Insights into The Pathogenesis Of Neurodegenerative Disease: Focus On Mitochondrial Dysfunction Thiab Oxidative Stress Part 4

Lwm qhov kev piav qhia feem ntau ntawm PD yog impaired mitochondrial dynamics thiab hloov mitochondrial morphology, nrog rau elongated los yog fragmented mitochondria [334,335].

Parkinson's disease yog ib yam kab mob neurological uas tuaj yeem cuam tshuam rau lub neej niaj hnub ntawm cov neeg mob. Tus kab mob no cuam tshuam rau tib neeg cov leeg nqaij thiab kev muaj peev xwm txav mus los, ua rau cov neeg mob muaj kev mob leeg thiab tshee. Txawm hais tias qhov tshwm sim ntawm tus kab mob no txaus ntshai rau cov neeg feem coob, cov kev tshawb fawb tsis ntev los no tau pom tias tsis muaj kev sib raug zoo ntawm Parkinson tus kab mob thiab kev nco, uas yog xov xwm zoo.

Zoo li ntau lwm yam kab mob neurological, cov neeg mob Parkinson tuaj yeem ntsib teeb meem kev paub. Cov teeb meem no feem ntau txwv rau kev muaj peev xwm ua tau ntau yam kev txawj ntse. Txawm li cas los xij, cov kev tshawb fawb tau pom tias feem ntau cov neeg mob Parkinson tseem khaws lawv cov kev nco mus ntev, tshwj xeeb tshaj yog rau cov khoom ntawm xyoo dhau los. Tsis tas li ntawd, nyob rau hauv ib txoj kev tshawb no, Parkinson tus kab mob cov neeg mob cov tshuaj tiv thaiv lub sij hawm thiab kev ua tau zoo nyob rau hauv kev saib xyuas thiab kev ua hauj lwm tsis qhia tej yam txawv tseem ceeb.

Yog li ntawd, txawm tias cov neeg mob Parkinson tuaj yeem ntsib qee qhov teeb meem nco, lawv tseem tuaj yeem teb tau zoo, uas yog qhov tseem ceeb rau lawv lub neej txhua hnub. Qhov no qhia tias cov neeg mob Parkinson tuaj yeem ntxiv dag zog rau lawv lub cim xeeb los ntawm kev paub txog kev xav thiab kev cob qhia los pab lawv hloov mus rau lub neej tiag tiag.

Zuag qhia tag nrho, txawm hais tias Parkinson tus kab mob yog qhov txaus ntshai, nws tsis tas yuav ua rau lub sijhawm ntev ntawm kev txawj ntse. Cov kev tshawb fawb tau pom tias feem ntau cov neeg mob nco thiab saib xyuas nyob rau hauv ib txwm muaj. Yog li ntawd, Parkinson cov neeg mob tsis tas yuav txhawj xeeb ntau dhau txog teeb meem nco thiab tuaj yeem ua haujlwm txuas ntxiv nrog tib neeg thiab txhua yam nyob ib puag ncig lawv kom hloov kho thiab txhim kho lawv lub neej kom ntau li ntau tau. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche yog cov tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Impaired mitochondrial fusion, tejzaum nws muaj feem xyuam rau qhov txo qis ntawm qhov luv luv ntawm Opa1 piav nyob rau hauv cov qauv hlwb ntawm cov neeg mob uas muaj idiopathic PD [336], pab txhawb kev degeneration ntawm nigral dopaminergic neurons, zoo li kev sib cuam tshuam ntawm mutant LRRK2 nrog Drp1, uas txhawb nqa fissionochon. 337] ib.

-synuclein tseem tuaj yeem khi rau OMM thiab txo qis mitochondrial fusion tus nqi [338], uas, ua ke nrog nce qib Mfn1 thiab Mfn2, txhawb kev tawg thiab luv ntawm mitochondria [339].

Tsis tas li ntawd, mutant LRRK2 cuam tshuam rau kev lag luam mitochondrial los ntawm kev cuam tshuam nrog MIRO1removal, uas ua rau MIRO1 txuam nrog, uas khi dynein thiab kinesin (microtubulemotors) rau mitochondria [340].

