Skip to content
2000
Volume 26, Issue 5
  • ISSN: 1389-2037
  • E-ISSN: 1875-5550

Abstract

Stroke is an acute cerebrovascular disease that causes brain tissue damage due to sudden blockage or rupture of blood vessels in the brain. According to the latest data from the Global Burden of Disease Study, the number of stroke patients worldwide is estimated to exceed 100 million, and more than 80% of patients suffer from stroke. Ischemic stroke is a type of stroke due to which two-thirds of the patients are disabled or even die, seriously affecting the patient's quality of life. Lactate is an indispensable substance in various physiological and pathological cells and plays a regulatory role in different aspects of energy metabolism and signal transduction. Studies have found that during cerebral ischemia and hypoxia, lactate concentration increases significantly, improving the energy supply to the ischemic area. Based on the scientific concept of lactate travelling through the brain, this article focuses on the important role of lactate as an energy source after ischemic stroke and analyzes the relationship between lactate as a signaling molecule and neuroprotection, angiogenesis, and anti-inflammatory effects. The aim of this study is to outline the molecular mechanisms by which lactate exerts its different effects in ischemic stroke. Some references are provided in this study for the research on lactate therapy for ischemic stroke.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cpps/10.2174/0113892037335945241029111720
2025-01-02
2025-09-04

  • From This Site

    /content/journals/cpps/10.2174/0113892037335945241029111720
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ZhaoY. ZhangX. ChenX. WeiY. Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment.Int. J. Mol. Med.20214921510.3892/ijmm.2021.5070
     [Google Scholar]
  2. AnnoniF. PelusoL. Gouvêa BogossianE. CreteurJ. ZanierE.R. TacconeF.S. Brain protection after anoxic brain injury: Is lactate supplementation helpful?Cells2021107171410.3390/cells10071714
     [Google Scholar]
  3. NovorolskyR.J. KashekeG.D.S. HakimA. FoldvariM. DorighelloG.G. SeklerI. VuligondaV. SandersM.E. RendenR.B. WilsonJ.J. RobertsonG.S. Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery.Front. Cell. Neurosci.202317122663010.3389/fncel.2023.1226630
     [Google Scholar]
  4. MelkonianE.A. SchuryM.P. Biochemistry, Anaerobic Glycolysis.StatPearlsTreasure Island (FL): StatPearls Publishing2023
     [Google Scholar]
  5. ZhaoX. LiS. MoY. LiR. HuangS. ZhangA. NiX. DaiQ. WangJ. DCA protects against oxidation injury attributed to cerebral ischemia-reperfusion by regulating glycolysis through PDK2-PDH-Nrf2 axis.Oxid. Med. Cell. Longev.202120211517303510.1155/2021/5173035
     [Google Scholar]
  6. RogatzkiM.J. FergusonB.S. GoodwinM.L. GladdenL.B. Lactate is always the end product of glycolysis.Front. Neurosci.201592210.3389/fnins.2015.00022
     [Google Scholar]
  7. FantinV.R. St-PierreJ. LederP. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.Cancer Cell20069642543410.1016/j.ccr.2006.04.02316766262
     [Google Scholar]
  8. LibertiM.V. LocasaleJ.W. The warburg effect: How does it benefit cancer cells?Trends Biochem. Sci.201641321121810.1016/j.tibs.2015.12.001PMC4783224
     [Google Scholar]
  9. LachmandasE. Beigier-BompadreM. ChengS.C. KumarV. van LaarhovenA. WangX. AmmerdorfferA. BoutensL. de JongD. KannegantiT.D. GresnigtM.S. OttenhoffT.H.M. JoostenL.A.B. StienstraR. WijmengaC. KaufmannS.H.E. van CrevelR. NeteaM.G. Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells.Eur. J. Immunol.201646112574258610.1002/eji.201546259
     [Google Scholar]
  10. ExleyR.M. GoodwinL. MoweE. ShawJ. SmithH. ReadR.C. TangC.M. Neisseria meningitidis lactate permease is required for nasopharyngeal colonization.Infect. Immun.20057395762576610.1128/IAI.73.9.5762‑5766.2005
     [Google Scholar]
  11. WuY. MaW. LiuW. ZhangS. Lactate: a pearl dropped in the ocean—an overlooked signal molecule in physiology and pathology.Cell Biol. Int.202347229530710.1002/cbin.11975
     [Google Scholar]
  12. SmithD. PernetA. HallettW.A. BinghamE. MarsdenP.K. AmielS.A. Lactate: A preferred fuel for human brain metabolism in vivo.J. Cereb. Blood Flow Metab.200323665866410.1097/01.WCB.0000063991.19746.11
     [Google Scholar]
  13. BoumezbeurF. PetersenK.F. ClineG.W. MasonG.F. BeharK.L. ShulmanG.I. RothmanD.L. The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy.J. Neurosci.20103042139831399110.1523/JNEUROSCI.2040‑10.2010
     [Google Scholar]
  14. SchurrA. MillerJ.J. PayneR.S. RigorB.M. An increase in lactate output by brain tissue serves to meet the energy needs of glutamate-activated neurons.J. Neurosci.1999191343910.1523/JNEUROSCI.19‑01‑00034.1999
     [Google Scholar]
  15. LeeT.Y. Lactate: a multifunctional signaling molecule.Yeungnam Univ. J. Med.202138318319310.12701/yujm.2020.00892
     [Google Scholar]
  16. MedinaJ.M. TaberneroA. Lactate utilization by brain cells and its role in CNS development.J. Neurosci. Res.2005791-221010.1002/jnr.20336
     [Google Scholar]
  17. ChengA. LuY. HuangQ. ZuoZ. Attenuating oxygen-glucose deprivation-caused autophagosome accumulation may be involved in sevoflurane postconditioning-induced protection in human neuron-like cells.Eur. J. Pharmacol.2019849849510.1016/j.ejphar.2019.01.051
     [Google Scholar]
  18. BanerjeeA. GhatakS. SikdarS.K. l -Lactate mediates neuroprotection against ischaemia by increasing TREK 1 channel expression in rat hippocampal astrocytes in vitro.J. Neurochem.2016138226528110.1111/jnc.13638
