Endogenous Mechanisms Of Neuroprotection: Kom Boost lossis Tsis Ua Part 3

Mitochondria yog thauj nyob ib ncig ntawm lub cell los ntawm cytoskeleton, lub cev muaj zog proteins, thiab cov adaptors tsim nyog. Hauv cov neurons, lawv tsuas yog muag ntawm MTs los ntawm adaptorsMiro thiab Milton / kev lag luam kinesin-binding protein 1 (TRAK) proteins [161].

Lub cytoskeleton yog ib qho ntawm cov khoom tseem ceeb ntawm lub cell keeb kwm yav dhau thiab yog lub ntsiab lus txiav txim siab ntawm lub xov tooj ntawm tes muab cov duab thiab cov khoom siv kho tshuab. Cov kev tshawb fawb tsis ntev los no tau pom tias cytoskeleton tuaj yeem cuam tshuam rau lub hlwb kev kawm thiab kev nco.

Neurons nyob rau hauv lub hlwb muaj ntau qhov ntev, filamentous projections hu ua dendrites uas tau txais thiab ua cov cim los ntawm lwm cov neurons. Telomere continua (TEL) yog ib qho cytoskeletal protein uas tseem muaj nyob rau hauv cov neurons. Cov kev tshawb fawb tau pom tias TEL cov proteins tuaj yeem cuam tshuam qhov loj thiab cov duab ntawm dendrites, yog li cuam tshuam rau kev sib txuas ntawm neuronal thiab kev ua cov teeb liab.

Lwm cytoskeletal protein, tubulin, kuj tuaj yeem cuam tshuam rau kev ua haujlwm ntawm lub paj hlwb. Neurons siv tubulin los tswj lawv cov duab thiab kev sib txuas, thiab cov kev tshawb fawb tau pom tias tubulin tuaj yeem cuam tshuam qhov ceev ntawm cov teeb liab neuronal.

Ntxiv nrog rau cov neurons, cytoskeletal proteins hauv lwm lub hlwb kuj tseem tuaj yeem cuam tshuam kev nco thiab kev kawm. Piv txwv li, synaptic kev sib txuas ntawm cov neurons feem ntau cuam tshuam los ntawm cov proteins matrix, ib chav kawm ntawm cov proteins nyob rau hauv extracellular matrix. Matrix proteins tuaj yeem cuam tshuam qhov kev pheej hmoo thiab plasticity ntawm kev sib txuas synaptic, yog li cuam tshuam rau kev tsim thiab kev saib xyuas ntawm kev nco.

Hauv cov ntsiab lus, cytoskeleton muaj qhov cuam tshuam tseem ceeb ntawm lub hlwb kev kawm, thiab nco. Kev nkag siab txog lub luag haujlwm thiab cov txheej txheem ntawm cytoskeleton tuaj yeem pab peb nkag siab zoo txog qhov tshwm sim thiab kev loj hlob ntawm cov kab mob hauv lub hlwb thiab kev kawm thiab kev nco tsis zoo, thiab muab lub hauv paus rau kev tshawb fawb tob rau kev txhim kho cov kev kuaj mob thiab kev kho mob. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub cov tshuaj ntxiv los txhawb kev nco

Cov mitochondria txav mus rau hauv cov neurons yog qhov tseem ceeb los tswj kev ua kom pom kev zoo hauv cov synapses, tsim lub zog, buffering Ca2+, thiab lwm yam. [162]. Mitochondria feem ntau nyob ze rau ER, tsim mitochondria-associated ER membranes, los yog mitochondria-associated membranes (MAMs).

Cov membrane microdomains no yog thim rov qab tethers uas co-regulate thiab cuam tshuam ntau yam txheej txheem ntawm tes, piv txwv li, synthesis/transport of lipids, Ca2+ dynamics/signaling, autophagy, mitochondrial shape and size, apoptosis, and energymetabolism [163].

MAMs tau hloov pauv hauv cov kab mob neurological xws li AD, PD, thiab ALS [164]. Mitochondria ua raws li lub hub ntawm ATGs, muab cov membranes rau kev tsim ntawm autophagosomes, thiab modulating autophagic flux [165].

Mitochondria kuj raug kev txom nyem UPR (mt), thiab nyob ntawm txoj kev ua kom muaj zog, nws tau txuas nrog lub neej ntev inworms thiab nas [166], tab sis nws overactivation ua rau neurodegeneration [167].

Mitochondrial dysfunction tshwm sim los ntawm tus naj npawb ntawm mitochondria tsis txaus, tsis muaj peev xwm muab cov substrates tsim nyog rau lawv, lossis kev ua haujlwm tsis zoo hauv lawv cov khoom siv hluav taws xob thiab ATP-synthesis machinery.