Qhov kev tshawb pom nthuav dav yog qhov yuav tsum tau ua kom acidify cov synapticvesicles rau kev thauj khoom ntawm dopamine rau hauv cov hlab ntsha no [341], ib txoj hauj lwm ua los ntawm vacuolar ATPases uas yuav tsum tau muaj cov qib ATP [330].

Raws li xws li, nyob rau hauv lub zog-deficientconditions, dopamine yog tsis tsim nyog packed rau hauv synaptic vesicles thiab nws cytoplasmic theem nce, tsim tej yam kev mob rau nws pib-oxidation [342].

6.3. Oxidative Stress hauv Amyotrophic Lateral Sclerosis

ALS yog tus thib peb cov kab mob neurodegenerative feem ntau, tom qab AD thiab PD [16], tshwm sim ob qho tib si tsis tu ncua (90-95% ntawm cov neeg mob) thiab raws li cov kab mob tshwm sim los ntawm cov noob caj noob ces.

Ntau qhov kev hloov pauv ua rau tsev neeg ALS tau piav qhia, feem ntau cov kev hloov pauv hauv SOD1, FUS (fused hauv sarcoma / translocated hauv liposarcoma lossis heterogenous nuclear ribonucleoprotein P2), C9orf72 (chromosome 9 open readingframe 72), thiab TARDP. binding protein 43) [343,344], txoj kev tshawb fawb uas tuaj yeem pab txheeb xyuas cov txheej txheem pathophysiologic ntawm tus kab mob.

Txo cov piam thaj metabolism nrog txo qis ATP tiam tau tshaj tawm nyob rau hauv lub paj hlwb cortex ntawm SOD1G93A nas ua ntej daim duab kho mob ntawm ALS tshwm sim, thaum lub qaum qaum tau nthuav tawm cov kev txawv txav no tsuas yog tom qab theem [345].

Cov kev txawv txav zoo sib xws tau pom nyob rau hauv tib neeg cov neeg mob ib yam nkaus [346], tejzaum nws muaj feem xyuam rau kev txo qis ntawm ob lub enzymes tseem ceeb hauv glycolysis, PGK (phosphoglycerate kinase) thiab PGM2L1 (phosphoglucomutase-2-zoo li 1) [347].

Nws zoo nkaus li tias qhov kev cuam tshuam metabolic no tsis cuam tshuam rau cov neeg nyob sib ze [348]. Hauv kev teb, neurons upregulate glycolysis [349] ntawm qhov kev siv nyiaj ntawm oxidative kev nyuaj siab los yog yuav tig mus rau lwm qhov chaw ntawm lub zog xws li ketone lub cev [350].

Beta-hydroxybutyrate pab txhawb oxidation ntawm NADH thiab nce NAD + / NADH piv, yog li inhibiting mitochondrial ROS ntau lawm [351] thiab ua kom SIRT1 thiab SIRT3 [31].

SIRT1, los ntawm kev deacetylation, hloov pauv cov haujlwm ntawm PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1- )/ERR- (estrogen-related receptor) complex, nrog lub luag haujlwm tseem ceeb hauv mitochondrial biogenesisregulation [350,352]. Kev cuam tshuam ntawm cellular calcium tuav yog lwm yam uas tau piav qhia hauv lub cev muaj zog neurons ntawm cov neeg mob ALS nrog rau hauv vitro thiab hauv vivo qauv qhia mutant SOD1 [353].

Tom qab AMPA ua kom muaj zog, kev rov qab los ntawm lub cev calcium ntau ntxiv yog ncua sijhawm inmotor neurons ntawm ALS qauv [354], ua rau lawv raug rau Ca2+-induced excitotoxicity [355]. Tsis tas li ntawd, kev soj ntsuam ntawm lub cev muaj zog neurons los ntawm cov neeg mob nrog TDP-43 kev hloov pauv tau qhia txog kev txhim kho ntawm AMPA thiab NMDA receptors thiab qhov tsis sib xws ntawm MICU1 thiab MICU2 ua rau txo qis mitochondrial calcium uptake [356].

