Stroke is the leading cause of physical disability and death among adults in most Western countries. Consecutive to a vascular occlusion, cells face a brutal reduction in supply of oxygen and glucose and thus an energy failure, which in turn triggers cell death mechanisms. Among brain cells, neurons are the most susceptible to ischemia because of their high metabolic demand and low reservoir of energy substrates. In neurons, glycolysis uses glucose coming from blood or from glycogen stored in astrocytes, underlying the deep astrocyte-neuron metabolic cooperation. During ischemia, both the aerobic and anaerobic pathways and thus energy production are compromised, which disrupts proper cell functioning, notably Na+/K+ ATPase and mitochondria. This results in altered Ca2+ homeostasis and overproduction of ROS, the latter being further exacerbated during the reperfusion phase. Consequently, glucose metabolism in the different brain cell populations plays a central role in injury and recovery after stroke, and has recently emerged as a promising target for therapeutic intervention. In this context, the overall objective of this article is to review the interconnections between stroke and brain glucose metabolism and to explore how its targeting may offer new therapeutic opportunities in addressing the global stroke epidemic.
CoppolaTBeraud-DufourSLebrunP, et al.
Bridging the gap between diabetes and stroke in search of high clinical relevance therapeutic targets. Neuromolecular Med2019;
21: 432–444.
2.
LoEHDalkaraTMoskowitzMA.Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci2003;
4: 399–415.
3.
CamaraRMateiNZhangJH.Evolution of the stroke paradigm: a review of delayed recanalization. J Cereb Blood Flow Metab2021;
41: 945–957.
4.
HeitJJWintermarkM.New developments in clinical ischemic stroke prevention and treatment and their imaging implications. J Cereb Blood Flow Metab2018;
38: 1533–1550.
5.
ChouchaniETPellVRJamesAM, et al.
A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab2016;
23: 254–263.
6.
BivardAKrishnamurthyVStanwellP, et al.
Spectroscopy of reperfused tissue after stroke reveals heightened metabolism in patients with good clinical outcomes. J Cereb Blood Flow Metab2014;
34: 1944–1950.
7.
DienelGA.Brain glucose metabolism: Integration of energetics with function. Physiol Rev2019;
99: 949–1045.
8.
VaishnaviSNVlassenkoAGRundleMM, et al.
Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A2010;
107: 17757–17762.
9.
KasischkeKAVishwasraoHDFisherPJ, et al.
Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science2004;
305: 99–103.
10.
ShulmanRGHyderFRothmanDL.Cerebral energetics and the glycogen shunt: neurochemical basis of functional imaging. Proc Natl Acad Sci U S A2001;
98: 6417–6422.
11.
BelangerMAllamanIMagistrettiPJ.Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab2011;
14: 724–738.
12.
van HallGStromstadMRasmussenP, et al.
Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab2009;
29: 1121–1129.
13.
ItohYEsakiTShimojiK, et al.
Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo. Proc Natl Acad Sci U S A2003;
100: 4879–4884.
14.
HåbergAQuHSaetherO, et al.
Differences in neurotransmitter synthesis and intermediary metabolism between glutamatergic and GABAergic neurons during 4 hours of middle cerebral artery occlusion in the rat: the role of astrocytes in neuronal survival. J Cereb Blood Flow Metab2001;
21: 1451–1463.
15.
BrownAMRansomBR.Astrocyte glycogen and brain energy metabolism. Glia2007;
55: 1263–1271.
16.
StinconeAPrigioneACramerT, et al.
The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc2015;
90: 927–963.
17.
VaughnAEDeshmukhM.Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol2008;
10: 1477–1483.
18.
StantonRC.Glucose-6-phosphate dehydrogenase, NADPH, and cell survival. IUBMB Life2012;
64: 362–369.
19.
Herrero-MendezAAlmeidaAFernándezE, et al.
The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol2009;
11: 747–752.
20.
RalserMWamelinkMMKowaldA, et al.
Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J Biol2007;
6: 10.
21.
FinelliMJParamoTPiresE, et al.
