Excitotoxicity-induced Endocytosis Raws li Lub Hom Phiaj Muaj Peev Xwm Rau Stroke Neuroprotection Part 2

Kev tiv thaiv ntawm TrkB-FL endocytosis tsis cuam tshuam rau kev mob stroke neuroprotection invivo: Txij li thaum endocytosis yog qhov yuav tsum tau muaj fornecrosis, cov tswv yim dav dav rau downregulateor deplete cov proteins tseem ceeb sib haum xeeb ntawm cov txheej txheem endocytic tau tsim thiab pom tias cuam tshuam nrog neurodegeneration (Troulinaki thiab Tavernarakis, 2).

Nyob rau hauv xyoo tas los no, mob stroke tau dhau los ua ib qho teeb meem tshwm sim, thiab vim tias kev puas tsuaj rau lub paj hlwb los ntawm kev mob stroke yuav cuam tshuam ncaj qha rau peb lub neej niaj hnub, kev nco tsis tshua muaj tshwm sim tom qab mob stroke. Yog li ntawd, kev sib raug zoo ntawm neuroprotection thiab nco tom qab mob stroke kuj tau dhau los ua lub ntsiab lus kub.

Ua ntej tshaj plaws, peb yuav tsum nkag siab tias tom qab mob stroke, cov hlab ntsha hauv lub hlwb yuav raug puas tsuaj rau qee yam, uas yuav cuam tshuam ncaj qha rau peb lub cim xeeb. Txawm li cas los xij, yog tias peb siv sijhawm kho thiab tiv thaiv kev ntsuas, peb tseem tuaj yeem tiv thaiv peb cov hlab ntsha thiab txhim kho peb lub cim xeeb.

Yuav ua li cas ua neuroprotection? Ua ntej, peb yuav tsum ua kom muaj kev tawm dag zog. Qhov no tsis tsuas yog txhim kho peb lub cev, tab sis nws kuj txhawb kev loj hlob ntawm paj hlwb thiab rov qab los. Qhov thib ob, txhim kho kev ua neej nyob zoo, xws li tswj kev pw tsaug zog txaus thiab noj kom zoo, kuj tseem yuav pab tau zoo rau peb cov kev tiv thaiv neuroprotect. Thaum kawg, thaum lub sijhawm kho, peb yuav tsum koom tes nrog tus kws kho mob txoj kev kho mob thiab tau txais kev cob qhia kev kho kom rov zoo sai sai, txhawm rau txhim kho peb lub paj hlwb kom zoo.

Tsis tas li ntawd, peb kuj tuaj yeem txhim kho peb lub cim xeeb los ntawm qee txoj kev. Piv txwv li, peb tuaj yeem txhim kho tus cwj pwm zoo xws li kev nyeem ntawv, mloog suab paj nruag, thiab ua si kev txawj ntse, uas tuaj yeem txhawb peb lub hlwb thiab txhawb kev tsim thiab kho kev nco. Tib lub sijhawm, peb kuj tuaj yeem sim qee qhov kev qhia nco, xws li nyeem cov lus, lej, thaj chaw, thiab lwm yam. Cov txheej txheem no tuaj yeem txhim kho peb lub peev xwm nco tau zoo.

Txawm hais tias mob stroke yuav ua rau peb lub neej tsis yooj yim, tsuav yog peb koom tes nrog kev kho mob thiab kev cob qhia kev kho mob, thiab txhim kho kev ua neej zoo thiab kev kawm, peb tseem tuaj yeem ua lub neej nquag thiab noj qab haus huv thiab tiv thaiv peb cov hlab ntsha thiab kev nco. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv cov kab mob. kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv kev loj hlob ntawm kev paub tsis meej thiab kab mob neurodegenerative.

Nyem paub los txhim kho lub cim xeeb luv luv

Yog li ntawd, generici nte r fe renceofendocy rau sismig ht yuav suav hais tias yog ib txoj kev kho mob nrog lub peev xwm los txo cov cell tuag vim kev thuam ntawm acutebrain. Txawm li cas los xij, muaj peev xwm caveats rau txoj hauv kev no yog qhov tsis zoo ntawm pleiotropic nws yuav tau txiav txim siab tias qhov tseem ceeb ntawm cov txheej txheem ntawm lub cev yuav raug cuam tshuam thiab. Raws li lwm txoj hauv kev, peb npaj siv cov molecules tuaj yeem cuam tshuam nrog pathological endocytosis ntawm cov proteinsurvival tshwj xeeb.
Ib tus neeg sib tw los txiav txim siab yog NMDAR, sab hauv los ntawm nws qhov kev txhawb nqa. Endocytosis ntawm GluN2B-muaj NMDARs tau pom tias muaj kev sib haum xeeb los ntawm cov txheej txheem tseem tsis tau paub (Wu li al., 2017).
Blockade ntawm cov txheej txheem clathrin-dependent endocytic siv lub cell-peptide (CPP) muaj peev xwm inhibit excitotoxicity hauv kab lis kev cai cortical neurons. CPP (Tat-YEKL) no muaj 11 aa qhov ntawm tib neeg kev tiv thaiv kab mob tiv thaiv kab mob hom 1 Tatprotein, uas tso cai rau cov khoom thauj txuas mus hla cov ntshav-hlwb thaiv thiab plasma membrane, ua raws li 12 aa ntawm GluN2B C-terminuscorresponding to the AP{{9} } khi motif.

