Ntu 1: Kev sim ntawm Neuroprotective Thiab Neuroregenerative Therapeutic Strategies hauv Ntau Yam Sclerosis

Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791

Pls nyem qhov no mus rau Ntu 2

Niklas Huntemann1,2 · Leoni Rolfes1 · Marc Pawlitzki2 · Tobias Ruck1 · Stefen Pfeufer2 · Heinz Wiendl2 · Sven G. Meuth1

Tau txais: 15 Plaub Hlis 2021 / Luam tawm online: 4 Lub Rau Hli 2021

© Tus sau 2021

Cistanche muaj cov nyhuv neuroprotective zoo heev

Abstract

Tsis ntev los no, ntau cov tshuaj tau pom zoo rau kev kho mob ntau yam sclerosis (MS). Cov kev kho mob no tsuas yog nyob rau hauv immunomodulatory los yog immunosuppressive tswv yim tab sis tsis txaus hais txog remyelination thiabneurotiv thaiv. Txawm li cas los xij, ob pebneurodegenerativeCov neeg ua haujlwm tau pom muaj peev xwm hauv kev tshawb fawb ua ntej thiab nkag mus rau Phase I mus rau III kev sim tshuaj. Txawm hais tias tsis muaj ib qho ntawm cov tebchaw no tseem tau mus rau kev pom zoo, kev nkag siab qhov ua rau tsis ua haujlwm tuaj yeem nthuav peb txoj kev paub txogneurotiv thaivthiabneuroregenerationhauv MS. Tsis tas li ntawd, feem ntau ntawm cov kev tshawb fawb tau pom los ntawm cov txheej txheem ntawm kev ua haujlwm zoo ib yam thiab ua pov thawj pom tias muaj txiaj ntsig zoo hauv kev tshawb fawb tsiaj. Yog li ntawd, kev kawm los ntawm lawv qhov tsis ua haujlwm yuav pab peb tswj hwm kev txhais lus ntawm cov kev tshawb pom uas tau txais hauv cov kev tshawb fawb ua ntej mus rau hauv daim ntawv thov kho mob. Ntawm no, peb sau cov kev sim siab ntawm MS kev kho mob tau tshaj tawm txij li xyoo 2015 uas tau ua tsis tiav lossis raug cuam tshuam vim tsis muaj txiaj ntsig, tsis zoo, lossis lwm yam laj thawj. Peb piav qhia ntxiv txog qhov laj thawj hauv qab cov tshuaj no thiab txheeb xyuas keeb kwm yav dhau los ntawm kev ua tsis tiav los sau cov kev nkag siab tshiab rau MS pathophysiology thiab txhim kho cov qauv kev kawm yav tom ntej. Txhawm rau kom meej meej, qhov kev tshuaj xyuas no tsom rau cov neeg ua haujlwm txhawb nqa remyelination thiab cov tshuaj nrog feem ntauneuroprotectivecov khoom los yog cov kev tsis sib haum xeeb. Cov kev sim tshuaj tsis ua tiav uas tau txais kev tiv thaiv immunomodulation tau nthuav tawm hauv ib tsab xov xwm cais.

K

Ntsiab Lus

Cov kev tshawb fawb tshiab tsim nrog cov qhab nia kho mob sib xyaw ua ke thiab lub sijhawm soj ntsuam ntev dua yog xav tau los piav qhianeuroregenerativethiabneuroprotectiveteebmeem.

Hauv particular, ntxiv-on kev sim sib txuas lus cog lusneuro-generativeCov tebchaw nrog cov kev kho mob monoclonal antibody zoo heev tuaj yeem yog txoj hauv kev zoo.

Cov teebmeem ntawm hnub nyoog, nrog rau kev cuam tshuam ntawm lub sijhawm tsis yooj yim, yuav tsum tau coj mus rau hauv tus account ntau ntxiv hauv kev tsim cov kev tshawb fawb soj ntsuam.neuroprotectivethiabneuron-generativetus neeg sawv cev.

1 Kev Taw Qhia

Kev kho mob ntawm ntau tus kab mob sclerosis (MS) tau dhau los ua kev puas tsuaj hauv 25 xyoo dhau los, nrog ntau tus neeg sawv cev tshiab tau txais kev pom zoo thiab muab ntau txoj kev kho mob rau cov neeg mob [1]. Feem ntau ntawm cov tshuaj no tau tsim los hloov kho lub cev tiv thaiv kab mob ua haujlwm, feem ntau tau txais txiaj ntsig zoo rau cov neeg mob rov qab-remitting MS (RRMS). Txawm li cas los xij, kwv yees li 10-15 feem pua ​​​​ntawm cov neeg mob tau qhia txog thawj qhov kev mob kis tau zoo (PPMS), thiab tseem nyob hauv RRMS, kev hloov mus rau theem nrab MS (SPMS) feem ntau tshwm sim [2]. Kev hloov pauv mus rau qib MS yog nrog los ntawm kev hloov pauv los ntawmneuroinflamation-driven kab mob pathogenesis rau neurodegeneration [3]. Yog li ntawd, qhov ua tau zoo ntawm kev kho mob immunomodulatory yog attenuated nyob rau hauv cov neeg mob uas muaj kab mob loj hlob [4, 5]. Yog li, kev kho mob txhawb nqaneuroregenerationyog urgently yuav tsum tau. Cov txheej txheem no yuav muaj xws li cov tswv yim uas txhawb nqa remyelination los ntawm inducing proliferation thiab sib txawv- pib ntawm oligodendrocyte precursor cells (OPCs) nrog rau kev ciaj sia ntawm cov laus oligodendrocytes [6]. Tshaj li remyelination, neuroregeneration kuj tuaj yeem ua tiav los ntawm cov neeg ua haujlwm muab kev tiv thaiv neuro. Cov neeg ua haujlwm no tsom mus rau qhov dav dav ntawm cov txheej txheem tsis zoo xws li excitotoxicity, mitochondrial tsis ua haujlwm, lossis oxidative stress [7]. Hmoov tsis zoo, tam sim no tsis muaj ib qho ntawm cov tshuaj neurodegenerative no tau ua lawv txoj hauv kev siv tshuaj kho mob[8].

