Crosstalk Ntawm Neuron Thiab Glial Cells hauv Oxidative Injury Thiab Neuroprotection Part 3

4. Microglia

4.1. Microglia hauv lub hlwb

Microglia, uas muaj ntau cov txheej txheem zoo thiab motile uas tshawb xyuas qhov chaw parenchymal, sawv cev kwv yees li 10% ntawm CNS hlwb. Txhua lub cell microglial muaj nws thaj chaw, uas yog kwv yees li 50 µm hauv txoj kab uas hla [66].

Microglia yog hom paj hlwb uas ua lub luag haujlwm tseem ceeb hauv peb lub hlwb. Lawv tshem tawm cov khoom pov tseg los ntawm ib puag ncig neurons, tswj kev noj qab haus huv neuron, thiab pab txhawb kev sib txuas lus ntawm cov neurons, txhua yam tsim nyog los tswj kev nco.

Ntawm microglia, muaj ib hom ntawm tes hu ua "astrocyte", uas muaj cov duab tshwj xeeb thiab kev ua haujlwm. Lawv saib xyuas thiab tswj kev sib txuas ntawm cov neurons, pab peb lub hlwb ua cov ntaub ntawv zoo dua. Qhov no zoo ib yam li cov thawj coj hauv chav computer uas niaj hnub saib xyuas cov xwm txheej ntawm kev sib txuas ntawm cov xov tooj hluav taws xob thiab cov cables kom ntseeg tau tias kev khiav ntawm tag nrho cov network.

Kev tshawb fawb qhia tau hais tias microglia kuj koom nrog hauv cov txheej txheem ntawm kev kawm thiab kev nco. Lawv tso cov neurotransmitters, pab txhawb kev sib txuas lus ntawm cov neurons, thiab txhim kho kev nco sib koom ua ke thiab rov qab. Nyob rau tib lub sijhawm, microglia tuaj yeem txhawb kev tsim cov kev sib txuas tshiab ntawm cov neurons, yog li txhim kho lub peev xwm nco.

Yog li ntawd, kev tswj hwm kev noj qab haus huv thiab tus naj npawb ntawm microglia hauv lub hlwb yog qhov tseem ceeb ntawm kev tswj kev nco. Peb tuaj yeem txhawb kev tsim thiab kev saib xyuas ntawm microglia los ntawm kev ua tib zoo saib xyuas kev noj zaub mov zoo, ua haujlwm kom tsim nyog, thiab tswj lub siab zoo. Tsuas yog los ntawm kev tswj hwm microglia zoo tuaj yeem ua rau peb lub hlwb nyob hauv cov hluas, noj qab haus huv, thiab muaj zog. Nco ntsoov yuav zoo dua. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Microglia, hu ua nyob rau hauv macrophages nyob rau hauv CNS, yog cov nyob ntev thiab nws tus kheej-renewing hlwb. Nyob rau hauv lub hlwb noj qab nyob zoo, microglia muaj ib tug ramified morphology thiab nyob rau hauv ib tug "quiescent" los yog "so" lub xeev [67].

Cov txheej txheem Microglial tau dhau mus tas li ntawm kev txuas ntxiv thiab tshem tawm, luam theej duab lawv ib puag ncig rau kev cuam tshuam hauv lub hlwb homeostasis, thiab ua haujlwm synapse los saib xyuas thiab tswj cov kev ua haujlwm neuronal ntawm ib qho kev qhia tshwj xeeb [68,69]. Microglia hloov lawv cov morphology los ntawm lub xeev so mus rau lub reactive amoeboid lub xeev thaum lub sij hawm ib tug pathological mob hlwb.

Reactive microglia, uas hloov mus rau hauv phagocytic los yog amoeboid microglia, muaj qhov loj ntawm lub cev ntawm lub cev, cov txheej txheem tsawg dua, txo cov txheej txheem ntev thiab cov ceg, thiab nce tus lej thiab kev loj hlob, qhia txog kev sib txuas ntawm morphology thiab kev ua haujlwm [70–73] (Daim duab 2).