Cov qib siab ntawm ROS thiab lwm hom reactive (RNS) tuaj yeem ua rau nruab nrab los ntawm dismutase enzymes thiab antioxidants [168]. Kev hloov pauv hauv cov enzymes thiab qee qhov mitochondrial respiratory complexes tau pom cov kab mob inneurodegenerative xws li ALS thiab PD [169].

Perturbations nyob rau hauv mitochondrialnumber thiab ua hauj lwm hnyav heev impair cellular homeostasis thiab ua rau qhov pib ntawm tus kab mob.Yog li ntawd, cov hlwb nrhiav kom muaj ib tug dynamic tshuav nyiaj li cas ntawm cov opposing txheej txheem ntawm mitochondrial biogenesis thiab clearance.

Lub tsub zuj zuj ntawm dysfunctional mitochondriaand / los yog poob ntawm nws biogenesis ua cell tuag. Cov kev kho mob tsis ntev los no los tiv thaiv neurodegeneration txhawm rau txhawb mitochondrial biogenesis los ntawm modulating NAD + [170], epigenetic marks [171], lossis modulating serotonin axis hauv lub hlwb [172]. Dysfunctionalmitochondrial clearance los ntawm mitophagy kuj yields neuroprotection.

Lub overexpression ntawm PTEN-induced kinase 1 (PINK1), uas yog qhov tseem ceeb rau kev pib cov txheej txheem mitophagy, nce neuronal ciaj sia nyob rau hauv tus qauv ya ntawm HD [45]. Tsis tas li ntawd, NAD + supplementation txo qis neurotoxicity hauv PINK1-mutant qauv ntawm PD [173].

Mitochondria muaj nuj nqi yog crosslinked nrog ROS thiab cellular antioxidant teb. Ua li ntawd, qhov kev hloov pauv ntawm Nuclear factor erythroid-derived factor 2-related factor 2(Nrf2) regulates the expression of cytoprotective and detoxifying genes to combat oxidativestress and neuroinflammation, aiming to txo ​​neural puas.

Yog li ntawd, nws tuaj yeem yog qhov kev siv tau zoo los ncua kev kis kab mob hauv cov kab mob neurodegenerative [174–176].Raws li kev txhawb nqa ntawm ROS, Nrf2 dissociates los ntawm Kelch-zoo li ECH-associated protein (Keap1), yog li tswj kev qhia ntawm antioxidant enzymes [177 ].

Nws tau raug piav qhia tias Keap1 kho kom haum rau ubiquitination ntawm p62 [178]. Thaum Keap1 yog downregulated, p62 accumulates nyob rau hauv hlwb thiab ua rau cytotoxicity, thaum nws overexpression txhawb lub degradation ntawm p62 ntawm txoj kev autophagy.

Ntawm qhov tod tes, p62 qhib Nrf2 dhau ntawm txoj kev autophagy los tsim p62-Keap1-Nrf2-antioxidant responsive element (ARE) txoj hauv kev thiab tiv thaiv oxidative puas tsuaj los ntawm ROS [179] .

Ntxiv mus, Nrf2 cov ntaub ntawv kev tswj hwm kev koom tes hauv kev tswj hwm ntawm mitochondrial biogenesis. Nrf2 nce qhov kev qhia ntawm peroxisome proliferator-activated receptor-gamma coactivator1-alpha (PGC-1 ) thiab nuclear respiratory factor (NRF1), uas ncaj qha koom nrog hauv kev tswj hwm ntawm mtDNA transcription.

Thaum kawg, Nrf2 tswj cov kev qhia ntawm PINK1, uas ua lub luag haujlwm tseem ceeb hauv mitophagy induction [180], qhia tias lub peev xwm antioxidant ntawm tes kuj cuam tshuam rau mitochondria xeev.

Cov kab mob neurodegenerative muaj feem xyuam rau ob qho tib si inhibition ntawm Nrf2 txoj hauv kev thiab kev ua haujlwm tsis zoo ntawm autophagy, uas ua rau muaj kev cuam tshuam ntawm ROS, senescent organelles, thiab misfolded proteins [181,182].

Cov kab mob neurodegenerative muaj feem xyuam rau ntau cov protein sib sau ua ke thiab ROS, ua rau p62-Keap1-Nrf2 cov lus pom zoo, uas yog kev tiv thaiv kev tiv thaiv hauv neurons [183,184]. Nrf2 qhia yog tsawg hauv AD tsiaj qauv thiab AD neeg mob hlwb [185]. Nrf2 khi rau ARE tshwm sim sai sai thaum lub sijhawm muaj kab mob, uas sib haum nrog kev nce hauv ROS ntau lawm [186].

