Journal of Cerebral Blood Flow and Metabolism最新文献

{"title":"Aging alters calcium signaling in vascular mural cells and drives remodeling of neurovascular coupling in the awake brain.","authors":"Xiao Zhang, Lechan Tao, Amalie H Nygaard, Yiqiu Dong, Teddy Groves, Xiaoqi Hong, Carolyn M Goddard, Chen He, Dmitry Postnov, Ilary Allodi, Martin J Lauritzen, Changsi Cai","doi":"10.1177/0271678X251320455","DOIUrl":"10.1177/0271678X251320455","url":null,"abstract":"<p><p>Brain aging leads to reduced cerebral blood flow and cognitive decline, but how normal aging affects neurovascular coupling (NVC) in the awake brain is unclear. Here, we investigated NVC in relation to calcium changes in vascular mural cells (VMCs) in awake adult and aged mice. We show that NVC responses are reduced and prolonged in the aged brain and that this is more pronounced at the capillary level than in arterioles. However, the overall NVC response, measured as the time integral of vasodilation, is the same in the two age groups. In adult, but not in aged mice, the NVC response correlated with Ca2+ signaling in VMCs, while the overall Ca2+ kinetics were slower in aged than in adult mice. In particular, the rate of Ca2+ transport, and the Ca2+ sensitivity of VMCs were reduced in aged mice, explaining the reduced and prolonged vasodilation. Spontaneous locomotion was less frequent and reduced in aged mice as compared to young adult mice, and this was reflected in the 'slow but prolonged' NVC and vascular Ca2+ responses. Taken together, our data characterize the NVC in the aged, awake brain as slow but prolonged, highlighting the remodeling processes associated with aging.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1265-1280"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11826828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans.","authors":"Kristian Larsen, Ulrich Lindberg, Brice Ozenne, Drummond E McCulloch, Sophia Armand, Martin K Madsen, Annette Johansen, Dea S Stenbæk, Gitte M Knudsen, Patrick M Fisher","doi":"10.1177/0271678X251323364","DOIUrl":"10.1177/0271678X251323364","url":null,"abstract":"<p><p>Psilocin, the active metabolite of psilocybin, is a psychedelic and agonist at the serotonin 2A receptor (5-HT2AR) that has shown positive therapeutic effects for brain disorders such as depression. To elucidate the brain effects of psilocybin, we directly compared the acute effects of 5-HT2AR agonist (psilocybin) and antagonist (ketanserin) on cerebral blood flow (CBF) using pseudo-continuous arterial spin labeling magnetic resonance imaging (MRI) in a single-blind, cross-over study in 28 healthy participants. We evaluated associations between plasma psilocin level (PPL) or subjective drug intensity (SDI) and CBF. We also evaluated drug effects on internal carotid artery (ICA) diameter using time-of-flight MRI angiography. PPL and SDI were significantly negatively associated with regional and global CBF (∼11.6% at peak drug effect, p < 0.0001). CBF did not significantly change following ketanserin (2.3%, p = 0.35). Psilocybin induced a significantly greater decrease in CBF compared to ketanserin in the parietal cortex (p_FWER < 0.0001). ICA diameter was significantly decreased following psilocybin (10.5%, p < 0.0001) but not ketanserin (-0.02%, p = 0.99). Our data support an asymmetric 5-HT2AR modulatory effect on CBF and provide the first in vivo human evidence that psilocybin constricts the ICA, which has important implications for understanding the neurophysiological mechanisms underlying its acute effects.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1385-1401"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary to \"Task activation results in regional ¹³C-lactate signal increase in the human brain\".","authors":"Fahmeed Hyder","doi":"10.1177/0271678X251327935","DOIUrl":"10.1177/0271678X251327935","url":null,"abstract":"<p><p>Metabolism is fundamental to functional brain imaging. While functional MRI (fMRI) has greatly benefited neuroscience, ¹³C-MRS measures coupling between neuroenergetics and neurotransmission. However, a hyperpolarized ¹³C-MRI study in human brain shows increased ¹³C-lactate (i.e., cytosolic aerobic glycolysis) with no ¹³C-bicarbonate change (i.e., mitochondrial oxidation) within fMRI-defined activated areas. We discuss (dis)advantages of hyperpolarized vs. non-hyperpolarized ¹³C experiments and metabolic implications regarding the lactate increase: Is lactate a fuel for oligodendrocytes, astrocytes, or neurons? Is lactate a neuromodulator or a vasomodulator? Is lactate a byproduct of astrocytic glycogenolysis? Caveats aside, there is great enthusiasm for hyperpolarized ¹³C-fMRI.