Microglia yog cov rhiab heev rau ib puag ncig cov cim thiab teb kom tswj tau lawv cov homeostatic phenotype nyob rau hauv cov kab mob tshwj xeeb thiab lub hlwb-tseem ceeb cheeb tsam. Dawb thiab grey teeb meem microglia qhia txog kev tiv thaiv kab mob sib txawv; cortex-associated microglia ua lub luag haujlwm hauv neurodegeneration thiab cov teeb meem dawb-txog microglia ua lub luag haujlwm hauv de-/remyelination [74].

Feem ntau, ua kom cov neurotransmitter receptors inhibits inflammatory activation ntawm microglia thiab inhibits zus tau tej cov molecules txawv txav thiab abnormalconcentrations ntawm physiological molecules.

Thaum qhib tau thaum lub hlwb raug mob los yog kis kab mob, microglia pib lub cev tiv thaiv kab mob thiab tsim ntau cytokines, chemokines, thiab loj hlob yam, thiab upregulate cov kev qhia ntawm cell nto receptors, xws li tus xov tooj hu-likereceptors (TLRs), phagocytic receptors, scavenger receptors, thiab ntau yam complementfactors [ 75, 76] ib. Microglia nthuav qhia ntau yam neurotransmitter receptors, suav nrog GABA, glutamate, dopamine, thiab noradrenaline [66,77].

4.2. Microglia hauv Oxidative Injury

Thaum lub sij hawm oxidative kev nyuaj siab, activated microglia tsim ob peb inflammatory mediators, nrog rau NO thiab superoxide, uas dawb do hla lub cell membrane thiab ua raws li signalingmolecules.

TSIS MUAJ thiab superoxide tuaj yeem tsim peroxynitrite, uas ua rau DNA tawg, thiab lipid oxidation, thiab induces neuronal tuag [78,79]. Nyob rau hauv kab lis kev cai microglia, superoxideproduction, uas yog catalyzed los ntawm nitrates / nitrites (NOx), yog induced los ntawm phorbol ester, thiab TSIS MUAJ ntau lawm yog stimulated los ntawm induction ntawm iNOS thaum kho nrog cov kab mob bacteriallipopolysaccharide (LPS) thiab interferon- (IFN ) [80,81 ].

Qhov kev qhia ntawm iNOS tom qab kev kho mob intrahippocampal nrog LPS yog induced sai nyob rau hauv microglia tshaj inastrocytes, thiab ib tug qis concentration ntawm LPS yog yuav tsum tau rau iNOS induction nyob rau hauv microgliathan nyob rau hauv astrocytes [82,83].

Tsis tas li ntawd, arginine yog lub npe hu ua physiological substrate ntawm NOS. Activated microglia nrog qhov tsis txaus ntawm arginine ua rau iNOS-mediatedproduction ntawm NO thiab superoxide, uas tsim cov tshuaj lom peroxynitrite [84]. Qhov induction ofiNOS lossis ua kom NOx ib leeg tsis ua rau muaj kev puas tsuaj loj rau microglia, tab sis tib lub sijhawm tsim cov superoxide thiab NO los ntawm NOx thiab iNOS muaj peev xwm ua rau mob microglia [85,86].

Nyob rau hauv activated microglia uas tsim superoxide thaum NOx activation, theoxygen thiab H2O2 qib sai sai ua tsis txaus thiab tej zaum yuav cuam tshuam rau microglial functions.ROS pab txhawb phagocytosis los ntawm amoeboid microglial hlwb thiab txhim kho vesicle tsim, uas tau pom raws li kev kho mob ntawm microglial hlwb nrog H2O2 [87]. Microglia-derivedROS tuaj yeem ua rau cov hlwb uas nyob ib sab.

Yog li ntawd, microglial proliferation thiab ROS ntau lawm yog lub hom phiaj kho mob uas yuav tiv thaiv lub hlwb los ntawm oxidative puas thiab kab mob neurodegenerative [88].