     [Google Scholar]
  19. FanH. YangF. XiaoZ. LuoH. ChenH. ChenZ. LiuQ. XiaoY. Lactylation: novel epigenetic regulatory and therapeutic opportunities.Am. J. Physiol. Endocrinol. Metab.20233244E330E33810.1152/ajpendo.00159.2022
     [Google Scholar]
  20. RabinowitzJ.D. EnerbäckS. Lactate: the ugly duckling of energy metabolism.Nat. Metab.20202756657110.1038/s42255‑020‑0243‑4
     [Google Scholar]
  21. MonsornoK. BuckinxA. PaolicelliR.C. Microglial metabolic flexibility: emerging roles for lactate.Trends Endocrinol. Metab.202233318619510.1016/j.tem.2021.12.001
     [Google Scholar]
  22. BrooksG.A. Lactate production under fully aerobic conditions: the lactate shuttle during rest and exercise.Fed. Proc.1986451329242929
     [Google Scholar]
  23. ZhouY. LiuX. HuangC. LinD. Lactate activates AMPK remodeling of the cellular metabolic profile and promotes the proliferation and differentiation of C2Cl2 Myoblasts.Int. J. Mol. Sci.202223221399610.3390/ijms232213996
     [Google Scholar]
  24. BrooksG.A. Cell–cell and intracellular lactate shuttles.J. Physiol.2009587235591560010.1113/jphysiol.2009.178350
     [Google Scholar]
  25. FelmleeM.A. JonesR.S. Rodriguez-CruzV. FollmanK.E. MorrisM.E. Monocarboxylate transporters (SLC16): Function, regulation, and role in health and disease.Pharmacol. Rev.202072246648510.1124/pr.119.018762
     [Google Scholar]
  26. Cortés-CamposC. ElizondoR. LlanosP. UrangaR.M. NualartF. GarcíaM.A. MCT expression and lactate influx/efflux in tanycytes involved in glia-neuron metabolic interaction.PLoS One201161e1641110.1371/journal.pone.0016411
     [Google Scholar]
  27. HalestrapA.P. The SLC16 gene family – Structure, role and regulation in health and disease.Mol. Aspects Med.2013342-333734910.1016/j.mam.2012.05.003
     [Google Scholar]
  28. HuiS. GhergurovichJ.M. MorscherR.J. JangC. TengX. LuW. EsparzaL.A. ReyaT. Le Zhan Yanxiang GuoJ. WhiteE. RabinowitzJ.D. Glucose feeds the TCA cycle via circulating lactate.Nature2017551767811511810.1038/nature24057
     [Google Scholar]
  29. FaubertB. LiK.Y. CaiL. HensleyC.T. KimJ. ZachariasL.G. YangC. DoQ.N. DoucetteS. BurgueteD. LiH. HuetG. YuanQ. WigalT. ButtY. NiM. TorrealbaJ. OliverD. LenkinskiR.E. MalloyC.R. WachsmannJ.W. YoungJ.D. KernstineK. DeBerardinisR.J. Lactate metabolism in human lung tumors.Cell20171712358371.e910.1016/j.cell.2017.09.019
     [Google Scholar]
  30. LuJ. TanM. CaiQ. The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism.Cancer Lett.201535622 Pt A15616410.1016/j.canlet.2014.04.001
     [Google Scholar]
  31. ShenY. DinhH.V. CruzE.R. ChenZ. BartmanC.R. XiaoT. CallC.M. RyseckR.P. PratasJ. WeilandtD. BaronH. SubramanianA. FatmaZ. WuZ.Y. DwaraknathS. HendryJ.I. TranV.G. YangL. YoshikuniY. ZhaoH. MaranasC.D. WührM. RabinowitzJ.D. Mitochondrial ATP generation is more proteome efficient than glycolysis.Nat. Chem. Biol.20242091123113210.1038/s41589‑024‑01571‑y
     [Google Scholar]
  32. Gómez-ValadésA.G. PozoM. VarelaL. BoudjadjaM.B. RamírezS. ChiviteI. EyreE. Haddad-TóvolliR. ObriA. Milà-GuaschM. AltirribaJ. SchneebergerM. ImbernónM. Garcia-RenduelesA.R. Gama-PerezP. Rojo-RuizJ. RáczB. AlonsoM.T. GomisR. ZorzanoA. D’AgostinoG. AlvarezC.V. NogueirasR. Garcia-RovesP.M. HorvathT.L. ClaretM. Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis.Cell Metab.202133918201835.e910.1016/j.cmet.2021.07.008
     [Google Scholar]
  33. TakadoY. ChengT. BastiaansenJ.A.M. YoshiharaH.A.I. LanzB. MishkovskyM. LengacherS. CommentA. Hyperpolarized 13C magnetic resonance spectroscopy reveals the rate-limiting role of the blood–brain barrier in the cerebral uptake and metabolism of l-lactate in vivo.ACS Chem. Neurosci.20189112554256210.1021/acschemneuro.8b00066
     [Google Scholar]
  34. Muñoz ManiegaS. CvoroV. ChappellF.M. ArmitageP.A. MarshallI. BastinM.E. WardlawJ.M. Changes in NAA and lactate following ischemic stroke.Neurology200871241993199910.1212/01.wnl.0000336970.85817.4a
     [Google Scholar]
  35. LiY. WangT. ZhangT. LinZ. LiY. GuoR. ZhaoY. MengZ. LiuJ. YuX. LiangZ.P. NachevP. Fast high-resolution metabolic imaging of acute stroke with 3D magnetic resonance spectroscopy.Brain2020143113225323310.1093/brain/awaa264
     [Google Scholar]
  36. KannO. Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations.J. Neurochem.20241685603-63110.1111/jnc.15867
     [Google Scholar]
  37. MedelV. CrossleyN. GajardoI. MullerE. BarrosL.F. ShineJ.M. SierraltaJ. Whole-brain neuronal MCT2 lactate transporter expression links metabolism to human brain structure and function.Proc. Natl. Acad. Sci. USA202211933e220461911910.1073/pnas.2204619119
     [Google Scholar]
  38. BergersenL.H. Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle.Neuroscience20071451111910.1016/j.neuroscience.2006.11.062
     [Google Scholar]
  39. LauritzenF. EidT. BergersenL.H. Monocarboxylate transporters in temporal lobe epilepsy: roles of lactate and ketogenic diet.Brain Struct. Funct.2015220111210.1007/s00429‑013‑0672‑x
     [Google Scholar]
  40. ZhangM. WangY. BaiY. DaiL. GuoH. Monocarboxylate transporter 1 may benefit cerebral ischemia via facilitating lactate transport from glial cells to neurons.Front. Neurol.20221378106310.3389/fneur.2022.781063
     [Google Scholar]
  41. RamljakS. SchmitzM. RepondC. ZerrI. PellerinL. Altered mRNA and protein expression of monocarboxylate transporter MCT1 in the cerebral cortex and cerebellum of prion protein knockout mice.Int. J. Mol. Sci.2021224156610.3390/ijms22041566
     [Google Scholar]