Cov kev xaiv ntawm CPPs li cov cuab yeej tiv thaiv kab mob kev kho mob rau kev kho mob zoo li tshwj xeeb yog tsim nyogNEURAL REGENERATION RESEARCH｜Vol 16｜No.2｜February 2021｜301Figure 1 ｜ Mechanism of action ofneuroprotective peptide TFLP457 tangle) uas tej zaum sib tw nrog TrkB-interacting protein (txiv kab ntxwv) tseem ceeb rau excitotoxicity-induced endocytosis, yog li tiv thaiv kev ua haujlwm thib ob thiab kev tuag ntawm neuronal.

Kev sib cuam tshuam ntawm TrkB nrog cov protein tsis paub tseeb no tau khaws cia nyob rau hauv lub xub ntiag ntawm kev tswj peptide TMyc (ntsuab lub voj voog) thiab kev tuag ntawm lub paj hlwb yog induced los ntawm excitotoxicinsult. CPP: Cell-peptide peptide; TFL457 thiabTMyc: Tat-derived CPPs; TrkB: tropomyosin-relatedkinase B; TrkB-FL: lub catalytically nquag ua haujlwm puv-lengthreceptor.

Txij li thaum lub siab endocytic neurons ntawm cheeb tsam theischemic tam sim no muaj kev txhim kho ntawm Tat-derived peptides (Vaslin li al., 2009) uas ua rau xaiv lub hom phiaj ntawm cov muaj peev xwm neuroprotective CPPs rau cov neurons puas.Yav tom ntej, nws yuav nthuav kom tsim tau qhov CPP no zoo ib yam neuroprotect. cuam ​​tshuam thaum siv hauv vivo thiab tuaj yeem cuam tshuam qhov cuam tshuam kev tuag ntawm NMDAR overactivationwhile khaws cia lwm yam receptor zog.

Lwm tus neeg tuaj sib tw yuav raug tshawb nrhiav raws li lub hom phiaj neuroprotective yog kinase D-interactingsubstrate ntawm 220 kDa (Kidins220), ib tug downstreameffector ntawm neurotrophin receptors thiab NMDARs tseem ceeb rau neuronal viability. Peb tau pom tias Kidins220 ua los ntawm calpain hauv excitotoxicity yog qhov thib ob rau kev khiav ntawm cov protein no mus rau Golgi apparatusand ua kom ntxov ntawm Rap1-GTPase (LópezMenéndez li al., 2019).

Nyob rau theem tom qab ntawm cov txheej txheem excitotoxic, Kidins220 downregulationgoverns Rap1 inactivation cuam tshuam nrog kev nce hauv ERK kev ua haujlwm uas cuam tshuam rau kev muaj sia nyob. Yog li ntawd, kev tiv thaiv ntawm excitotoxicity-induced Kidins220 endocytosism yuav raug tshawb xyuas raws li ib txoj hauv kev los inhibit calpainprocessing ntawm Rap1 activation complexes thiab, yog li, cuam tshuam nrog kev kaw ntawm Kidins220/Rap1/ERK prosurvival cascades.

Thaum kawg, peb twb tau pom tias kev cuam tshuam ntawm TrkB-FL endocytosis yog ib qho kev cuam tshuam txog kev tiv thaiv kab mob hauv vitro thiab hauv vivo. Peb tau pom tias excitotoxicity txo qis cov theem saum npoo ntawm cov receptor no thiab, ua ntu zus, txhawb nqa nws cov txheej txheem intracellular los ntawm ntau cov proteases (Tejeda etal., 2019). Lub tshuab tseem ceeb ntawm TrkB-FLdownregulation yog qhov cleavage ntawm nws cheeb tsam intracellularjuxtamembrane los ntawm calpain (Vidaurre etal., 2012; Daim duab 1).

Ib tug thib ob mechanism rau TrkB-FL, tab sis thawj rau TrkB-T1 kev cai, yog tswj intramembrane proteolysis los ntawm sequential metalloproteinase / -secretaseaction, tsim cov shedding los ntawm cov isoforms ntawm zoo tib yam receptor ectodomainsthat peb tau ua yeeb yam raws li BDNF1etalcaveng.