Oxidation resistance 1 modulates glycolytic pathways in the cerebellum via an interaction with glucose-6-Phosphate isomerase. Mol Neurobiol2019;
56: 1558–1577.
22.
OliverPLFinelliMJEdwardsB, et al.
Oxr1 is essential for protection against oxidative stress-induced neurodegeneration. PLoS Genet2011;
7: e1002338.
23.
KaragiannisAGallopinTLacroixA, et al.
Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity. eLife2021;
10: e71424.
24.
CarteronLSolariDPatetC, et al.
Hypertonic lactate to improve cerebral perfusion and glucose availability after acute brain injury. Crit Care Med2018;
46: 1649–1655.
25.
HungYPAlbeckJGTantamaM, et al.
Imaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor. Cell Metab2011;
14: 545–554.
26.
YellenG.Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism. J Cell Biol2018;
217: 2235–2246.
27.
GebrilHMAvulaBWangYH, et al.
(13)C metabolic flux analysis in neurons utilizing a model that accounts for hexose phosphate recycling within the pentose phosphate pathway. Neurochem Int2016;
93: 26–39.
28.
CerdanSRodriguesTBSierraA, et al.
The redox switch/redox coupling hypothesis. Neurochem Int2006;
48: 523–530.
29.
SchousboeAScafidiSBakLK, et al.
Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol2014;
11: 13–30.
30.
OzGBerkichDAHenryPG, et al.
Neuroglial metabolism in the awake rat brain: CO2 fixation increases with brain activity. J Neurosci2004;
24: 11273–11279.
31.
MagistrettiPJChattonJY.Relationship between L-glutamate-regulated intracellular Na+ dynamics and ATP hydrolysis in astrocytes. J Neural Transm (Vienna)2005;
112: 77–85.
32.
BrownAMSickmannHMFosgerauK, et al.
Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter. J Neurosci Res2005;
79: 74–80.
33.
BrownAGouldstoneAFoxE, et al.
Description and preliminary results from a structured specialist behavioural weight management group intervention: specialist lifestyle management (SLiM) programme. BMJ Open2015;
5: e007217.
34.
GandhiGKCruzNFBallKK, et al.
Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J Neurochem2009;
111: 522–536.
35.
HossainMIRoulstonCLStapletonDI.Molecular basis of impaired glycogen metabolism during ischemic stroke and hypoxia. PLoS One2014;
9: e97570.
36.
CaiYGuoHFanZ, et al.
Glycogenolysis is crucial for astrocytic glycogen accumulation and brain damage after reperfusion in ischemic stroke. iScience2020;
23: 101136.
37.
LiddelowSABarresBA.Reactive astrocytes: Production, function, and therapeutic potential. Immunity2017;
46: 957–967.
38.
GuttenplanKAWeigelMKPrakashP, et al.
Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature2021;
599: 102–107.
39.
BorborMYinDBrockmeierU, et al.
Neurotoxicity of ischemic astrocytes involves STAT3-mediated metabolic switching and depends on glycogen usage. Glia2023;
71: 1553–1569.
40.
PatabendigeASinghAJenkinsS, et al.
Astrocyte activation in neurovascular damage and repair following ischaemic stroke. Int J Mol Sci2021;
22.
41.
VernooijMWvan der LugtAIkramMA, et al.
Total cerebral blood flow and total brain perfusion in the general population: the Rotterdam scan study. J Cereb Blood Flow Metab2008;
28: 412–419.
42.
GuoHFanZWangS, et al.
Astrocytic A1/A2 paradigm participates in glycogen mobilization mediated neuroprotection on reperfusion injury after ischemic stroke. J Neuroinflammation2021;
18: 230.
43.
LiQBarresBA.Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol2018;
18: 225–242.
44.
DurafourtBAMooreCSZammitDA, et al.
Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia2012;
60: 717–727.
45.
ChhorVLe CharpentierTLebonS, et al.
Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav Immun2013;
32: 70–85.
46.
PearceEL.Metabolism as a driver of immunity. Nat Rev Immunol2021;
21: 618–619.
47.
BernierLPYorkEMKamyabiA, et al.
Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat Commun2020;
11: 1559.
