUrl":"10.1111/jnc.70254","url":null,"abstract":"<p><p>Nitric oxide (NO) is a gaseous transmitter that is involved in the regulation of multiple behavioral processes in the brain. Here, we review the participation of this molecule in zebrafish neurobehavioral responses to stress. NO signaling pathways are considerably conserved in this species, and different pathways appear to be related to the complex regulation of behavior by this molecule. NO acts as a downstream integrator of responses to different upstream signals, including glutamate, serotonin, and inflammatory mediators; as a result, it participates in both anxiolytic and anxiogenic effects of drugs acting at different targets. There is considerable evidence for the participation of both a glutamate/NOS-1 pathway and a KCNN/NOS-2 pathway in long-term behavioral sensitization to stress in zebrafish, suggesting that this molecule regulates metaplasticity in circuits that mediate defensive responses. Important questions remain unanswered, including the relationship between NO signaling, oxidative stress, and neuroinflammation, as well as the actual mechanisms of metaplasticity in the zebrafish brain.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":"e70254"},"PeriodicalIF":4.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232879","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":"Serum Proteome Profiling Implicates Dysregulation of Immune Response and Inflammatory Mechanisms in Methylmalonic Acidemia With Brain Injury","authors":"Yumei Su,&nbsp;Jing Wei,&nbsp;Shuqi Sun,&nbsp;Lulu Jia,&nbsp;Qiliang Li","doi":"10.1111/jnc.70242","DOIUrl":"10.1111/jnc.70242","url":null,"abstract":"<div>\u0000 \u0000 <p>Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Brain injury represents the most common clinical manifestation among MMA patients and is often associated with a poor prognosis. Currently, the mechanisms of MMA with brain injury are unclear, and there are no reliable biomarkers available for diagnosing MMA with brain injury. Consequently, a proteomic analysis was performed on the serum from 40 patients with MMA with brain injury (MBI), 15 MMA without brain injury (MNBI), 15 hyperhomocysteinemia patients (HHCY), and 25 healthy controls (CTRL). The differentially expressed proteins were analyzed by bioinformatics, and then the potential biomarkers were validated by the enzyme-linked immunosorbent assays in another independent cohort. The results showed that a total of 503 proteins were identified in the serum samples, of which 49 differentially expressed proteins were identified in the MBI and MNBI groups. Two key molecules were identified as candidate molecules for further validation. The combination of ACE and MMP9 might be a biomarker panel for MMA with brain injury (AUC 0.847, sensitivity 0.750, specificity 0.867). The down-regulation of immune response and up-regulation of inflammatory response were mainly enriched in MMA brain injury patients. Our research indicated that dysregulation of immune response and neuroinflammation might be potential mechanisms of MMA with brain injury. In addition, it provided a candidate biomarker panel for early diagnosing MMA with brain injury, facilitating early intervention and prognosis improvement.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Botulinum Neurotoxin A Signaling in Pain Modulation Within Human Sensory Neurons”","authors":"","doi":"10.1111/jnc.70248","DOIUrl":"10.1111/jnc.70248","url":null,"abstract":"<p>Gabriel, K. A., K. Hankerd, P. Barragan-Iglesias, et al. 2025. “Botulinum Neurotoxin A Signaling in Pain Modulation Within Human Sensory Neurons.” <i>Journal of Neurochemistry</i> 169, no. 9: e70236. https://doi.org/10.1111/jnc.70236.</p><p>In the paper by Gabriel et al. (2025), the affiliations should read as follows:</p><p>Katherin A. Gabriel¹, Kali Hankerd¹, Paulino Barragan-Iglesias², Amy D. Brideau-Andersen², Lance E. Steward², Steve McGaraughty³, Edwin Vazquez-Cintron², Theodore J. Price¹</p><p>¹Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, USA.</p><p>²Allergan Aesthetics, an AbbVie company, Irvine, CA, USA.</p><p>³AbbVie, North Chicago, IL, USA.</p><p>These have been corrected in the original article.</p><p>The funding line should read as follows:</p><p>Allergan Aesthetics, an AbbVie Company, funded this study and participated in the study design, research, analysis, interpretation of data, reviewing, and approval of the publication.</p><p>We apologize for this error.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186107","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":"Neuronal Damage Induced by Gradual Oxidative Stress in iPSC-Derived Neurons: Implications for Ferroptosis Involvement and ALS Drug Evaluation","authors":"Hayato Kobayashi,&nbsp;Hitoshi Suzuki-Masuyama,&nbsp;Hirokazu Tanabe,&nbsp;Hiroshi Kato,&nbsp;Setsu Endoh-Yamagami","doi":"10.1111/jnc.70246","DOIUrl":"10.1111/jnc.70246","url":null,"abstract":"<p>The molecular mechanisms underlying neurodegenerative diseases are not fully understood, but oxidative stress is known to play a central role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). In this study, we developed a method to induce gradual oxidative stress in induced pluripotent stem cell (iPSC)-derived motor neurons and cortical excitatory neurons by omitting antioxidants in the media, aiming to create a platform for studying oxidative stress-dependent neuronal damage in neurodegenerative diseases. Neuroprotective effects in this platform were observed with edaravone, an approved ALS medicine, in iPSC-derived motor neurons, suggesting its potential for ALS drug evaluation. The oxidative stress-induced neuronal damage was accompanied by increased lipid peroxidation, and it was suppressed by ferroptosis inhibitors and an iron-specific chelator, suggesting that neurons died through ferroptosis. Furthermore, through a compound screen, a cholesterol biosynthesis inhibitor, AY 9944, was identified as being capable of inhibiting neuronal damage induced by oxidative stress. Additionally, neuroprotective activity was observed with 7-dehydrocholesterol, an immediate precursor of cholesterol, while the efficacy of AY 9944 was compromised by knockout of the <i>EBP</i> gene, which encodes an enzyme involved in cholesterol biosynthesis. These findings suggest the involvement of ferroptosis in the progression of neurodegenerative diseases and the inhibition of ferroptosis by modulating the cholesterol biosynthesis pathway, providing potential insights for drug development.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 10","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186095","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}