  42. PellerinL MagistrettiPJ Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.Proc. Natl. Acad. Sci. USA1994912210625910.1073/pnas.91.22.10625
     [Google Scholar]
  43. ArdanazC.G. RamírezM.J. SolasM. Brain metabolic alterations in Alzheimer’s disease.Int. J. Mol. Sci.2022237378510.3390/ijms23073785
     [Google Scholar]
  44. DebernardiR. PierreK. LengacherS. MagistrettiP.J. PellerinL. Cell-specific expression pattern of monocarboxylate transporters in astrocytes and neurons observed in different mouse brain cortical cell cultures.J. Neurosci. Res.200373214115510.1002/jnr.10660
     [Google Scholar]
  45. DienelG.A. The metabolic trinity, glucose–glycogen–lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression.Neurosci. Lett.2017637182510.1016/j.neulet.2015.02.052
     [Google Scholar]
  46. KaragiannisA. SylantyevS. HadjihambiA. HosfordP.S. KasparovS. GourineA.V. Hemichannel-mediated release of lactate.J. Cereb. Blood Flow Metab.20163671202121110.1177/0271678X15611912
     [Google Scholar]
  47. Veloz CastilloM.F. MagistrettiP.J. CalìC. l-Lactate: Food for thoughts, memory and behavior.Metabolites202111854810.3390/metabo11080548
     [Google Scholar]
  48. MasonS. Lactate shuttles in neuroenergetics—homeostasis, allostasis and beyond.Front. Neurosci.2017114310.3389/fnins.2017.00043
     [Google Scholar]
  49. MahmoudS. GharagozlooM. SimardC. GrisD. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release.Cells20198218410.3390/cells8020184
     [Google Scholar]
  50. HanssonE. RönnbäckL. Astrocytes in glutamate neurotransmission.FASEB J.19959534335010.1096/fasebj.9.5.7534736
     [Google Scholar]
  51. Sotelo-HitschfeldT. NiemeyerM.I. MächlerP. RuminotI. LerchundiR. WyssM.T. StobartJ. Fernández-MoncadaI. ValdebenitoR. Garrido-GerterP. Contreras-BaezaY. SchneiderB.L. AebischerP. LengacherS. San MartínA. Le DouceJ. BonventoG. MagistrettiP.J. SepúlvedaF.V. WeberB. BarrosL.F. Channel-mediated lactate release by K+-stimulated astrocytes.J. Neurosci.201535104168417810.1523/JNEUROSCI.5036‑14.2015
     [Google Scholar]
  52. RouachN. KoulakoffA. AbudaraV. WilleckeK. GiaumeC. Astroglial metabolic networks sustain hippocampal synaptic transmission.Science200832259071551155510.1126/science.1164022
     [Google Scholar]
  53. PrichardJ RothmanD NovotnyE Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation.Proc Natl Acad Sci1991881358293110.1073/pnas.88.13.5829
     [Google Scholar]
  54. HuY WilsonGS A temporary local energy pool coupled to neuronal activity: fluctuations of extracellular lactate levels in rat brain monitored with rapid-response enzyme-based sensor.J Neurochem.1997694148490
     [Google Scholar]
  55. RosJ. PecinskaN. AlessandriB. LandoltH. FillenzM. Lactate reduces glutamate-induced neurotoxicity in rat cortex.J. Neurosci. Res.200166579079410.1002/jnr.10043
     [Google Scholar]
  56. JourdainP. AllamanI. RothenfusserK. FiumelliH. MarquetP. MagistrettiP.J. L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade.Sci. Rep.2016612125010.1038/srep21250
     [Google Scholar]
  57. MagistrettiP.J. AllamanI. Lactate in the brain: from metabolic end-product to signalling molecule.Nat. Rev. Neurosci.201819423524910.1038/nrn.2018.19
     [Google Scholar]
  58. BonventoG. BolañosJ.P. Astrocyte-neuron metabolic cooperation shapes brain activity.Cell Metab.20213381546156410.1016/j.cmet.2021.07.006
     [Google Scholar]
  59. MagistrettiP.J. PellerinL. Astrocytes couple synaptic activity to glucose utilization in the brain.Physiology (Bethesda)199914517718210.1152/physiologyonline.1999.14.5.177
     [Google Scholar]
  60. ZhouJ. ZhangL. PengJ. ZhangX. ZhangF. WuY. HuangA. DuF. LiaoY. HeY. XieY. GuL. KuangC. OuW. XieM. TuT. PangJ. ZhangD. GuoK. FengY. YinS. CaoY. LiT. JiangY. Astrocytic LRP1 enables mitochondria transfer to neurons and mitigates brain ischemic stroke by suppressing ARF1 lactylation.Cell Metab.202436920542068.e1410.1016/j.cmet.2024.05.016
     [Google Scholar]
  61. YaoZ.M. SunX.R. HuangJ. ChenL. DongS.Y. Astrocyte-neuronal communication and its role in stroke.Neurochem. Res.202348102996300610.1007/s11064‑023‑03966‑0
     [Google Scholar]
  62. XueX. LiuB. HuJ. BianX. LouS. The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule.Nutr. Metab. (Lond.)20221915210.1186/s12986‑022‑00687‑z
     [Google Scholar]
  63. PatchingS.G. Glucose transporters at the blood-brain barrier: Function, regulation and gateways for drug delivery.Mol. Neurobiol.20175421046107710.1007/s12035‑015‑9672‑6
     [Google Scholar]
  64. ShiC. XuJ. DingY. ChenX. YuanF. ZhuF. DuanC. HuJ. LuH. WuT. JiangL. MCT1-mediated endothelial cell lactate shuttle as a target for promoting axon regeneration after spinal cord injury.Theranostics202414145662568110.7150/thno.96374
     [Google Scholar]
  65. RoumesH PellerinL Bouzier-SoreAK Neuroprotective role of lactate in neonatal hypoxia-ischemia.Med Sci2020361197397610.1051/medsci/2020179
     [Google Scholar]
  66. WangJ. CuiY. YuZ. WangW. ChengX. JiW. GuoS. ZhouQ. WuN. ChenY. ChenY. SongX. JiangH. WangY. LanY. ZhouB. MaoL. LiJ. YangH. GuoW. YangX. Brain endothelial cells maintain lactate homeostasis and control adult hippocampal neurogenesis.Cell Stem Cell2019256754767.e910.1016/j.stem.2019.09.009
     [Google Scholar]
  67. TsengM.T. ChanS.A. SchurrA. Ischemia-induced changes in monocarboxylate transporter 1 reactive cells in rat hippocampus.Neurol. Res.2003251838610.1179/016164103101200978
     [Google Scholar]
  68. PucinoV. BombardieriM. PitzalisC. MauroC. Lactate at the crossroads of metabolism, inflammation, and autoimmunity.Eur. J. Immunol.2017471142110.1002/eji.201646477