48.
GhoshSCastilloEFriasES, et al.
Bioenergetic regulation of microglia. Glia2018;
66: 1200–1212.
49.
ChurchwardMATchirDRToddKG.Microglial function during glucose deprivation: inflammatory and neuropsychiatric implications. Mol Neurobiol2018;
55: 1477–1487.
50.
LoppiSHTavera-GarciaMABecktelDA, et al.
Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke. J Cereb Blood Flow Metab2023;
43: 1099–1114.
51.
FannDYSantroTManzaneroS, et al.
Intermittent fasting attenuates inflammasome activity in ischemic stroke. Exp Neurol2014;
257: 114–119.
52.
FuSPWangJFXueWJ, et al.
Anti-inflammatory effects of BHBA in both in vivo and in vitro parkinson's disease models are mediated by GPR109A-dependent mechanisms. J Neuroinflammation2015;
12: 9.
53.
RahmanMMuhammadSKhanMA, et al.
The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun2014;
5: 3944.
54.
GulyasBTothMSchainM, et al.
Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [((11))C]vinpocetine. J Neurol Sci2012;
320: 110–117.
55.
PriceCJWangDMenonDK, et al.
Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke2006;
37: 1749–1753.
56.
XuSLuJShaoA, et al.
Glial cells: Role of the immune response in ischemic stroke. Front Immunol2020;
11: 294.
57.
ThielARadlinskaBAPaquetteC, et al.
The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J Nucl Med2010;
51: 1404–1412.
58.
GirardSBroughDLopez-CastejonG, et al.
Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices. Glia2013;
61: 813–824.
59.
TakedaHYamaguchiTYanoH, et al.
Microglial metabolic disturbances and neuroinflammation in cerebral infarction. J Pharmacol Sci2021;
145: 130–139.
60.
JinWNShiSXLiZ, et al.
Depletion of microglia exacerbates postischemic inflammation and brain injury. J Cereb Blood Flow Metab2017;
37: 2224–2236.
61.
SzalayGMartineczBLenartN, et al.
Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun2016;
7: 11499.
62.
NarineMColognatoH.Current insights into oligodendrocyte metabolism and its power to sculpt the myelin landscape. Front Cell Neurosci2022;
16: 892968.
63.
CheliVTCorrealeJPaezPM, et al.
Iron metabolism in oligodendrocytes and astrocytes, implications for myelination and remyelination. ASN Neuro2020;
12: 1759091420962681.
64.
FunfschillingUSupplieLMMahadD, et al.
Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature2012;
485: 517–521.
65.
RoskoLSmithVNYamazakiR, et al.
Oligodendrocyte bioenergetics in health and disease. Neuroscientist2019;
25: 334–343.
66.
SimonsMNaveKA.Oligodendrocytes: myelination and axonal support. Cold Spring Harb Perspect Biol2015;
8: a020479.
67.
MifsudGZammitCMuscatR, et al.
Oligodendrocyte pathophysiology and treatment strategies in cerebral ischemia. CNS Neurosci Ther2014;
20: 603–612.
68.
MarinMACarmichaelST.Mechanisms of demyelination and remyelination in the young and aged brain following white matter stroke. Neurobiol Dis2019;
126: 5–12.
69.
ObermeierBDanemanRRansohoffRM.Development, maintenance and disruption of the blood-brain barrier. Nat Med2013;
19: 1584–1596.
70.
GaoHMChenHCuiGY, et al.
Damage mechanism and therapy progress of the blood-brain barrier after ischemic stroke. Cell Biosci2023;
13: 196.
71.
LeeHWXuYZhuX, et al.
Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance. EMBO J2022;
41: e109890.
72.
MathiasKMachadoRSStorkS, et al.
Blood-brain barrier permeability in the ischemic stroke: an update. Microvasc Res2024;
151: 104621.
73.
HeoJHHanSWLeeSK.Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med2005;
39: 51–70.
74.
WuSRenXSShiY.Early and enduring: targeting the endothelium for blood-brain barrier protection. J Cereb Blood Flow Metab2024;
44: 1674–1676.
75.