4.3. Microglia-Mediated Antioxidant Tiv Thaiv

Txhawm rau tiv thaiv oxidative kev nyuaj siab los ntawm ROS, microglia muaj cov cellular siab GSH concentration thiab nthuav qhia thiab txhim kho ntau yam antioxidant enzymes, suav nrog SOD, GPx, GR, thiab catalase.

Lub hlwb kab lis kev cai sau nrog fluorescence pom tias microglia qhia siab dua GSH dua li lwm hom cell hauv nas hlwb [89]. Qhov no siab concentration ntawm intracellular GSH nyob rau hauv microglia pab txhawb rau nws antioxidant tiv thaiv kab mob tiv thaiv radical thiab peroxide-mediated puas. Microglial kab lis kev cai txhawb nqa nrog TNF pom ob zaug GSH ntau dua li cov kab lis kev cai tsis muaj zog microglial [90].

Txawm li cas los xij, cellular GSH cov ntsiab lus qis dua hauv microglia kho nrog LPS / IFN, uas ua rau iNOS ntau lawm, tab sis cov ntsiab lus mitochondrial GSH tsis cuam tshuam [91]. Yog li, lub microglial GSH cov ntsiab lus qhia txog cov txiaj ntsig binary, uas nws nce ntxiv rau kev txhim kho hauv GSH synthesis thiab txo qis thaum nce GSH noj, nyob ntawm seb hom stimulation.

SOD, lwm cov tshuaj tiv thaiv antioxidant, tau pom los ntawm immunocytochemical staining hauv activatedmicroglia tom qab kev kho mob quinolinic acid tab sis tsis pom hauv microglia hauv qab basalconditions [92,93]. Cov haujlwm tshwj xeeb ntawm MnSOD yog 20 thiab 4 npaug siab dua hauv kab lis kev cai microglia dua li hauv kab lis kev cai astrocytes thiab oligodendrocytes, raws li [94]. Hauv microgliatreated nrog LPS / IFN lossis TNF los ua kom muaj kev ntxhov siab oxidative, mitochondrial MnSOD qhia tau kho, uas txhim kho lub peev xwm ntawm cov hlwb kom decompose mitochondrialsuperoxide [90,95].

Kev ua haujlwm siab SOD hauv activated microglia txo qhov kev pheej hmoo ntawm celldamage los ntawm superoxide-derived hydroxyl radicals thiab peroxynitrite. Lub upregulation ntawm GSH peroxidases (GPx) nyob rau hauv microglia kuj yog ib tug tseem ceeb mechanism tiv thaiv oxidative kev nyuaj siab.Qhov tshwj xeeb kev ua ntawm GPx thiab GSH reductase (GR) yog ho ntau dua nyob rau hauv microglia dua nyob rau hauv neurons [96–98].

Txawm li cas los xij, cov haujlwm tshwj xeeb ntawm catalase zoo ib yam thiab / lossis qis dua hauv microglia dua li lwm hom hlwb hlwb, suav nrog cov neurons, astrocytes, andoligodendrocytes [97,99]. Txawm hais tias microglial GSH disulfide (GSSG) nce mus rau yuav luag 30% ntawm tag nrho cov cellular GSH tom qab raug rau H2O2, microglial GSSG tsis tshua pom muaj nyob rau hauv cov xwm txheej basal [98,100].

5. Neuron-Glia Crosstalk hauv Antioxidant Defense Mechanism

Neurons nyob ntawm cov khoom noj tsis tu ncua ntawm cov piam thaj thiab cov pa oxygen los ntawm sab nraud ntawm lub paj hlwb ntawm cov ntshav cerebral, txawm tias lawv tsis hu ncaj qha rau microvessels. Txawm li cas los xij, 99% ntawm lub paj hlwb capillary nto yog npog nrog cov txheej txheem astrocyte kawg-ko taw, qhia tias cov neurons yuav tsum cuam tshuam nrog astrocytes kom tau txais cov ntaub ntawv tseem ceeb los ntawm cerebralcirculation [101].