Nrf2 neuroprotectsby txo ROS tiam thiab A -mediated ROS-induced toxicity [187,188]. Hauv HD, muaj kev ua haujlwm tsis zoo ntawm mitochondrial complex II, ua rau muaj kev nce hauv ROS [48]. Hauv thawj theem ntawm HD, kev kho mob nrog Nrf2 agonist ua rau muaj kev nce ntxiv ntawm cov noob caj noob ces ntawm Keap1-Nrf2-ARE hauv astrocytes thiab microglia [189].

Kev ua haujlwm ntawm Keap1-Nrf2-ARE txoj hauv kev los ntawm cov molecules me me hauv astrocytes accelerates cov kev tiv thaiv ntawm cov neurons rau non-excitotoxic glutamate toxicity [46-48].

Kev hloov pauv mitochondria muaj nuj nqi, biogenesis, thiab mitophagy yog cov yam ntxwv tseem ceeb hauv PD, thiab Nrf2 yog qhov tseem ceeb ntawm kev hloov pauv uas tswj hwm mitochondrial zoo tswj thiab homeostasis [190].Hauv PD, muaj kev ua haujlwm ntawm Nrf2-ARE system [191,192] thiab nws pharmacologicalactivation tiv thaiv PD kev loj hlob [49,50].

Nrf2 activation plays lub luag haujlwm tiv thaivROS thiab cell tuag los ntawm superoxide dismutase 1 (SOD1) mutant protein. Tsis tas li ntawd, astrocyte Nrf2 overexpression ua rau kom muaj sia nyob ntawm SC MNs thiab txuas ntxiv txoj sia nyob hauv SOD1 transgenic nas [51,52].

Tsis tas li ntawd, kev sib tham ntawm p62 thiab Keap1-Nrf2 txoj hauv kev hauv cov ntsiab lus ntawm autophagy tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tshem tawm ROS, tiv thaiv kev puas tsuaj oxidative thiab modulating ER kev ntxhov siab thaum lub sij hawm cerebralischemia-reperfusion raug mob [53].

Thaum kawg, mitochondria tsav neuronal ciaj sia, vim tias lawv hnov ​​​​txog cov neeg tuag sab hauv thiab sab nraud, ua rau muaj kev cuam tshuam ntawm cov mitochondria thiab tom qab ntawd rov-diverge mus rau ib lossis ntau txoj kev tuag ntawm tes uas ua rau muaj ntau hom kev tuag ntawm tes (xws li intrinsic apoptosis) [ 193] ib.

4. Targeting Systemic Modulation

4.1. Caloric txwv

Caloric restriction (CR) ncua kev ua neej nyob hauv cov kab mob sib txawv thiab muaj kev tiv thaiv ntawm ntau lub cev. CR cuam tshuam rau tag nrho cov kab mob: los ntawm cov txheej txheem milieu mus rau cov neeg sib txawv subcellular.

Hauv xyoo 2010, Kromer thiab cov neeg koom tes tau qhia tias CR cov txiaj ntsig yog nyob ntawm SIRT1-dependent autophagy [194]. Ntawm qhov tod tes, nws tau taw qhia tias CR yog neuroprotective hauv PD tus kab mob los ntawm ghrelin-AMPK axis, nrog AMPK yog ib qho tseem ceeb inducer ntawm autophagy [195].

Muab qhov tsis pom tseeb ntawm kev tswj hwm CR mus sij hawm ntev, kev kho mob txaus siab tau tsa hauv kev tshawb pom tshiab CR "mimetics" (CRM), uas ua rau lub cev muaj zog ntawm CR hauv lub cev [196]. Ob leeg CR thiab CR-mimetics tau ua haujlwm tau zoo hauv AD nas qauv los ntawm kev txhim kho kev txawj ntse los ntawm autophagyinduction [197], yog li lawv yog cov kev kho tshiab rau kev kho mob neurodegeneration.

4.2. Kev tawm dag zog

Kev tawm dag zog lub cev tau txais kev txaus siab vim nws lub peev xwm los txo cov kab mob pathophysiological xws li mob neuropathic lossis txhim kho cov txiaj ntsig zoo hauv cov qauv mob stroke [198].

Nws kuj tseem ua rau qeeb PD kev loj hlob los ntawm inhibition ntawm cov tshuaj tiv thaiv kab mob thiab ua kom muaj zog ntawm cov tshuaj tiv thaiv antioxidant [199]. Nws tau piav qhia tias kev tawm dag zog ua haujlwm los ntawm kev nce qib endogenous ntawm neurotrophic yam [200,201].

Ntxiv mus, nws modulates cov leeg nqaij hormone secretion, txhawb kev tiv thaiv los ntawm lub hlwb, neurogenesis, thiab amelioratingbrain laus [202]. Tsis ntev los no nws tau piav qhia tias tib yam tshuaj hormones, irisin, muaj lub luag haujlwm hauv kev tsim cov pob txha [203], qhia tias kev tawm dag zog cuam tshuam rau tag nrho lub cev.