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1413-1416"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11993549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphodiesterase inhibition restores hypoxia-induced cerebrovascular dysfunction subsequent to improved systemic redox homeostasis: A randomized, double-blind, placebo-controlled crossover study.","authors":"Benjamin S Stacey, Christopher J Marley, Hayato Tsukamoto, Tony G Dawkins, Thomas S Owens, Thomas A Calverley, Lewis Fall, Angelo Iannetelli, Ifan Lewis, James M Coulson, Mike Stembridge, Damian M Bailey","doi":"10.1177/0271678X251313747","DOIUrl":"10.1177/0271678X251313747","url":null,"abstract":"<p><p>To what extent sildenafil, a selective inhibitor of the type-5 phosphodiesterase modulates systemic redox status and cerebrovascular function during acute exposure to hypoxia remains unknown. To address this, 12 healthy males (aged 24 ± 3 y) participated in a randomized, placebo-controlled crossover study involving exposure to both normoxia and acute (60 min) hypoxia (Fi<math><msub><mrow><mtext>O</mtext></mrow><mrow><mn>2</mn></mrow></msub></math> = 0.14), followed by oral administration of 50 mg sildenafil and placebo (double-blinded). Venous blood was sampled for the ascorbate radical (A^•-: electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (NO: ozone-based chemiluminescence). Transcranial Doppler ultrasound was employed to determine middle cerebral artery velocity (MCAv), cerebral delivery of oxygen <math><msub><mrow><mtext>(CDO</mtext></mrow><mrow><mn>2</mn></mrow></msub><mtext>),</mtext></math> dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to hypo/hypercapnia (CVR_{CO2HYPO/HYPER}). Cortical oxyhemoglobin (cO₂Hb) and oxygenation index (OI) were assessed using pulsed continuous wave near infra-red spectroscopy. Hypoxia decreased total plasma NO (<i>P = </i>0.008), <math><msub><mrow><mtext>CDO</mtext></mrow><mrow><mn>2</mn></mrow></msub></math> (<i>P</i> = <0.001) and cO₂Hb (<i>P = </i>0.005). In hypoxia, sildenafil selectively reduced A^•- (<i>P = </i>0.018) and MCA_V (<i>P = </i>0.018), and increased dCA metrics of low-frequency phase (<i>P = </i>0.029) and CVR_CO2HYPER (<i>P = </i>0.007) compared to hypoxia-placebo. Collectively, these findings provide evidence for a PDE-5 inhibitory pathway that enhances select aspects of cerebrovascular function in hypoxia subsequent to a systemic improvement in redox homeostasis and independent of altered vascular NO bioavailability.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1343-1356"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypocapnia, eucapnia and hypercapnia during \"Where's Waldo\" search paradigms: Neurovascular coupling across the cardiac cycle and biological sexes.","authors":"Nathan E Johnson, Joel S Burma, Matthew G Neill, Joshua J Burkart, Elizabeth Ks Fletcher, Jonathan D Smirl","doi":"10.1177/0271678X251318922","DOIUrl":"10.1177/0271678X251318922","url":null,"abstract":"<p><p>This investigation explored the impact of partial pressure of end-tidal carbon dioxide (P_ETCO₂) alterations on temporal neurovascular coupling (NVC) responses across the cardiac cycle and the influence of biological sex via a complex visual scene-search task (\"<i>Where's Waldo?</i>\"). 10 females and 10 males completed five puzzles, each with 40 seconds of eyes open and 20 seconds of eyes closed, under P_ETCO₂ clamped at ∼40 mmHg (eucapnia), ∼55 mmHg (hypercapnia), and ∼25 mmHg (hypocapnia). Cerebral blood velocity (CBv) in the middle and posterior cerebral arteries (MCAv, PCAv) were measured via Transcranial Doppler ultrasound. Linear mixed-effects models with participants as a random effect analyzed NVC metrics, including baseline and peak CBv, relative increase, and area-under-the-curve (AUC30). During hypercapnic trials, reductions in PCAv and MCAv AUC30 were noted across the cardiac cycle (all <i>p < 0.001</i>). Hypocapnic PCAv AUC30 was reduced (all <i>p < 0.012</i>), as was systolic MCAv AUC30 (<i>p = 0.003</i>). Females displayed greater baseline PCA diastole (<i>p = 0.048</i>). No other biological sex differences were observed across conditions in baseline (all <i>p > 0.050</i>), peak (all <i>p</i> > <i>0.054</i>), relative increase (all <i>p > 0.511</i>), and AUC30 metrics (all <i>p > 0.514</i>). Despite differences in responses to hypercapnic and hypocapnic stimuli, NVC responses to complex visual tasks remain robust, across the physiological CO₂ range.