     [Google Scholar]
  69. SofroniewM.V. Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci.2009321263864710.1016/j.tins.2009.08.002
     [Google Scholar]
  70. ZhangG. QinQ. ZhangC. SunX. KazamaK. YiB. ChengF. GuoZ.F. SunJ. NDRG1 signaling is essential for endothelial inflammation and vascular remodeling.Circ. Res.2023132330631910.1161/CIRCRESAHA.122.321837
     [Google Scholar]
  71. FlüggeG. Araya-CallisC. Garea-RodriguezE. Stadelmann-NesslerC. FuchsE. NDRG2 as a marker protein for brain astrocytes.Cell Tissue Res.20143571314110.1007/s00441‑014‑1837‑5
     [Google Scholar]
  72. ZhangZ. MaZ. ZouW. ZhangL. LiY. ZhangJ. LiuM. HouW. MaY. N-myc downstream-regulated gene 2 controls astrocyte morphology via Rho-GTPase signaling.J. Cell. Physiol.201923411208472085810.1002/jcp.28689
     [Google Scholar]
  73. Takarada-IemataM. YoshikawaA. TaH.M. OkitaniN. NishiuchiT. AidaY. KamideT. HattoriT. IshiiH. TamataniT. LeT.M. RoboonJ. KitaoY. MatsuyamaT. NakadaM. HoriO. N-myc downstream-regulated gene 2 protects blood–brain barrier integrity following cerebral ischemia.Glia20186671432144610.1002/glia.23315
     [Google Scholar]
  74. YinA. GuoH. TaoL. CaiG. WangY. YaoL. XiongL. ZhangJ. LiY. NDRG2 protects the brain from excitotoxicity by facilitating interstitial glutamate uptake.Transl. Stroke Res.202011221422710.1007/s12975‑019‑00708‑9
     [Google Scholar]
  75. XuJ. JiT. LiG. ZhangH. ZhengY. LiM. MaJ. LiY. ChiG. Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen–glucose deprivation conditions.J. Neuroinflammation202219131410.1186/s12974‑022‑02678‑6
     [Google Scholar]
  76. KwonH.S. KohS.H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes.Transl. Neurodegener.2020914210.1186/s40035‑020‑00221‑2
     [Google Scholar]
  77. AndersonM.A. BurdaJ.E. RenY. AoY. O’SheaT.M. KawaguchiR. CoppolaG. KhakhB.S. DemingT.J. SofroniewM.V. Astrocyte scar formation aids central nervous system axon regeneration.Nature2016532759819520010.1038/nature17623
     [Google Scholar]
  78. SwansonR. YingW. KauppinenT. Astrocyte influences on ischemic neuronal death.Curr. Mol. Med.20044219320510.2174/1566524043479185
     [Google Scholar]
  79. WuX. ChenP.S. DallasS. WilsonB. BlockM.L. WangC.C. KinyamuH. LuN. GaoX. LengY. ChuangD.M. ZhangW. LuR.B. HongJ.S. Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons.Int. J. Neuropsychopharmacol.20081181123113410.1017/S1461145708009024
     [Google Scholar]
  80. RosenbergP.A. AizenmanE. Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex.Neurosci. Lett.1989103216216810.1016/0304‑3940(89)90569‑72570387
     [Google Scholar]
  81. ChenY. VartiainenN.E. YingW. ChanP.H. KoistinahoJ. SwansonR.A. Astrocytes protect neurons from nitric oxide toxicity by a glutathione-dependent mechanism.J. Neurochem.20017761601161010.1046/j.1471‑4159.2001.00374.x
     [Google Scholar]
  82. de PabloY. NilssonM. PeknaM. PeknyM. Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen–glucose deprivation and reperfusion.Histochem. Cell Biol.20131401819110.1007/s00418‑013‑1110‑0
     [Google Scholar]
  83. DringenR. BrandmannM. HohnholtM.C. BlumrichE.M. Glutathione-dependent detoxification processes in astrocytes.Neurochem. Res.201540122570258210.1007/s11064‑014‑1481‑1
     [Google Scholar]
  84. LiuJ.H. ZhangM. WangQ. WuD.Y. JieW. HuN.Y. LanJ.Z. ZengK. LiS.J. LiX.W. YangJ.M. GaoT.M. Distinct roles of astroglia and neurons in synaptic plasticity and memory.Mol. Psychiatry202227287388510.1038/s41380‑021‑01332‑6
     [Google Scholar]
  85. SabaJ. TuratiJ. RamírezD. CarnigliaL. DurandD. LasagaM. CarusoC. Astrocyte truncated tropomyosin receptor kinase B mediates brain-derived neurotrophic factor anti-apoptotic effect leading to neuroprotection.J. Neurochem.2018146668670210.1111/jnc.14476
     [Google Scholar]
  86. CocoM. CaggiaS. MusumeciG. PerciavalleV. GrazianoA.C.E. PannuzzoG. CardileV. Sodium L-lactate differently affects brain-derived neurothrophic factor, inducible nitric oxide synthase, and heat shock protein 70 kDa production in human astrocytes and SH-SY5Y cultures.J. Neurosci. Res.201391231332010.1002/jnr.23154
     [Google Scholar]
  87. TufekciK.U. Civi BayinE. GencS. GencK. The Nrf2/ARE pathway: A promising target to counteract mitochondrial dysfunction in Parkinson’s disease.Parkinsons Dis.2011201111410.4061/2011/314082
     [Google Scholar]
  88. SongH. StevensC.F. GageF.H. Astroglia induce neurogenesis from adult neural stem cells.Nature20024176884394410.1038/417039a
     [Google Scholar]
  89. MauchD.H. NäglerK. SchumacherS. GöritzC. MüllerE.C. OttoA. PfriegerF.W. CNS synaptogenesis promoted by glia-derived cholesterol.Science200129455451354135710.1126/science.294.5545.1354
     [Google Scholar]
  90. ChristophersonK.S. UllianE.M. StokesC.C.A. MullowneyC.E. HellJ.W. AgahA. LawlerJ. MosherD.F. BornsteinP. BarresB.A. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.Cell2005120342143310.1016/j.cell.2004.12.020
     [Google Scholar]
  91. LinT.N. KimG.M. ChenJ.J. CheungW.M. HeY.Y. HsuC.Y. Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion.Stroke200334117786
     [Google Scholar]
  92. BeardE. LengacherS. DiasS. MagistrettiP.J. FinsterwaldC. Astrocytes as key regulators of brain energy metabolism: New therapeutic perspectives.Front. Physiol.20221282581610.3389/fphys.2021.82581635087428
     [Google Scholar]
  93. AlmeidaA. MoncadaS. BolañosJ.P. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway.Nat. Cell Biol.200461455110.1038/ncb1080
     [Google Scholar]