Mitochondrial kev tswj tau zoo kuj pom tias muaj qhov tsis txaus, nrog rau qhov txawv txav ntawm qhov o thiab vacuolated organelles faib feem ntau hauv lub cev ntawm tes thiab cov axon ntawm motorneurons [357]. Feem ntau, mitochondrial mitophagic receptors OPTN thiab NDP52 lub hom phiaj mitochondria los ntawm lawv cov ubiquitin-binding domain thiab nrhiav autophagosomes [358].

Kev hloov pauv ntawm OPTN thiab TBK1, encoding ib qho OPTN-muaj kinase, tau pom nyob rau hauv cov neeg mob ALS [359], ua rau muaj kev puas tsuaj ntawm mitophagy thiab tsub zuj zuj ntawm puas mitochondria uas ntxiv cov piam thaj metabolism thiab ATP tiam.

Tshaj dhauROS ua rau Drp1, nrog rau qhov ua rau muaj qhov nce ntawm mitochondrial fission, thaum txo ATPlevels ua rau tsis muaj zog autophagy thiab txo qis proteasomal protein degradation nrog rau tom qab ntawm cov protein aggregates uas tuaj yeem ua rau ER kev nyuaj siab [360].

Txawm hais tias oxidative kev nyuaj siab yuav tsis yog qhov tshwm sim, nws yuav ua rau ALS kev loj hlob, thiab, dua, mitochondria tseem ua rau lub cim ntawm ROS.

Kev hloov pauv SOD1 txo qis qhov kev sib raug zoo ntawm Cu / ZnSOD rau Zn, hloov kho nws cov khoom tiv thaiv antioxidant [361], thiab kom muaj kev puas tsuaj ntau dua ntawm DNA, tej zaum vim poob ntawm kev tiv thaiv nuclear [350]. Cov oxidants/antioxidants piv tau ntxiv hloov los ntawm qhov txo qis ntawm GSH pom nyob rau hauv lub cev muaj zog cortex ntawm ALS cov neeg mob hauv kev sib piv nrog cov neeg ua haujlwm noj qab haus huv [362].

Kev hloov pauv calcium homeostasis ua rau mitochondrial dysfunction thiab ua kom lub cev (los ntawm mitochondrial tso tawm cov cim kev tuag) lossis extrinsic (los ntawm cov ligands tshwj xeeb khi rau kev tuag receptors zoo li Fas lossis DR6-kev tuag receptor 6) [363 apoptosis. ].

Lub cev muaj zog neurons hauv thaj tsam cuam tshuam ntawm ALS cov neeg mob tau nce qib ntawm p53 [364], tejzaum nws tshwm sim los ntawm kev txo qis proteasomal degradation ntawm p53 [365], uas ua rau txo qis hauv Bcl-2 thiab nce hauv Bax, Fas, thiab caspases 8 ib., 366.

Tsis tas li ntawd, astrocytes thiab microglia tau qhib ua haujlwm, ua rau muaj kev mob ntev thiab kev tsim ntxiv ntawm ROS. Kab lis kev cai ntawm nas astroglia raug rau CSF los ntawm ALS cov neeg mob pom tau tias muaj kev tso tawm ntawm inflammatory cytokines IL-6 thiab TNF, txo cov tshuaj tiv thaiv kab mob cytokine IL10, nce kev tsim ntawm cyclooxygenase-2 thiab prostaglandinE2, thiab txo qis ntawm trophic yam xws li GDNF ( glial cell-derived neurotrophicfactor) lossis VEGF (vascular endothelial growth factor) [367].

Ntxiv mus, astrocytes los ntawm ALSpatients tso tawm cov teeb meem neurotoxic tuaj yeem ua rau lub cev muaj zog neurons los ntawm Bax-dependentmechanism [368] thiab proliferate rau ib puag ncig degenerating lub cev muaj zog neurons thiab tsim cov molecules uas inhibit axonal regrowth [369].

Activated microglia kuj yog tshuaj lom rau motorneurons. Hauv kev kawm txog qhov cuam tshuam ntawm TDP43 kev hloov pauv, microglial ua kom ua rau NF-κBand NLRP3 (NLR tsev neeg pyrin domain muaj 3) inflammasome-dependent cascade uas ua rau lub cev muaj zog neurons, thaum tsis muaj microglia, lub cev muaj zog neurons tau muaj sia nyob [370].