Crosstalk ntawm astrocytes thiab neurons yog qhov tseem ceeb rau neuronaldefense tiv thaiv ROS. Ua kom cov astrocytes nthuav tawm cov khoom tsis zoo xws li A1 thiab A2 astrocytes. A1 astrocytes ua rau poob neuronal los ntawm kev txhawb o ntawm NF-kBpathway, uas poob lub peev xwm los tiv thaiv neurons thiab tswj synaptogenesis [102,103].

A2 astrocytes txhawb nqa neuronal ciaj sia los ntawm Janus kinase / signal transducer thiab activator ntawm transcription 3 (JAK-STAT3) signaling txoj kev los ntawm upregulating neurotrophicfactors [104].Neurons tsim glutamate, uas stimulates ascorbate tso tawm ntawm astrocytes thaum lub sij hawm glutamatergic enters thiab synaptic kev ua si. neurons inhibits glucoseconsumption, thiab txhawb nqa lactate thauj.

Cov tshuaj tiv thaiv antioxidant thiab metabolic interplaybetween neurons thiab astrocytes tau piav qhia hauv daim duab 3. Astrocytes yog lub luag haujlwm rau kev tu thiab kev txhawb nqa ntawm cov neurons los ntawm kev tswj cov oxidative kev nyuaj siab ntawm GSH ntau lawm thiab glucose transformation rau hauv lactate, uas ua kom lub zog txhawb nqa ntawm neurons [105] .Lub intrinsic antioxidant GSH , uas yog tsim nyob rau hauv ob qho tib si neurons thiab astrocytes, ua raws li anindependent ROS scavenger thiab raws li ib tug substrate rau ib tug antioxidant. Neuronal hlwb nyob ntawm astrocyte-derived GSH, piv txwv li, neurons nyob ntawm shuttling ntawm GSH precursorfrom astrocytes mus rau neurons. Cysteine ​​yog tus nqi-txheej substrate rau GSH synthesis, andextracellular cysteine ​​yog nkag tau pib-oxidized rau cystine [53].
Cystine uptake tshwm sim los ntawm cov cystine / glutamate pauv pauv thauj hauv astrocytes, thiab tom qab ntawd astrocytes txo cystineback rau cysteine ​​rau GSH synthesis. GSH ncaj qha reacts nrog ROS los yog ua raws li ib tug substrate rau GSH S-transferase los yog GSH peroxidase [50]. Rau kev siv tau zoo ntawm extracellular cystineas ib qho cysteine ​​precursor, neurons nyob ntawm astrocytes los muab cysteine, txawm tias neurons tuaj yeem tsim GSH [54,106].

Nws tau pom tias cov qib neuronal GSH yog qhov tseem ceeb siab dua thaum co-cultured nrog astrocytes [107]. Raws li H2O2-induced oxidativestress, noradrenaline kev kho mob tiv thaiv neurons los ntawm nce cov khoom ntawm GSH los ntawm astrocytes rau neurons los ntawm stimulation ntawm beta3-adrenoreceptor hauv astrocytes [108]. Lwm qhov kev sib cuam tshuam ntawm cov neurons thiab astrocytes uas cuam tshuam nrog kev ua haujlwm antioxidant suav nrog astrocyte-neuron lactate shuttle thiab kev rov ua dua ntawm ascorbate [55]. Astrocytes ua lub luag haujlwm tseem ceeb hauv kev sib txuas cov haujlwm neuronal thiab lub hlwb cov piam thaj los ntawm anastrocyte-neuron lactate shuttle [109].

Neuronal kev ua haujlwm ua rau cov piam thaj metabolism hauv inastrocytes; Cov piam thaj hloov mus rau pyruvate los ntawm glycolysis thiab hloov mus rau lactate, uas tawm los ntawm astrocytes thiab coj los ntawm cov neurons rau oxidative phosphorylation. Ascorbatehat yog concentrated nyob rau hauv lub hlwb yog tso tawm los ntawm glial reservoirs mus rau hauv lub extracellular space thiab coj los ntawm neurons. Kev ua haujlwm siab neurons tsim ROS, uas oxidize ascorbateto dehydroascorbic acid (DHA), thiab tshem tawm ROS los ntawm kev noj ascorbate [110,111].