  94. XuJ. ZhengY. LvS. KangJ. YuY. HouK. LiY. ChiG. Lactate promotes reactive astrogliosis and confers axon guidance potential to astrocytes under oxygen-glucose deprivation.Neuroscience2020442546810.1016/j.neuroscience.2020.06.041
     [Google Scholar]
  95. SchurrA. WestC.A. RigorB.M. Lactate-supported synaptic function in the rat hippocampal slice preparation.Science198824048571326132810.1126/science.3375817
     [Google Scholar]
  96. ShettyP.K. GaleffiF. TurnerD.A. Cellular links between neuronal activity and energy homeostasis.Front. Pharmacol.201234310.3389/fphar.2012.00043
     [Google Scholar]
  97. ZhouX. MoonC. ZhengF. LuoY. SoellnerD. NuñezJ.L. WangH. N-methyl-D-aspartate-stimulated ERK1/2 signaling and the transcriptional up-regulation of plasticity-related genes are developmentally regulated following in vitro neuronal maturation.J. Neurosci. Res.200987122632264410.1002/jnr.22103
     [Google Scholar]
  98. MagistrettiP.J. AllamanI. A cellular perspective on brain energy metabolism and functional imaging.Neuron201586488390110.1016/j.neuron.2015.03.035
     [Google Scholar]
  99. YangJ. RuchtiE. PetitJ.M. JourdainP. GrenninglohG. AllamanI. MagistrettiP.J. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons.Proc. Natl. Acad. Sci. USA201411133122281223310.1073/pnas.1322912111
     [Google Scholar]
  100. JourdainP. RothenfusserK. Ben-AdibaC. AllamanI. MarquetP. MagistrettiP.J. Dual action of L-Lactate on the activity of NR2B-containing NMDA receptors: from potentiation to neuroprotection.Sci. Rep.2018811347210.1038/s41598‑018‑31534‑y
     [Google Scholar]
  101. MargineanuM.B. MahmoodH. FiumelliH. MagistrettiP.J. L-lactate regulates the expression of synaptic plasticity and neuroprotection genes in cortical neurons: A transcriptome analysis.Front. Mol. Neurosci.20181137510.3389/fnmol.2018.00375
     [Google Scholar]
  102. BélangerM. AllamanI. MagistrettiP.J. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation.Cell Metab.201114672473810.1016/j.cmet.2011.08.016
     [Google Scholar]
  103. BergersenL.H. Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction.J. Cereb. Blood Flow Metab.201535217618510.1038/jcbfm.2014.206
     [Google Scholar]
  104. BarrosL.F. Metabolic signaling by lactate in the brain.Trends Neurosci.201336739640410.1016/j.tins.2013.04.002
     [Google Scholar]
  105. LiuC. WuJ. ZhuJ. KueiC. YuJ. SheltonJ. SuttonS.W. LiX. YunS.J. MirzadeganT. MazurC. KammeF. LovenbergT.W. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81.J. Biol. Chem.200928452811282210.1074/jbc.M806409200
     [Google Scholar]
  106. VardjanN. ChowdhuryH.H. HorvatA. VelebitJ. MalnarM. MuhičM. KreftM. KrivecŠ.G. BobnarS.T. MišK. PirkmajerS. OffermannsS. HenriksenG. Storm-MathisenJ. BergersenL.H. ZorecR. Enhancement of astroglial aerobic glycolysis by extracellular lactate-mediated increase in cAMP.Front. Mol. Neurosci.20181114810.3389/fnmol.2018.00148
     [Google Scholar]
  107. CauliB. DusartI. LiD. Lactate as a determinant of neuronal excitability, neuroenergetics and beyond.Neurobiol. Dis.202318410620710.1016/j.nbd.2023.106207
     [Google Scholar]
  108. AnderssonAK RönnbäckL HanssonE Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures.J. Neurochem.2005935132733
     [Google Scholar]
  109. LiuJ. ZhaoF. QuY. Lactylation: A novel post-translational modification with clinical implications in CNS diseases.Biomolecules2024149117510.3390/biom14091175
     [Google Scholar]
  110. ZhangD. TangZ. HuangH. ZhouG. CuiC. WengY. LiuW. KimS. LeeS. Perez-NeutM. DingJ. CzyzD. HuR. YeZ. HeM. ZhengY.G. ShumanH.A. DaiL. RenB. RoederR.G. BeckerL. ZhaoY. Metabolic regulation of gene expression by histone lactylation.Nature2019574777957558010.1038/s41586‑019‑1678‑1
     [Google Scholar]
  111. PanR.Y. HeL. ZhangJ. LiuX. LiaoY. GaoJ. LiaoY. YanY. LiQ. ZhouX. ChengJ. XingQ. GuanF. ZhangJ. SunL. YuanZ. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease.Cell Metab.2022344634648.e610.1016/j.cmet.2022.02.013
     [Google Scholar]
  112. HagiharaH. ShojiH. OtabiH. ToyodaA. KatohK. NamihiraM. MiyakawaT. Protein lactylation induced by neural excitation.Cell Rep.202137210982010.1016/j.celrep.2021.109820
     [Google Scholar]
  113. WuY. HuH. LiuW. ZhaoY. XieF. SunZ. ZhangL. DongH. WangX. QianL. Hippocampal lactate-infusion enhances spatial memory correlated with monocarboxylate transporter 2 and lactylation.Brain Sci.202414432710.3390/brainsci14040327
     [Google Scholar]
  114. LiuY.F. ChenH. WuC.L. KuoY.M. YuL. HuangA.M. WuF.S. ChuangJ.I. JenC.J. Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I.J. Physiol.2009587133221323110.1113/jphysiol.2009.173088
     [Google Scholar]
  115. XuJ. ChenE. LuC. HeC. Recombinant ciliary neurotrophic factor promotes nerve regeneration and induces gene expression in silicon tube-bridged transected sciatic nerves in adult rats.J. Clin. Neurosci.200916681281710.1016/j.jocn.2008.08.035
     [Google Scholar]
  116. DmitrievaV.G. PovarovaO.V. SkvortsovaV.I. LimborskaS.A. MyasoedovN.F. DergunovaL.V. Semax and Pro-Gly-Pro activate the transcription of neurotrophins and their receptor genes after cerebral ischemia.Cell. Mol. Neurobiol.2010301717910.1007/s10571‑009‑9432‑0
     [Google Scholar]
  117. El HayekL. KhalifehM. ZibaraV. Abi AssaadR. EmmanuelN. KarnibN. El-GhandourR. NasrallahP. BilenM. IbrahimP. YounesJ. Abou HaidarE. BarmoN. JabreV. StephanJ.S. SleimanS.F. Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF).J. Neurosci.201939131661-1810.1523/JNEUROSCI.1661‑18.2019
     [Google Scholar]