Ua ke, cov txheej txheem no ua rau muaj kev hloov pauv loj ntawm BDNF teeb liab los ntawm excitotoxicity, pom tsis tsuas yog mob stroke tab sis kuj nyob rau hauv lwm yam kab mob neurological (Tejeda thiab Diaz-Guerra, 2017).

Txhawm rau khaws BDNF-tswj txoj hauv kev muaj sia nyob, peb tau tsim Tat-derivedCPP (TFL 457) uas muaj qhov luv luv TrkB-FLjuxtamembrane ib ntus (aa 457-471) uas peb xav tias yuav yog ib qho tseem ceeb rau kev tswj hwm ntawm receptor stability thiab kev ua haujlwm inexcitotoxicity.

Cov kev xaiv ib ntus yog ib feem ntawm thaj chaw intracellular tsim los ua qhov tseem ceeb rau kev tswj hwm ntawm TrkB-FL qhov chaw thiab ua haujlwm los ntawm kev sib cuam tshuam nrog cov txheej txheem sib txawv uas suav nrog Hrs (Huang et al., 2009).

Peb pom tias peptide TFL457 tshwj xeeb tiv thaiv thaum ntxov TrkB-FL endocytosis activatedby excitotoxicity, txawv ntawm kev tswj tsis zoo CPP uas tsis muaj feem cuam tshuam (TMyc). Peb xav tias TFL457 tej zaum yuav sib tw nrog qee cov protein / s kev sib cuam tshuam / tsim los ntawm ntu 457-471 hauv TrkB-FL uas yuav xav tau rau kev txhawb nqa ntawm excitotoxicity-induced endocytosis.

Txij li cov peptide no tsuas yog cuam tshuam rau kev sib cuam tshuam tshwj xeeb tsim los ntawm TrkB-FL, endocytosis ntawm lwm cov proteins yuav tsis cuam tshuam. Los ntawm kev khaws cov receptor uas tsis tau ua tiav hauv lub xov tooj ntawm tes, TFL457 thib ob cuam tshuam nrog TrkB-FL cleavage los ntawm calpain thiab regulatedintramembrane proteolysis thiab, yog li, receptorTyr816 phosphorylation thiab BDNF / TrkB / PLC -signaling yog tswj.

Qhov tshwm sim yog kev khaws cia ntawm cAMP cov lus teb-cov ntsiab lus sib txuas cov protein thiab myocyte enhancer yam 2promoter kev ua ub no downstream no cascade, uas pib lub tswv yim tswv yim nyiam nthuav qhia txog qhov tseem ceeb prosurvivalproteins hauv neurons, xws li BDNF lossis TrkBreceptor nws tus kheej, ua rau muaj zog neuronalviability.

Cov tsim neuroprotectivepeptide tuaj yeem muaj feem cuam tshuam rau kev kho mob stroke vim, hauv tus qauv nas ntawm kev mus tas li, nws tawm tsam TrkB-FL downregulationin infarct thiab ua rau txo qis infarctsize ze li 30% (Tejeda li al., 2019).

Tsis tas li ntawd, TFL457 txhim kho cov txiaj ntsig ntawm neurological, raws li pom los ntawm kev txo qis ntawm 42% hauv qhov nruab nrab ntawm cov ntawv hla hauv qhov kev ntsuas ntsuas ntsuas qhov sib npaug thiab kev sib koom ua ke ntawm lub cev muaj zog.

Yog li, cov txiaj ntsig no tshem tawm cov kab mob endocytosis ntawm TrkB-FLinduced los ntawm excitotoxicity raws li qhov tshiab thiab muaj feem cuam tshuam rau kev kho mob stroke thiab qhib txoj hauv kev tshiab rau kev txhim kho cov tshuaj tshiab tshwj xeeb qhia rau lwm cov ciaj sia taus.

Margarita Díaz-Guerra*

Instituto de Investigaciones Biomédicas "AlbertoSols", Consejo Superior de InvestigacionesCientíficas-Universidad Autónoma de Madrid(CSIC-UAM), Madrid, Spain

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Qhib cov neeg txheeb xyuas: Rayudu Gopalakrishna, University of Southern California, USA.Cov ntaub ntawv ntxiv: Qhib cov ntaub ntawv txheeb xyuas cov phooj ywg 1.

Cov ntaub ntawv

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3. López-Menéndez C, Simón-García A, Gamir-Morralla A, Pose-Utrilla J, Luján R, Mochizuki N, Díaz-Guerra M, Iglesias T (2019) Excitotoxic targeting of Kidins220 tothe Golcedescleavage apparatin 1- ua kom cov complexes. Cell Death Dis 10:535.

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