Daim duab 3. Daim duab no sawv cev rau cov neuron-glia crosstalk koom nrog hauv neuroprotection thiab antioxidant tiv thaiv mechanism.Astrocyte-neuron: Astrocytes muaj ntau yam antioxidant molecules, suav nrog glutathione (GSH), ascorbate, vitamin E (VE), thiab ROS-detoxifying enzymes. , xws li GSH S-transferase, GSH peroxidase, thioredoxin reductase, thiab catalase.

Astrocytes tsim cov txheej txheem kawg-taw mus rau lub hlwb capillary nto kom astrocytes tswj kev txav ntawm cov molecules thiab cov hlwb ntawm cov hlab ntsha thiab lub hlwb. Nyob rau hauv lub lactate shuttle, astrocytes txhawb cov neurons los ntawm kev tswj cov piam thaj hloov mus rau lactate, uas ua kom muaj kev txhawb zog ntawm cov neurons. Neuronal kev ua ub no ua rau glucose metabolism hauv astrocytes. Glucose hloov mus rau pyruvate los ntawm glycolysis thiab lactate, uas yog tso tawm los ntawm astrocytes thiab coj los ntawm neurons (xub xub).

Astrocytes tuaj yeem tsim GSH los ntawm kev ua haujlwm ntawm Nrf2 thiab tuaj yeem xa GSHprecursors mus rau neurons rau GSH synthesis. Astrocytes tso GSH rau hauv qhov chaw extracellular thiab neurons coj GSH ncaj qha los yog siv extracellular neuronal aminopeptidase N los ua glycine thiab cysteine ​​(dub xub). Hauv glutamate uptake andrecycling, glutamate los ntawm qhov chaw synaptic nkag mus rau astrocytes los ntawm EAAT thiab hloov los ntawm glutamine synthetase (GS) rau inactive glutamine. Tom qab nws tso tawm thiab ntshuam mus rau hauv cov neurons, glutamine tuaj yeem hloov mus rau glutamate (xub xub liab).

Recycled ascorbate tuaj yeem rub ncaj qha ROS thiab ua raws li cov cofactor rau kev rov ua dua ntawm oxidized vE thiab GSH. Astrocytestake up dehydroascorbic acid (DHA), cov khoom oxidation ntawm ascorbate, los ntawm qhov chaw extracellular thiab recycle nws rov qab toascorbic acid. Astrocytes ntes thiab thauj ntau tshaj K + mus rau astrocytic syncytium los ntawm Na + / K + ATPase.Nrf2 induction ntawm glutamate cysteine ​​ligase (GCL) tsub kom GSH synthesis hauv astrocytes, thiab GSH yog tom qab xa mus rau qhov nruab nrab extracellular.

Astrocytes kuj koom nrog cov hlau sequestration hauv lub hlwb los tiv thaiv cov tiam ntawm dawb radicals los ntawm redox-active hlau. Microglia-neuron: Microglia muaj cov cellular siab GSH concentration thiab nthuav qhia thiab txhim kho ntau yam antioxidant enzymes. Kev qhia ntawm classical antioxidant proteins yog tswj los ntawm Nrf2 inmicroglia. Heme oxygenase-1 (HO-1), ib qho antioxidant enzyme upregulated los ntawm Nrf2, inhibits NOX2 activation.