  118. KowiańskiP. LietzauG. CzubaE. WaśkowM. SteligaA. MoryśJ. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity.Cell. Mol. Neurobiol.201838357959310.1007/s10571‑017‑0510‑4
     [Google Scholar]
  119. ChenX. ZhangM. ChenL. ZhouZ. ChenB. WangC. XieY. ZhangY. Roxarsone promotes glycolysis and angiogenesis by inducing hypoxia-inducible factor-1α in vitro and in vivo.ACS Omega20216149559956610.1021/acsomega.1c00072
     [Google Scholar]
  120. PorporatoP.E. PayenV.L. De SaedeleerC.J. PréatV. ThissenJ.P. FeronO. SonveauxP. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice.Angiogenesis201215458159210.1007/s10456‑012‑9282‑0
     [Google Scholar]
  121. HuntT.K. AslamR. HussainZ. BeckertS. Lactate, with oxygen, incites angiogenesis.Adv. Exp. Med. Biol.2008614738010.1007/978‑0‑387‑74911‑2_9
     [Google Scholar]
  122. MorlandC. AnderssonK.A. HaugenØ.P. HadzicA. KleppaL. GilleA. RinholmJ.E. PalibrkV. DigetE.H. KennedyL.H. StølenT. HennestadE. MoldestadO. CaiY. PuchadesM. OffermannsS. VervaekeK. BjøråsM. WisløffU. Storm-MathisenJ. BergersenL.H. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1.Nat. Commun.2017811555710.1038/ncomms15557
     [Google Scholar]
  123. ZhangS. WuF. ZhanL. LinW. LiangC. PangY. ZhangJ. MuZ. Exercise regulates the lactate receptor HCAR1 and ERK1/2-PI3K/Akt pathways to promote cerebral angiogenesis.Iran. J. Public Health202251102298230710.18502/ijph.v51i10.10988
     [Google Scholar]
  124. ZhouJ. LiuT. GuoH. CuiH. LiP. FengD. HuE. HuangQ. YangA. ZhouJ. LuoJ. TangT. WangY. Lactate potentiates angiogenesis and neurogenesis in experimental intracerebral hemorrhage.Exp. Mol. Med.201850711210.1038/s12276‑018‑0113‑2
     [Google Scholar]
  125. Yetkin-ArikB. VogelsI.M.C. Nowak-SliwinskaP. WeissA. HoutkooperR.H. Van NoordenC.J.F. KlaassenI. SchlingemannR.O. The role of glycolysis and mitochondrial respiration in the formation and functioning of endothelial tip cells during angiogenesis.Sci. Rep.2019911260810.1038/s41598‑019‑48676‑2
     [Google Scholar]
  126. LemmonM.A. SchlessingerJ. Cell signaling by receptor tyrosine kinases.Cell201014171117113410.1016/j.cell.2010.06.011
     [Google Scholar]
  127. MustonenT. AlitaloK. Endothelial receptor tyrosine kinases involved in angiogenesis.J. Cell Biol.1995129489589810.1083/jcb.129.4.895
     [Google Scholar]
  128. ShiojimaI. WalshK. Role of Akt signaling in vascular homeostasis and angiogenesis.Circ. Res.200290121243125010.1161/01.RES.0000022200.71892.9F
     [Google Scholar]
  129. RuanG.X. KazlauskasA. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis.J. Biol. Chem.201328829211612117210.1074/jbc.M113.474619
     [Google Scholar]
  130. LeeD.C. SohnH.A. ParkZ.Y. OhS. KangY.K. LeeK. KangM. JangY.J. YangS.J. HongY.K. NohH. KimJ.A. KimD.J. BaeK.H. KimD.M. ChungS.J. YooH.S. YuD.Y. ParkK.C. YeomY.I. A lactate-induced response to hypoxia.Cell2015161359560910.1016/j.cell.2015.03.011
     [Google Scholar]
  131. ParkK.C. LeeD.C. YeomY.I. NDRG3-mediated lactate signaling in hypoxia.BMB Rep.201548630130210.5483/BMBRep.2015.48.6.080
     [Google Scholar]
  132. AfoninaI.S. ZhongZ. KarinM. BeyaertR. Limiting inflammation—the negative regulation of NF-κB and the NLRP3 inflammasome.Nat. Immunol.201718886186910.1038/ni.3772
     [Google Scholar]
  133. VégranF. BoidotR. MichielsC. SonveauxP. FeronO. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis.Cancer Res.20117172550256010.1158/0008‑5472.CAN‑10‑2828
     [Google Scholar]
  134. TakadaY. KobayashiY. AggarwalB.B. Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion.J. Biol. Chem.200528017172031721210.1074/jbc.M500077200
     [Google Scholar]
  135. GloireG. Legrand-PoelsS. PietteJ. NF-κB activation by reactive oxygen species: Fifteen years later.Biochem. Pharmacol.200672111493150510.1016/j.bcp.2006.04.011
     [Google Scholar]
  136. BernierL.P. YorkE.M. MacVicarB.A. Immunometabolism in the Brain: How Metabolism Shapes Microglial Function.Trends Neurosci.2020431185486910.1016/j.tins.2020.08.008
     [Google Scholar]
  137. GhoshS. CastilloE. FriasE.S. SwansonR.A. Bioenergetic regulation of microglia.Glia20186661200121210.1002/glia.23271
     [Google Scholar]
  138. FodelianakiG. LansingF. BhattaraiP. TroullinakiM. ZeballosM.A. CharalampopoulosI. GravanisA. MirtschinkP. ChavakisT. AlexakiV.I. Nerve Growth Factor modulates LPS - induced microglial glycolysis and inflammatory responses.Exp. Cell Res.20193771-2101610.1016/j.yexcr.2019.02.023
     [Google Scholar]
  139. GericI. SchoorsS. ClaesC. GressensP. VerderioC. VerfaillieC.M. Van VeldhovenP.P. CarmelietP. BaesM. Metabolic reprogramming during microglia activation.Immunometabolism201911e19000210.20900/immunometab20190002
     [Google Scholar]
  140. Arango DuqueG. DescoteauxA. Macrophage cytokines: involvement in immunity and infectious diseases.Front. Immunol.2014549110.3389/fimmu.2014.00491
     [Google Scholar]
  141. Galván-PeñaS. O’NeillL.A. Metabolic reprograming in macrophage polarization.Front. Immunol.2014542010.3389/fimmu.2014.00420
     [Google Scholar]
  142. LiX. YangY. ZhangB. LinX. FuX. AnY. ZouY. WangJ.X. WangZ. YuT. Lactate metabolism in human health and disease.Signal Transduct. Target. Ther.20227130510.1038/s41392‑022‑01151‑336050306
     [Google Scholar]
  143. GharibS.A. McMahanR.S. EddyW.E. LongM.E. ParksW.C. AitkenM.L. ManiconeA.M. Transcriptional and functional diversity of human macrophage repolarization.J. Allergy Clin. Immunol.201914341536154810.1016/j.jaci.2018.10.046
     [Google Scholar]