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1310-1325"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclooxygenase-1 and cyclooxygenase-2 densities measured using positron emission tomography are not altered in the brains of individuals with stable multiple sclerosis.","authors":"Shiyu Tang, Daniel M Harrison, Amanda Bardhoshi, Raven Cureton, Xuefeng Yan, Paul A Parcon, Cheryl L Morse, Christina Ecker, Seongjin Choi, Victor W Pike, Robert B Innis, Paolo Zanotti-Fregonara","doi":"10.1177/0271678X251332490","DOIUrl":"10.1177/0271678X251332490","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system that involves immune-mediated demyelination and axonal degeneration. Clinical imaging techniques play a critical role in diagnosing and assessing the prognosis of MS. Magnetic resonance imaging has been most frequently used to visualize demyelination and detect acute and chronic active lesions, which are key indicators of clinical course of illness. Previous research has also highlighted the effectiveness of translocator protein 18-kDa (TSPO) positron emission tomography (PET) imaging for identifying chronic active lesions and progressive pathology. Building on this work, the present study used PET imaging to explore the role of cyclooxygenase-1 and -2 (COX-1 and COX-2)-key enzymes involved in neuroinflammation-in individuals with MS. Five participants with MS were recruited, and lesions were identified using 7 Tesla MRI. No significant differences in COX radioligand binding were observed in the co-registered PET images between lesioned areas and normal-appearing brain tissues, nor between individuals with MS and healthy volunteers. The negative findings underscore the complexity of MS pathology and raise several important considerations for planning future studies using COX PET for imaging in MS.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1417-1427"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Task activation results in regional ¹³C-lactate signal increase in the human brain.","authors":"Biranavan Uthayakumar, Nicole Ic Cappelletto, Nadia D Bragagnolo, Albert P Chen, Nathan Ma, William J Perks, Ruby Endre, Fred Tam, Simon J Graham, Chris Heyn, Kayvan R Keshari, Hany Soliman, Charles H Cunningham","doi":"10.1177/0271678X251314683","DOIUrl":"10.1177/0271678X251314683","url":null,"abstract":"<p><p>Hyperpolarized-¹³C magnetic resonance imaging (HP-¹³C MRI) was used to image changes in ¹³C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain ¹³C-pyruvate, ¹³C-lactate and ¹³C-bicarbonate production was imaged in healthy volunteers (N = 6, ages 24-33) for the two conditions using two separate hyperpolarized ¹³C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. ¹³C-metabolite signal was normalized by ¹³C-metabolite signal from the brainstem and the percentage change in ¹³C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in ¹³C-lactate in regions of activation when compared to the remainder of the brain (<math><mi>p</mi><mo>=</mo><mn>0.02</mn></math>). No significant increase was observed in ¹³C-pyruvate signal (<math><mi>p</mi><mo>=</mo><mn>0.11</mn></math>) or ¹³C-bicarbonate signal (<math><mi>p</mi><mo>=</mo><mn>0.95</mn></math>). The results show an increase in ¹³C-lactate production in activated regions that is measurable with HP-¹³C MRI.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1223-1231"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11765303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo two-photon microscopy imaging of focused ultrasound-mediated glymphatic transport in the mouse brain.","authors":"Yan Gong, Kevin Xu, Dezhuang Ye, Yaoheng Yang, Mark J Miller, Ziang Feng, Song Hu, Hong Chen","doi":"10.1177/0271678X251323369","DOIUrl":"10.1177/0271678X251323369","url":null,"abstract":"<p><p>The glymphatic system regulates cerebrospinal fluid (CSF) transport and brain waste clearance. Focused ultrasound combined with microbubbles (FUSMB) has shown feasibility for manipulating glymphatic transport, yet its mechanisms remain poorly understood. In this work, we used in vivo two-photon microscopy to reveal how FUSMB manipulates the CSF tracer transport in the mouse brain. A FUS transducer was confocally aligned with the objective of a two-photon microscope. Fluorescently labeled albumin was infused into the CSF via cisterna magna. FUS sonication was applied following an intravenous injection of microbubbles. Dynamic imaging was performed through a cranial window to record local changes in vessel and tracer dynamics. The fluorescence intensity of the CSF tracer within the treated region decreased rapidly upon FUSMB treatment. Concurrently, vessel deformation was observed, and the fastest diameter changes were observed during FUSMB treatment. A linear correlation was identified between the rate of vessel diameter change and the rate of tracer intensity change. Moreover, given the same rate of vessel diameter change, the tracer intensity changed faster around larger vessels than smaller vessels. These findings offer insight into the potential biophysical mechanism of FUSMB-mediated glymphatic transport.