Fractalkine (FKN) feem ntau qhia hauv cov hlwb neuronal, thiab microglia thiab neurons tshwj xeeb tshaj tawm cov fractalkine receptor (CX3CR1); qhov no yog qhov nthuav qhia axis rau kev sib txuas lus. Cov ntawv luv: YOG, cov lus teb antioxidant; ASC, ascorbate; ApoE, apolipoprotein E; xCT, cysteine-glutamate exchanger; Cys, cysteine; DHA, dehydroascorbic acid; DMT1, divalent hlau thauj khoom; EAAT, excitatory amino acid transporter; mFKN, membrane-anchored fractalkine; sFKN, soluble fractalkine; CX3CR1, fractalkine receptor; Glc, qabzib; GLUT, glucose transporter; Glu, glutamate; Gln, glutamine; GSH, glutathione; GCL, glutamate-cysteine ​​ligase; GS, glutamine synthetase; GLAST, glutamate aspartate transporter; GLT1, glutamate transporter 1; Glycine; HO-1, heme oxygenase-1; JNK, c-Jun amino-terminal kinase; LRP, lipoproteinreceptor-muaj protein ntau; MCT, monocarboxylate transporter; Nrf2, nuclear erythroid-related factor 2; Pyr, pyruvate; SVTC-2, sodium-dependent transporter; TRPC, ib ntus receptor muaj peev xwm canonical.

Hauv cov neurotransmitters, overstimulation nrog glutamate induces excitotoxicity, uas yog koom nrog hauv pathogenesis ntawm ntau lub hlwb. Astrocytes siv ob lub thauj khoom loj, excitatory amino acid transporter1 (EAAT1) / glutamate aspartate transporter (GLAST) thiab EAAT2 / glutamate transporter-1 (GLT1), coj glutamate thiab rov glutamate rau cov neurons los ntawm kev tsim kom zoo glutamate-glutamine. Lub voj voog uas koom nrog astrocyte-specific enzyme glutamine synthetase (GS), uas hloov glutamine intoglutamate.

Yog hais tias tsis ua hauj lwm los hloov glutamine rov qab mus rau glutamate tshwm sim, lub glutamate pas dej ua ke inpresynaptic terminals yuav sai sai depleted thiab excitatory neurotransmission yuav cuam tshuam [112,113]. Ib qho khoom tsis txaus ntawm glutamine rau GABAergic neurons induces GABAergic dysfunction [114,115]. Glutamine hauv astrocytes yog qhov tseem ceeb rau GABA ntxiv los ntawm glutamate decarboxylase, hu ua GABA-glutamine voj voog, hauv GABAergicneurons [116].

Neuronal kev ua ub no thiab kev ua haujlwm muaj peev xwm ua rau muaj cov cellular K + nyob rau hauv qhov chaw txwv thiab ua rau muaj peev xwm ua rau lub cev muaj zog thaum tsis muaj kev tswj hwm nruj [117]. Astrocytes muaj ntau cov membrane K + channels thiab siab K + permeability [118,119]. Astrocytes ntes thiab thauj cov tshaj tawm ntawm K + mus rau theastrocytic syncytium los ntawm Na + / K + ATPase.

Astrocytes kuj tswj cov Ca2+ concentration nyob rau hauv neurons ntawm astrocytic calcium signaling thiab astrocyte-neuron crosstalk.Neuronal activation, uas induces ib tug txo nyob rau hauv extracellular Ca2+, evokes spatiotemporal hloov ntawm lub Ca2+ /Na+exchanger nyob rau hauv astrocytes thiab generates astrocytic Ca2+ wavesthat propagate los ntawm lub cytoplasm mus rau lub extracellular chaw [120,121].

Astrocytes kuj tseem muaj kev cuam tshuam zoo heev, thiab kev poob qis hauv extracellular Ca2+ vim yog kev ua haujlwm synaptic ua rau kev tso tawm ntawm ATP los ntawm astrocytes los ntawm kev qhib connexin 43 hemichannels [122–124].Neuronal kev ua haujlwm tuaj yeem cuam tshuam cov kev hloov pauv hauv astrocytes ntawm dual. Na+ thiab Ca2+ signaling, uas ua rau cov ntshav qabzib ntau thiab glycolysis los txhawb kev ua haujlwm ntawm lub paj hlwb.Astrocytic metabolism cuam tshuam nrog kev xav tau ntawm cov metabolic siab los ntawm neurons [125,126].

For more information:1950477648nn@gmail.com