  144. BohnT. RappS. LutherN. KleinM. BruehlT.J. KojimaN. Aranda LopezP. HahlbrockJ. MuthS. EndoS. PektorS. BrandA. RennerK. PoppV. GerlachK. VogelD. LueckelC. Arnold-SchildD. PouyssegurJ. KreutzM. HuberM. KoenigJ. WeigmannB. ProbstH.C. von StebutE. BeckerC. SchildH. SchmittE. BoppT. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages.Nat. Immunol.201819121319132910.1038/s41590‑018‑0226‑8
     [Google Scholar]
  145. LiuN. LuoJ. KuangD. XuS. DuanY. XiaY. WeiZ. XieX. YinB. ChenF. LuoS. LiuH. WangJ. JiangK. GongF. TangZ. ChengX. LiH. LiZ. LaurenceA. WangG. YangX.P. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression.J. Clin. Invest.2019129263164610.1172/JCI123027
     [Google Scholar]
  146. Costa LeiteT. Da SilvaD. Guimarães CoelhoR. ZancanP. Sola-PennaM. Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis.Biochem. J.2007408112313010.1042/BJ20070687
     [Google Scholar]
  147. ZhangJ. MuriJ. FitzgeraldG. GorskiT. Gianni-BarreraR. MasscheleinE. D’HulstG. GilardoniP. TurielG. FanZ. WangT. PlanqueM. CarmelietP. PellerinL. WolfrumC. FendtS.M. BanfiA. StockmannC. Soro-ArnáizI. KopfM. De BockK. Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization.Cell Metab.202031611361153.e710.1016/j.cmet.2020.05.004
     [Google Scholar]
  148. AbebayehuD. SpenceA.J. CaslinH. TaruselliM. HaqueT.T. KiwanukaK.N. KolawoleE.M. ChumanevichA.P. SellS.A. OskeritzianC.A. RyanJ. KeeS.A. Lactic acid suppresses IgE-mediated mast cell function in vitro and in vivo.Cell. Immunol.201934110391810.1016/j.cellimm.2019.04.006
     [Google Scholar]
  149. ZhaiX. LiJ. LiL. SunY. ZhangX. XueY. lvJ. GaoY. LiS. YanW. YinS. XiaoZ. L-lactate preconditioning promotes plasticity-related proteins expression and reduces neurological deficits by potentiating GPR81 signaling in rat traumatic brain injury model.Brain Res.2020174614694510.1016/j.brainres.2020.146945
     [Google Scholar]
  150. PeterK. RehliM. SingerK. Renner-SattlerK. KreutzM. Lactic acid delays the inflammatory response of human monocytes.Biochem. Biophys. Res. Commun.2015457341241810.1016/j.bbrc.2015.01.005
     [Google Scholar]
  151. YangK. XuJ. FanM. TuF. WangX. HaT. WilliamsD.L. LiC. Lactate suppresses macrophage pro-inflammatory response to LPS stimulation by inhibition of YAP and NF-κB activation via GPR81-mediated signaling.Front. Immunol.20201158791310.3389/fimmu.2020.587913
     [Google Scholar]
  152. HoqueR. FarooqA. GhaniA. GorelickF. MehalW.Z. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.Gastroenterology201414671763177410.1053/j.gastro.2014.03.014
     [Google Scholar]
  153. BisriT. UtomoB. FuadiI. Exogenous lactate infusion improved neurocognitive function of patients with mild traumatic brain injury.Asian J. Neurosurg.201611215115910.4103/1793‑5482.145375
     [Google Scholar]
  154. HornT. KleinJ. Neuroprotective effects of lactate in brain ischemia: Dependence on anesthetic drugs.Neurochem. Int.201362325125710.1016/j.neuint.2012.12.017
     [Google Scholar]
  155. MahanV.L. Effects of lactate and carbon monoxide interactions on neuroprotection and neuropreservation.Med. Gas Res.202111415817310.4103/2045‑9912.318862
     [Google Scholar]
  156. BrooksG.A. The science and translation of lactate shuttle theory.Cell Metab.201827475778510.1016/j.cmet.2018.03.008
     [Google Scholar]
  157. MölströmS. NielsenT.H. NordströmC.H. ForsseA. MöllerS. VenöS. MamaevD. TencerT. SchmidtH. ToftP. Bedside microdialysis for detection of early brain injury after out-of-hospital cardiac arrest.Sci. Rep.20211111587110.1038/s41598‑021‑95405‑9
     [Google Scholar]
  158. BerthetC. LeiH. ThevenetJ. GruetterR. MagistrettiP.J. HirtL. Neuroprotective role of lactate after cerebral ischemia.J. Cereb. Blood Flow Metab.200929111780178910.1038/jcbfm.2009.97
     [Google Scholar]
  159. BerthetC. CastilloX. MagistrettiP.J. HirtL. New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration.Cerebrovasc. Dis.2012345-632933510.1159/000343657
     [Google Scholar]
  160. AlberiniC.M. CruzE. DescalziG. BessièresB. GaoV. Astrocyte glycogen and lactate: New insights into learning and memory mechanisms.Glia20186661244126210.1002/glia.23250
     [Google Scholar]
  161. BriquetM. RocherA.B. AlessandriM. RosenbergN. de Castro AbrantesH. Wellbourne-WoodJ. SchmuzigerC. GinetV. PuyalJ. PralongE. DanielR.T. OffermannsS. ChattonJ.Y. Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.J. Cereb. Blood Flow Metab.20224291650166510.1177/0271678X221080324
     [Google Scholar]
  162. SchurrA. PayneR.S. MillerJ.J. TsengM.T. RigorB.M. Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia.Brain Res.20018951-226827210.1016/S0006‑8993(01)02082‑0
     [Google Scholar]
  163. LeziE. SwerdlowR.H. Lactate's effect on human neuroblastoma cell bioenergetic fluxes.Biochem. Pharmacol.2016998810010.1016/j.bcp.2015.11.002
     [Google Scholar]
  164. KangB.S. ChoiB.Y. KhoA.R. LeeS.H. HongD.K. ParkM.K. LeeS.H. LeeC.J. YangH.W. WooS.Y. ParkS.W. KimD.Y. ParkJ.B. ChungW.S. SuhS.W. Effects of pyruvate kinase M2 (PKM2) gene deletion on astrocyte-specific glycolysis and global cerebral ischemia-induced neuronal death.Antioxidants202312249110.3390/antiox12020491
     [Google Scholar]
  165. PellerinL. ConnesP. BisbalC. LambertK. Editorial: Lactate as a major signaling molecule for homeostasis.Front. Physiol.20221391056710.3389/fphys.2022.910567
     [Google Scholar]
  166. CerinaM. LeversM. KellerJ.M. FregaM. Neuroprotective role of lactate in a human in vitro model of the ischemic penumbra.Sci. Rep.2024141797310.1038/s41598‑024‑58669‑5
     [Google Scholar]