XuNJiangXZhangW, et al.
Endothelial peroxiredoxin-4 is indispensable for blood-brain barrier integrity and long-term functional recovery after ischemic stroke. Proc Natl Acad Sci U S A2024;
121: e2400272121.
76.
ZhaoXLiSMoY, et al.
DCA protects against oxidation injury attributed to cerebral ischemia-reperfusion by regulating glycolysis through PDK2-PDH-Nrf2 axis. Oxid Med Cell Longev2021;
2021: 5173035.
GuoZSunXHeZ, et al.
Matrix metalloproteinase-9 potentiates early brain injury after subarachnoid hemorrhage. Neurol Res2010;
32: 715–720.
79.
ZhaoRZJiangSZhangL, et al.
Mitochondrial electron transport chain, ROS generation and uncoupling (review). Int J Mol Med2019;
44: 3–15.
80.
ChenQVazquezEJMoghaddasS, et al.
Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem2003;
278: 36027–36031.
81.
St-PierreJBuckinghamJARoebuckSJ, et al.
Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem2002;
277: 44784–44790.
82.
GutteridgeJMCHalliwellB.Mini-review: oxidative stress, redox stress or redox success?Biochem Biophys Res Commun2018;
502: 183–186.
83.
DringenR.Metabolism and functions of glutathione in brain. Prog Neurobiol2000;
62: 649–671.
84.
GouixEBuissonANieoullonA, et al.
Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress. Pharmacol Res2014;
87: 8–17.
85.
EltzschigHKEckleT.Ischemia and reperfusion – from mechanism to translation. Nat Med2011;
17: 1391–1401.
86.
OrreniusSGogvadzeVZhivotovskyB.Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol2007;
47: 143–183.
87.
RaedscheldersKAnsleyDMChenDD.The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion. Pharmacol Ther2012;
133: 230–255.
88.
AbramovAYScorzielloADuchenMR.Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci2007;
27: 1129–1138.
89.
KahlesTBrandesRP.Which NADPH oxidase isoform is relevant for ischemic stroke? The case for nox 2. Antioxid Redox Signal2013;
18: 1400–1417.
90.
BrennanAMSuhSWWonSJ, et al.
NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci2009;
12: 857–863.
91.
KimHABraitVHLeeS, et al.
Brain infarct volume after permanent focal ischemia is not dependent on Nox2 expression. Brain Res2012;
1483: 105–111.
92.
Coimbra-CostaDAlvaNDuranM, et al.
Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol2017;
12: 216–225.
93.
BraginDEZhouBRamamoorthyP, et al.
Differential changes of glutathione levels in astrocytes and neurons in ischemic brains by two-photon imaging. J Cereb Blood Flow Metab2010;
30: 734–738.
94.
TanSSchubertDMaherP.Oxytosis: a novel form of programmed cell death. Curr Top Med Chem2001;
1: 497–506.
95.
MaherPCurraisASchubertD.Using the oxytosis/ferroptosis pathway to understand and treat age-associated neurodegenerative diseases. Cell Chem Biol2020;
27: 1456–1471.
96.
WeiCXiaoZZhangY, et al.
Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke. Cell Death Differ2024;
31: 983–998.
97.
YingWHanSKMillerJW, et al.
Acidosis potentiates oxidative neuronal death by multiple mechanisms. J Neurochem1999;
73: 1549–1556.
98.
HyacintheJNBuscemiLLeTP, et al.
Evaluating the potential of hyperpolarised [1-(13)C] L-lactate as a neuroprotectant metabolic biosensor for stroke. Sci Rep2020;
10: 5507.
99.
CaoLZhangDChenJ, et al.
G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway. Free Radic Biol Med2017;
112: 433–444.
100.
MeerwaldtAEStraathofMOosterveldW, et al.
In vivo imaging of cerebral glucose metabolism informs on subacute to chronic post-stroke tissue status – a pilot study combining PET and deuterium metabolic imaging. J Cereb Blood Flow Metab2023;
43: 778–790.
101.
SuhSWShinBSMaH, et al.
Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol2008;
64: 654–663.
102.