Tsis tas li ntawd, thaiv cov NF-κB teeb liab txoj hauv kev hauv microglia rescuedmotor neurons hauv tus qauv tsiaj ntawm ALS [362] .Table 2 qhia txog cov protein tsis txawv txav cuam tshuam nrog peb cov kab mob neurodegenerative sib tham thiab lawv cov kev ua phem rau kev ua haujlwm mitochondrial.

7. Txhais Kev Paub Txog Kev Txawj Ntse rau Kev Kho Mob

7.1. Targeting Oxidative Stress thiab Mitochondrial Dysfunction hauv Alzheimer's Disease

Kev sim kho mob ntawm kev kho mob-kho kho mob feem ntau ua tsis tiav, AD kev kho mob ua pov thawj ib qho nyuaj tshaj plaws hauv cov tshuaj niaj hnub no txawm tias muaj qhov tshwm sim thiab qhov tshwm sim ntawm tus kab mob [387].

Tam sim no, muaj rau FDA-pom zoo tshuaj siv rau kev kho mob ntawm AD, plaub ntawm cov uas (tacrine, donepezil, rivastigmine, thiab galantamine) yog acetylcholinesterase inhibitors, memantine yog NMDA antagonist, thaum qhov kev sib cav tsis ntev los no tau pom zoo aducanumab yog amyloid beta-directed. monoclonalantibid [388].

Tsuas yog rau lub xeem molecule, tsis muaj ib tug ntawm lawv yog tus kab mob-hloov.Nyob rau hauv ib tug ntev daim ntawv teev cov kev sim uas cim los ntawm inconclusive tau los yog tsis ua hauj lwm, ob peb antioxidant molecules tau rov ntsuam xyuas dua.

Curcumin tuaj yeem tshem tawm cov dawb radicals (ROS lossis reactive nitrogen hom) [389], txwv tsis pub cov enzymes koom nrog hauv cov dawb radical tiam xws li cyclooxygenasesand xanthine oxidase [390], modulate cov haujlwm ntawm endogenous antioxidants xws li glutathione peroxidase, catalase, thiab superoxide dismutases. [391], kom txo qis lipidperoxidation, thiab txo cov kev qhia ntawm NF-κB, ERK, inducible nitric oxide synthase, thiab inflammatory cytokines IL-1 thiab IL-6 [392].

Kev ua tau zoo ntawm 24-lub lim tiam curcuminsupplementation ntawm AD kev nce qib tau raug soj ntsuam nrog cov txiaj ntsig tsis txaus ntseeg hauv aphase 2 randomized, ob qhov muag tsis pom kev, kev sim tshuaj placebo (NCT 00099710) [393], ua raws li kev tshawb fawb thib ob ntawm curcumin thiab Gingko extracts tau tswj hwm ntau dua 6 lub hlis (NCT00164749), cov txiaj ntsig uas tsis tau tso tawm rau hnub tim [394].

Lwm qhov kev sim ua haujlwm, NCT01811381, lub hom phiaj los ntsuas qhov ua tau zoo ntawm curcumin hauv kev koom nrog yoga cov neeg mob uas muaj kev paub tsis meej me ntsis [394].Resveratrol tau pom tias txhim kho txoj hauv kev PI3K / Akt thiab kev hloov pauv nuclear ntawm Nrf2 [395], txhawm rau txhawm rau NF. -κB thiab MAPK txoj kev ua kom, thiab kom txo qis microglial tso tawm ntawm TNF- thiab pro-inflammatory IL-1 [396].

Ib theem 2, ob-dig muag, placebo-tswj txoj kev tshawb fawb (NCT01504854) ntawm cov nyhuv ntawm cov tshuaj resveratrol nyob rau hauv cov neeg mob uas tej zaum AD tseem tsis tau luam tawm cov txiaj ntsig [394]. NCT00678431 yog lwm qhov kev tshawb fawb ua tiav kev soj ntsuam seb puas noj zaub mov ntxiv nrog Resveratrol, qabzib, thiab malate tuaj yeem ua rau qeeb ntawm AD.