  167. RoumesH. DumontU. SanchezS. MazuelL. BlancJ. RaffardG. ChateilJ.F. PellerinL. Bouzier-SoreA.K. Neuroprotective role of lactate in rat neonatal hypoxia-ischemia.J. Cereb. Blood Flow Metab.202141234235810.1177/0271678X20908355
     [Google Scholar]
  168. CarrardA. ElsayedM. MargineanuM. Boury-JamotB. FragnièreL. MeylanE.M. PetitJ-M. FiumelliH. MagistrettiP.J. MartinJ-L. Peripheral administration of lactate produces antidepressant-like effects.Mol. Psychiatry201823239239910.1038/mp.2016.179
     [Google Scholar]
  169. DohertyJ.R. ClevelandJ.L. Targeting lactate metabolism for cancer therapeutics.J. Clin. Invest.201312393685369210.1172/JCI69741
     [Google Scholar]
  170. ReussA.M. GroosD. BuchfelderM. SavaskanN. The acidic brain—glycolytic switch in the microenvironment of malignant glioma.Int. J. Mol. Sci.20212211551810.3390/ijms22115518
     [Google Scholar]
  171. WatsonM.J. VignaliP.D.A. MullettS.J. Overacre-DelgoffeA.E. PeraltaR.M. GrebinoskiS. MenkA.V. RittenhouseN.L. DePeauxK. WhetstoneR.D. VignaliD.A.A. HandT.W. PoholekA.C. MorrisonB.M. RothsteinJ.D. WendellS.G. DelgoffeG.M. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.Nature2021591785164565110.1038/s41586‑020‑03045‑2
     [Google Scholar]
  172. LiuR. WuJ. GuoH. YaoW. LiS. LuY. JiaY. LiangX. TangJ. ZhangH. Post-translational modifications of histones: Mechanisms, biological functions, and therapeutic targets.MedComm202043e29210.1002/mco2.292
     [Google Scholar]
  173. MarinE. Bouchet-DelbosL. RenoultO. LouvetC. Nerriere-DaguinV. ManaghA.J. EvenA. GiraudM. Vu ManhT.P. AguesseA. BériouG. ChiffoleauE. Alliot-LichtB. PrieurX. CroyalM. HutchinsonJ.A. ObermajerN. GeisslerE.K. VanhoveB. BlanchoG. DalodM. JosienR. PecqueurC. CuturiM.C. MoreauA. Human tolerogenic dendritic cells regulate immune responses through lactate synthesis.Cell Metab.201930610751090.e810.1016/j.cmet.2019.11.011
     [Google Scholar]
  174. XuK. YinN. PengM. StamatiadesE.G. ShyuA. LiP. ZhangX. DoM.H. WangZ. CapistranoK.J. ChouC. LevineA.G. RudenskyA.Y. LiM.O. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity.Science2021371652740541010.1126/science.abb2683
     [Google Scholar]
  175. FangY. LiZ. YangL. LiW. WangY. KongZ. MiaoJ. ChenY. BianY. ZengL. Emerging roles of lactate in acute and chronic inflammation.Cell Commun. Signal.202422127610.1186/s12964‑024‑01624‑8
     [Google Scholar]
  176. IvashkivL.B. The hypoxia–lactate axis tempers inflammation.Nat. Rev. Immunol.2020202858610.1038/s41577‑019‑0259‑8
     [Google Scholar]
  177. FaulhaberM. GröbnerK. RauschL. GattererH. MenzV. Effects of acute hypoxia on lactate thresholds and high-intensity endurance performance-A pilot study.Int. J. Environ. Res. Public Health20211814757310.3390/ijerph18147573
     [Google Scholar]
  178. SuzukiA. SternS.A. BozdagiO. HuntleyG.W. WalkerR.H. MagistrettiP.J. AlberiniC.M. Astrocyte-neuron lactate transport is required for long-term memory formation.Cell2011144581082310.1016/j.cell.2011.02.018
     [Google Scholar]
  179. VelentzasP.D. ZhangL. DasG. ChangT.K. NelsonC. KobertzW.R. BaehreckeE.H. The proton-coupled monocarboxylate transporter hermes is necessary for autophagy during cell death.Dev. Cell2018473281293.e410.1016/j.devcel.2018.09.015
     [Google Scholar]
  180. YuJ. ChaiP. XieM. GeS. RuanJ. FanX. JiaR. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma.Genome Biol.20212218510.1186/s13059‑021‑02308‑z
     [Google Scholar]
  181. WangT. YeZ. LiZ. JingD. FanG. LiuM. ZhuoQ. JiS. YuX. XuX. QinY. Lactate-induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer.Cell Prolif.20235610e1347810.1111/cpr.13478
     [Google Scholar]
  182. ScheimanJ. LuberJ.M. ChavkinT.A. MacDonaldT. TungA. PhamL.D. WibowoM.C. WurthR.C. PunthambakerS. TierneyB.T. YangZ. HattabM.W. Avila-PachecoJ. ClishC.B. LessardS. ChurchG.M. KosticA.D. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism.Nat. Med.20192571104110910.1038/s41591‑019‑0485‑4
     [Google Scholar]
  183. BrooksG.A. Lactate as a fulcrum of metabolism.Redox Biol.20203510145410.1016/j.redox.2020.101454
     [Google Scholar]
  184. HallerH.L. SanderF. PoppD. RappM. HartmannB. DemircanM. NischwitzS.P. KamolzL.P. Oxygen, pH, lactate, and metabolism-How old knowledge and new insights might be combined for new wound treatment.Medicina (Kaunas)20215711119010.3390/medicina57111190
     [Google Scholar]
  185. DengQ. WuC. LiuT.C.Y. DuanR. YangL. Exogenous lactate administration: A potential novel therapeutic approach for neonatal hypoxia-ischemia.Exp. Neurol.202336711445010.1016/j.expneurol.2023.114450
     [Google Scholar]
  186. PaulS. Candelario-JalilE. Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies.Exp. Neurol.202133511351810.1016/j.expneurol.2020.113518
     [Google Scholar]
  187. PhillisJ.W. O’ReganM.H. Evidence for swelling-induced adenosine and adenine nucleotide release in rat cerebral cortex exposed to monocarboxylate-containing or hypotonic artificial cerebrospinal fluids.Neurochem. Int.200240762963510.1016/S0197‑0186(01)00113‑9
     [Google Scholar]
/content/journals/cpps/10.2174/0113892037335945241029111720
Loading
The Role of Lactate in Ischemic Stroke: As an Energy Source and Signaling Molecule
Curr. Protein Pept. Sci. 26, 334 (2025); https://doi.org/10.2174/0113892037335945241029111720
/content/journals/cpps/10.2174/0113892037335945241029111720
/content/journals/cpps/10.2174/0113892037335945241029111720
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): angiogenesis; anti-inflammation; glycolysis; Ischemic stroke; lactate; neuroprotection

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test