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1281-1292"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early metabolic changes in the brain of Alzheimer's disease rats are driven by GLAST+ cells.","authors":"William J Morrey, Kelly Ceyzériat, Quentin Amossé, Aurélien M Badina, Ben Dickie, Ingo Schiessl, Stergios Tsartsalis, Philippe Millet, Hervé Boutin, Benjamin B Tournier","doi":"10.1177/0271678X251318923","DOIUrl":"10.1177/0271678X251318923","url":null,"abstract":"<p><p>Glucose metabolic dysfunction is a hallmark of Alzheimer's disease (AD) pathology and is used to diagnose the disease or predict imminent cognitive decline. The main method to measure brain metabolism <i>in vivo</i> is positron emission tomography with 2-Deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG-PET). The cellular origin of changes in the [¹⁸F]FDG-PET signal in AD is controversial. We addressed this by combining [¹⁸F]FDG-PET with subsequent cell-sorting and γ-counting of [¹⁸F]FDG-accumulation in sorted cell populations. 7-month-old male TgF344-AD rats and wild-type controls (n = 24/group) received sham or ceftriaxone (200 mg/kg) injection prior to [¹⁸F]FDG-PET imaging to increase glutamate uptake and glucose utilisation. The same animals were injected again one week later, and radiolabelled brains were dissected, with hippocampi taken for magnetically-activated cell sorting of radioligand-treated tissues (MACS-RTT). Radioactivity in sorted cell populations was measured to quantify cell-specific [¹⁸F]FDG uptake. Transcriptional analyses of metabolic enzymes/transporters were also performed. <i>Hypo</i>metabolism in the frontal association cortex of TgF344-AD rats was identified using [¹⁸F]FDG-PET, whereas <i>hyper</i>metabolism was identified in the hippocampus using MACS-RTT. Hypermetabolism was primarily driven by GLAST+ cells. This was supported by transcriptional analyses which showed alteration to metabolic apparatus, including upregulation of hexokinase 2 and altered expression of glucose/lactate transporters. See Figure 1 for summary.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1326-1342"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The miR-451a facilitates natural killer cell-associated immune deficiency after ischemic stroke.","authors":"Yan Li, Xiuchen Guan, Tian Lan, Zhuo-Ran Zhang, Ying Zhang, Shihe Jiang, Minshu Li, Fu-Dong Shi, Wei-Na Jin","doi":"10.1177/0271678X251321641","DOIUrl":"10.1177/0271678X251321641","url":null,"abstract":"<p><p>Ischemic stroke is a devastating neurological disease. Brain ischemia impairs systemic immune responses and heightens susceptibility to infections, though the underlying mechanisms remain incompletely understood. Natural killer (NK) cells exhibited decreased frequency and compromised function after acute stage of stroke, resulting in NK cell-associated immune deficiency and increased risk of infection. MicroRNAs (miRNAs) are post-transcriptional molecular modulators. Our previous study revealed a significant upregulation of miR-451a in circulating NK cells from patients with ischemic stroke, but its effects and precise mechanism on immune defense remain elusive. In this study, we observed a substantial elevation of miR-451a level in brain and splenic NK cells in murine model of ischemic stroke miR-451a mimics suppressed NK cell activation and cytotoxicity within the ischemic brain and periphery, including a downregulation of activation marker CD69, and reduced production of effector molecules IFN-γ and perforin. Conversely, miR-451a inhibitor preserved NK cell activation and cytotoxicity, rescuing local inflammation, and reducing bacterial burden in the lung. Pharmacological inhibition of Akt-mTOR pathway with AZD8055 effectively blocked the impacts of miR-451a on NK cell functions. Collectively, these findings suggest miR-451a negatively regulates NK cell cytotoxicity in both the brain and periphery, which could be re-addressed by modulating the Akt-mTOR signaling pathway.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":" ","pages":"1371-1384"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}