Raws li cov txiaj ntsig tau tshaj tawm, qhov sib txawv ntawm cov caj npab nquag thiab cov placebo tsis yog qhov tseem ceeb [397].A tam sim no nrhiav neeg ua haujlwm theem 1 (NCT02502253) yuav tshuaj xyuas BBB nkag mus thiab bioavailability ntawm grape noob extract nrog rau nws cov kev ua tau zoo nyob rau hauv me me kev txawj ntse, prediabetes, thiab hom 2 mob ntshav qab zib mellitus [394].

Raws li ib qho antioxidant, quercetin scavenges dawb radicals [398], upregulates antioxidant enzymes xws li glutathione transferase, glutathione peroxidase, SOD, catalase, thiab thioredoxin [398], thiab induces Nrf2-YOG txoj kev [399].

Kev sim SToMP-AD (SenolyticTherapy to Modulate Progression of Alzheimer's Disease, NCT04063124) yog ib qho kev sim txuas ntxiv I/II kev soj ntsuam bioavailability thiab kev nyab xeeb ntawm dasatinib + quercetin hauv cov neeg laus nrog rau theem AD, thaum ALSEN475partic03 tam sim no recruiting theem Kev sim I/II los ntsuas kev nyab xeeb thiab kev ua siab ntev ntawm kev sib xyaw ua ke [394].

Sulforaphane muaj peev xwm nyob rau hauv cov qauv tsiaj ntawm AD los hloov kho txoj hauv kev Nrf2/ARE, inhibit NFκB, thiab upregulate neurotrophin qhia [400]. Ib qho kev tsis tu ncua randomized, ob-dig muag, placebo-tswj sim (NCT04213391) lub hom phiaj los soj ntsuam kev nyab xeeb thiab kev ua tau zoo ntawm sulforaphane hauv cov neeg mob mob Alzheimer's mob me thiab nruab nrab [394].

Cov txiaj ntsig zoo ntawm kev txawj ntse hauv cov neeg mob AD tau txais nrog lwm cov khoom noj khoom haus antioxidant, kua isoflavone, hauv cov placebo-tswj, ob qhov muag tsis pom kev kawm (NCT00205179) uas randomized 73 tus neeg mob [401].

8-hydroxy daidzein, ib qho sib xyaw los ntawm cov kua txiv hmab txiv ntoo, nthuav tawm cov khoom antioxidant los ntawm quenching ROS, inhibiting microglialTNF- , thiab IL-6 tso tawm, thiab txhawb nqa Nrf2 antioxidant thiab Akt/NF-κB antiinflammatory pathways [402].

Chlorogenic acid, lub ntsiab compound ntawm kas fes, muaj peev xwm nyob rau hauv vitro kom txo tau intracellular ROS tsub kom, nres ua kom -secretases, BACE-1, los yog MAPK, andattenuate GSH depletion [403]. Hauv cov qauv tsiaj ntawm AD, polyphenols los ntawm kas fes txo hippocampal amyloid plaque plaque lub nra, yog li txo qis kev nco thiab kev paub tsis meej [404].

CAFCA (NCT04570085) yog multicenter, randomized, ob-dig muag, placebo-tswj kev sim npaj los ntawm University of Lille, aiming ntawm kev soj ntsuam cov nyhuv ntawm ib lub lim tiam caffeine rau kev txawj ntse muaj nuj nqi nyob rau hauv thaum ntxov thiab nruab nrab theem ntawm Alzheimer tus kab mob [ 394] ib.

Lipoic acid yog ib qho molecule nrog kev tiv thaiv kev ua haujlwm, tuaj yeem txo NF-κBactivity hauv vitro hauv cov hlwb txhawb nrog TNF- [405], thiab tuaj yeem rov ua cov vitamins C, E, thiab glutathione [406].

Ib theem me me I/II sim randomized 39 AD cov neeg mob kom tau txais lipoicacid, roj ntses, lossis cov placebo thiab ntsuas tus nqi ntawm kev paub tsis meej tshaj 12 lub hlis, qhia cov txiaj ntsig tau zoo [407] thiab tau ua raws li lwm theem I / II txoj kev tshawb fawb, NCT01058941 , nrog 67 tus neeg koom ua raws li 18 lub hlis, cov txiaj ntsig uas tseem tsis tau tshaj tawm.