5. Nrhiav Neuroprotectant zoo: Dab tsi muaj thiab qhov twg peb mus

Cov cim tseem ceeb ntawm cov kab mob neurodegenerative yog ib qho kev ua kom tsis raug ntawm UPR, kev txuam nrog cov txheej txheem autophagic, mitochondrial kev ua haujlwm tsis zoo, thiab lwm yam. Nyob rau hauv tas li ntawd, lawv yuav overwhelm neurons, provoking lawv demise.

Ib qho tshuaj tiv thaiv neuroprotectant yuav tsum kho cov txheej txheem no los ntawm kev txhawb nqa lub cell nrog kev ua tiav rau kev laus / kev thuam. Peb yuav tsum tau hloov kho tag nrho cov molecular network nyob rau hauv lub cell, thawb nws mus rau ib tug ua tiav rov qab ua hauj lwm.

Pom zoo tshuaj xws li Riluzole rau ALS [204], lossis kev sim tshuaj, xws li Rapamycin rau ALS [204], Spermidine, thiab DH rau AD [205,206], tsuas yog tsom ib qho ntawm cov txheej txheem degenerative, thiab cov neuronis cuam tshuam los ntawm lwm tus. Txawm hais tias lawv tuaj yeem ua rau muaj txiaj ntsig zoo, peb proposeto nrhiav cov noob caj noob ces lossis tshuaj kho mob kom pom zoo rau txoj hauv kev sib txawv molecular-multitarget therapy-es tsis yog ib lub hom phiaj xwb.

Kev nthuav qhia tshwj xeeb ntawm qee cov proteins xws li SIRT1, BIP, thiab / lossis ATG5 pab txhawb kev muaj sia nyob tom qab paj hlwb, thiab lawv tiv thaiv cov kab mob neurodegenerative.

Lawv feem ntau zoo-tune UPR lossis autophagy tes hauj lwm. Kev ua kom SIRT1 los ntawm kev siv cov nas transgenic lossis cov kab mob kis tau pom muaj kev tiv thaiv hauv cov kab mob sib txawv xws li ALS, AD, thiab HD [207-209] thiab tom qab raug mob paj hlwb [55].

SIRT1 deacetylase kev ua haujlwm pom zoo sib txawv endogenous mechanisms ntawm kev tiv thaiv: autophagy modulatesUPR los ntawm attenuating PERK tsub kom ATF6 cleavage [23,210], muaj anti-apoptotic teebmeem, thiab modulates AKT kev ua rau inhibit anoikis [211,212].

Yog li ntawd, qhov tseeb modulation ntawm nws yuav txhim khu cellular resilience. Los ntawm peb txoj kev tshawb fawb tsis ntev los no, peb xaus lus tias modulatingSIRT1 deacetylase kev ua haujlwm yog qhov tseem ceeb ntawm lub network molecular kom ua tiav cellular resilience [54,55]. Thaum kawg, BIP overexpression tiv thaiv cov aggregates thiab inducesautophagy thiab mitophagy [99], yog li nws cov kev hloov kho kuj yog ib txoj hauv kev zoo rau pawg sib txawv neuroprotective txoj hauv kev.

6. Cov lus xaus

Boosting endogenous mechanisms ntawm neuroprotection qhib kev kho mob zoo siab los kho cov kab mob neurodegenerative lossis tswj cov ntaub so ntswg homeostasis tom qab neurotrauma. Txawm hais tias qhov no yog qhov chaw tsis tau tshawb nrhiav tam sim no, nws tuaj yeem txhawb nqa biomedical txiaj ntsig zoo dua li thaiv cov cim qhia ntawm pathophysiological.

Yog li, kev pom zoo rau lawv los ntawm kev tshuaj ntsuam genetic, pharmacological, los yog kev kho mob-kho kev kho mob tuaj yeem ncua kev txhim kho pathology thiab txhim kho kev ua haujlwm zoo. Txoj kev kho kom zoo tshaj plaws yuav tsum koom nrog kev hloov pauv ntawm cov txheej txheem endogenous ntawm kev tiv thaiv tore-qauv lub network tiav thiab ua tiav kev tiv thaiv.

Tus sau kev koom tes: DR-G. thiab SM-M.-A. tau sau cov ntawv sau thiab CC ua qhov kev tshuaj xyuas tseem ceeb.Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Cov Nyiaj Txiag: Cov kev tshawb fawb no tsis tau txais nyiaj txiag sab nraud.

Cov Lus Qhia Txog Cov Ntaub Ntawv: Tsis muaj cov ntaub ntawv tshiab raug tsim lossis tshuaj xyuas hauv qhov kev tshawb fawb no. Kev sib faib cov ntaub ntawv tsis siv rau kab lus no.

Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab.

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