Brennan-MinnellaAMWonSJSwansonRA.NADPH oxidase-2: linking glucose, acidosis, and excitotoxicity in stroke. Antioxid Redox Signal2015;
22: 161–174.
103.
KleinschnitzCGrundHWinglerK, et al.
Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol2010;
8.
104.
LeeMCVelayuthamMKomatsuT, et al.
Measurement and characterization of superoxide generation from xanthine dehydrogenase: a redox-regulated pathway of radical generation in ischemic tissues. Biochemistry2014;
53: 6615–6623.
105.
SimsNRMuydermanH.Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta2010;
1802: 80–91.
106.
DominguezCDelgadoPVilchesA, et al.
Oxidative stress after thrombolysis-induced reperfusion in human stroke. Stroke2010;
41: 653–660.
107.
PulsinelliWAWaldmanSRawlinsonD, et al.
Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology1982;
32: 1239–1246.
108.
LiPAShuaibAMiyashitaH, et al.
Hyperglycemia enhances extracellular glutamate accumulation in rats subjected to forebrain ischemia. Stroke2000;
31: 183–192.
109.
WagnerKRKleinholzMde Courten-MyersGM, et al.
Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size. J Cereb Blood Flow Metab1992;
12: 213–222.
110.
XiongZGZhuXMChuXP, et al.
Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell2004;
118: 687–698.
111.
RussellJWGolovoyDVincentAM, et al.
High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. Faseb J2002;
16: 1738–1748.
112.
da-SilvaWSGomez-PuyouA, dGomez-PuyouMT, et al.
Mitochondrial bound hexokinase activity as a preventive antioxidant defense: steady-state ADP formation as a regulatory mechanism of membrane potential and reactive oxygen species generation in mitochondria. J Biol Chem2004;
279: 39846–39855.
113.
DaveKRTamarizJDesaiKM, et al.
Recurrent hypoglycemia exacerbates cerebral ischemic damage in streptozotocin-induced diabetic rats. Stroke2011;
42: 1404–1411.
114.
ShuklaVFuchsPLiuA, et al.
Recurrent hypoglycemia exacerbates cerebral ischemic damage in diabetic rats via enhanced post-ischemic mitochondrial dysfunction. Transl Stroke Res2019;
10: 78–90.
115.
BhardwajSKSharmaMLGulatiG, et al.
Effect of starvation and insulin-induced hypoglycemia on oxidative stress scavenger system and electron transport chain complexes from rat brain, liver, and kidney. Mol Chem Neuropathol1998;
34: 157–168.
116.
AlmdalTScharlingHJensenJS, et al.
The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med2004;
164: 1422–1426.
117.
TunNNArunagirinathanGMunshiSK, et al.
Diabetes mellitus and stroke: a clinical update. World J Diabetes2017;
8: 235–248.
118.
RebelosELatva-RaskuAKoskensaloK, et al.
Insulin-stimulated brain glucose uptake correlates with brain metabolites in severe obesity: a combined neuroimaging study. J Cereb Blood Flow Metab2024;
44: 407–418.
119.
PhippsMSJastreboffAMFurieK, et al.
The diagnosis and management of cerebrovascular disease in diabetes. Curr Diab Rep2012;
12: 314–323.
120.
WichaPDasSMahakkanukrauhP.Blood-brain barrier dysfunction in ischemic stroke and diabetes: the underlying link, mechanisms and future possible therapeutic targets. Anat Cell Biol2021;
54: 165–177.
121.
MitsiosJPEkinciEIMitsiosGP, et al.
Relationship between glycated hemoglobin and stroke risk: a systematic review and meta-analysis. J Am Heart Assoc2018;
7.
122.
SmithLChakrabortyDBhattacharyaP, et al.
Exposure to hypoglycemia and risk of stroke. Ann N Y Acad Sci2018;
1431: 25–34.
123.
BondsDEMillerMEBergenstalRM, et al.
The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. Bmj2010;
340: b4909.
124.
RolekBHaberMGajewskaM, et al.
SGLT2 inhibitors vs. GLP-1 agonists to treat the heart, the kidneys and the brain. J Cardiovasc Dev Dis2023;
10: 322.