Lwm qhov kev sim nrog cov tshuaj antioxidants kuj tau ua los yog tab tom ua. Piv txwv li, NCT00117403 yog ib theem 1 sim nrog cov caj npab nquag noj ua ke ntawm cov vitamins E, thiab C, lipoic acid, thiab coenzyme Q10 rau 4 lub hlis. Txawm hais tias CSF kev soj ntsuam tau qhia tias txo qis ntawm cov cim ntawm oxidative kev nyuaj siab, cov neeg tshawb xyuas tau ceeb toom tawm tsam kev poob qis dua [408].

Ib txoj kev tshawb fawb yav tom ntej nrog 4246 tus neeg koom (PREADVISE, NCT00040378) ua raws li 7-12 xyoo xaus tias tsis muaj vitamin E lossis selenium tuaj yeem cuam tshuam tus nqi ntawm kev txawj ntse poob [409].

Ntxiv mus, theem 3 mus sib piv cov txiaj ntsig ntawm tocopherol (TEAM-AD, NCT00235716) qhia tias cov vitamin E pom tau tias muaj txiaj ntsig zoo tshaj plaws ntawm cov placebo hauv kev txo qis kev txawj ntse tab sis tsis ntxiv rau cov nyhuv ntawm memantine [410].

Ib txoj kev tshawb nrhiav tam sim no theem 1, NCT04430517, yuav ntsuas qhov txiaj ntsig ntawm qhov ncauj 1000 mg ntawm nicotinamide riboside noj rau 12 lub lis piam ntawm redox txheej xwm, GSH qib, thiab mitochondrial muaj nuj nqi nrog rau kev paub hauv cov neeg koom nrog kev paub tsis meej ntawm AD [394], ib theem 1 sim ntawm supplementation ntawm glycine, alanine, thiab N-acetylcysteine ​​​​(Glutathione hauv Alzheimer's kab mob, NCT04430517) rau 24 lub lis piam yog sau npe tab sis tseem tsis tau nrhiav [394].

Latrepirdine tau pom nyob rau hauv cov kev tshawb fawb preclinical los tiv thaiv lipid peroxidation thiab inhibit qhov qhib ntawm MPTP nrog rau voltage-gated calcium ion (Ca{1}}) channelsin neurons, tiv thaiv A-induced neurotoxicity [411], thaum muaj lowacetylcholinesterase- inhibitory kev txiav txim, tsis zoo li lwm yam tshuaj antihistamine.

Nyob rau hauv ib lub lim tiam qhib-label pilot kawm ntawm 14 cov neeg mob AD, latrepirdine tau pom cov txiaj ntsig kho mob [411], uas tau ua rau theem 2 randomized, ob-dig muag, kev sim tshuaj placebo ntawm 60 mg latrepirdine hauv qhov ncauj rau 26 lub lis piam hauv 183 AD cov neeg mob (NCT00377715), uas tau lees paub qhov txiaj ntsig zoo ntawm kev paub, kev coj cwj pwm, thiab kev ua haujlwm thoob ntiaj teb [412].

Txawm li cas los xij, CONNECTIONtrial (NCT00675623), theem 3 kev soj ntsuam ntawm 60 mg latrepirdine rau 6 lub hlis hauv 598 tus neeg mob tsis tuaj yeem ua rau muaj kev cuam tshuam loj ntawm cov tshuaj piv rau cov placebo [413], thiab tsis tuaj yeem CONCERT (NCT00829374), theem 3. Kev sim tshuaj ntsuam xyuas piv ob koob tshuaj latrepirdine rau cov placebo hauv 1003 tus neeg mob.

Ib qho kev soj ntsuam ntawm ntau qhov kev tshawb fawb nrog latrepirdine hauv cov neeg mob me-rau-mob AD tau xaus lus tias txawm tias qee qhov txiaj ntsig zoo ntawm tus cwj pwm, kev paub, thiab kev ua haujlwm tsis cuam tshuam [414].

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