125.
SatoKKamedaMYasuharaT, et al.
Neuroprotective effects of liraglutide for stroke model of rats. Int J Mol Sci2013;
14: 21513–21524.
126.
ShuklaVShakyaAKPerez-PinzonMA, et al.
Cerebral ischemic damage in diabetes: an inflammatory perspective. J Neuroinflammation2017;
14: 21.
127.
PrasadSSajjaRKNaikP, et al.
Diabetes mellitus and blood-brain barrier dysfunction: an overview. J Pharmacovigil2014;
2: 125.
128.
ZhouPGuanTJiangZ, et al.
Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses. CNS Neurosci Ther2018;
24: 126–134.
129.
CaoYXuWLiuQ.Alterations of the blood-brain barrier during aging. J Cereb Blood Flow Metab2024;
44: 881–895.
130.
GoyalMSVlassenkoAGBlazeyTM, et al.
Loss of brain aerobic glycolysis in normal human aging. Cell Metab2017;
26: 353–360 e3.
131.
AanerudJBorghammerPRodellA, et al.
Sex differences of human cortical blood flow and energy metabolism. J Cereb Blood Flow Metab2017;
37: 2433–2440.
132.
CaiLZhangYZhouY, et al.
Aging affects the mouse brain in a region-specific manner. J Cereb Blood Flow Metab2025;
45: 373–375.
133.
YoshiiFBarkerWWChangJY, et al.
Sensitivity of cerebral glucose metabolism to age, gender, brain volume, brain atrophy, and cerebrovascular risk factors. J Cereb Blood Flow Metab1988;
8: 654–661.
134.
KawachiTIshiiKSakamotoS, et al.
Gender differences in cerebral glucose metabolism: a PET study. J Neurol Sci2002;
199: 79–83.
135.
FujimotoTMatsumotoTFujitaS, et al.
Changes in glucose metabolism due to aging and gender-related differences in the healthy human brain. Psychiatry Res2008;
164: 58–72.
136.
ShinSKimKNamHY, et al.
Sex difference in cerebral blood flow and cerebral glucose metabolism: an activation-likelihood estimation meta-analysis. Nucl Med Commun2021;
42: 410–415.
137.
FranxBAvan TilborgGATahaA, et al.
Hyperperfusion profiles after recanalization differentially associate with outcomes in a rat ischemic stroke model. J Cereb Blood Flow Metab2024;
44: 209–223.
138.
MagistrettiPJAllamanI.Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci2018;
19: 235–249.
139.
HashimotoTHussienRBrooksGA.Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metab2006;
290: E1237–44.
140.
BrooksGA.Intra- and extra-cellular lactate shuttles. Med Sci Sports Exerc2000;
32: 790–799.
ZhangDTangZHuangH, et al.
Metabolic regulation of gene expression by histone lactylation. Nature2019;
574: 575–580.
143.
ZhangWXuLYuZ, et al.
Inhibition of the glycolysis prevents the cerebral infarction progression through decreasing the lactylation levels of LCP1. Mol Biotechnol2023;
65: 1336–1345.
144.
XuJJiTLiG, et al.
Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen-glucose deprivation conditions. J Neuroinflammation2022;
19: 314.
145.
PlourdeGRoumesHSuissaL, et al.
Neuroprotective effects of lactate and ketone bodies in acute brain injury. J Cereb Blood Flow Metab2024;
44: 1078–1088.
146.
TakadoYChengTBastiaansenJAM, et al.
Hyperpolarized (13)C 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 Neurosci2018;
9: 2554–2562.
147.
BerthetCLeiHThevenetJ, et al.
Neuroprotective role of lactate after cerebral ischemia. J Cereb Blood Flow Metab2009;
29: 1780–1789.
148.
RoumesHDumontUSanchezS, et al.
Neuroprotective role of lactate in rat neonatal hypoxia-ischemia. J Cereb Blood Flow Metab2021;
41: 342–358.
149.
JayarajRLAzimullahSBeiramR, et al.
Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation2019;
16: 142.
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