Txawm li cas los xij, cov tshuaj uas tau sim hauv kev sim tshuaj feem ntau yog ua raws li qhov laj thawj pom tseeb thiab tau raug ntsuas ntau dhau hauv kev sim tsiaj. Cov laj thawj qhia txog lawv qhov tsis ua tiav yog ntau yam.

Hauv qee qhov kev tshawb fawb, kev nkag siab tau txais los ntawm cov qauv tsiaj tsuas yog tsis txhais tau rau kev sim tshuaj, txawm hais tias lawv tsis muaj kev xav txog kev xav ntawm pathophysiological. Hauv lwm qhov xwm txheej, cov xwm txheej tsis txaus ntseeg tau tshwm sim (AEs) tshwm sim lossis cov txheej txheem tsis txaus ua rau pom qhov muaj txiaj ntsig zoo ntawm cov tshuaj tshawb fawb. Cov kev txwv hauv kev sim tsim no suav nrog cov ntsiab lus ntawm kev kawm tsis tsim nyog, tsis muaj sijhawm taug qab tsis txaus, thiab cov qauv tsis zoo. Yog li, kev tshuaj xyuas ntawm cov kev tshawb fawb no yog qhov tseem ceeb rau kev nce qib hauv kev tshawb fawb ua ntej thiab kho mob.

Qhov kev tshuaj xyuas no ntsuasneuroregenerativethiab lwm cov tswv yim kho mob hauv MS txij li xyoo 2015 uas tau nkag mus rau kev sim tshuaj Phase I-III thiab ua tsis tiav lossis raug cuam tshuam. Ua ntej, peb piav qhia txog cov txheej txheem ntawm kev ua raws li (pre-) cov ntaub ntawv kho mob hauv qab txhua txoj hauv kev. Tom qab piav qhia txog qhov kev sim, peb txheeb xyuas cov laj thawj tseem ceeb rau kev ua tsis tiav thiab qhia txog qhov tshwm sim rau kev tshawb fawb yav tom ntej ntawm autoimmuneneuroinflamationthiab MS.

zaj tshuaj ntsuab cistancherauAlzheimer tus kab mob

2 Txoj kev

Txhawm rau txheeb xyuas cov kev sim cuam tshuam, peb tau tshawb nrhiav MEDLINE rau cov khoom tsim nyog raws li tau piav qhia yav dhau los [9]. Peb suav nrog cov ntawv uas tau luam tawm thaum Lub Ib Hlis 01, 2015 thiab 31 Lub Kaum Ob Hlis 2020. Cov ntsiab lus siv hauv Cov Ntsiab Lus Kho Mob yog 'ntau yam sclerosis', 'sim', thiab 'kev kho' lossis 'kev kho'. Txij li thaum cov kev sim siab nrog cov txiaj ntsig tsis zoo tsuas yog luam tawm raws li kev paub daws teeb meem lossis tsis yog tag nrho, peb kuj tau tshawb nrhiav cov kev tshawb fawb cuam tshuam los ntawm cov rooj sib tham thoob ntiaj teb (Lub Rooj Sib Tham Txhua Xyoo ntawm American Academy of Neurology [AAN], European / Asmeskas Pawg Neeg Saib Xyuas Kev Kho Mob thiab Kev Tshawb Fawb Hauv Ntau Yam Sclerosis [ ECTRIMS/ACTRIMS]), kev sab laj ntawm lub teb chaws thiab thoob ntiaj teb kev sau npe rau kev sim tshuaj (United States National Library of Medicine; clinicaltrials.gov; European Union Drug Regulating Authority Clinical Trials Database [EudraCT]), thiab kev sib txuas lus ntawm tus kheej nrog cov kws sau ntawv. Tom qab tshem tawm cov duplicates, peb tau ua qhov kev ntsuam xyuas paub daws teeb meem lossis cov ntawv nyeem tag nrho kom tsis suav nrog kev sim ntawm cov tebchaw uas yog:

i. mus txog qhov kawg ntawm qhov kev kawm thawj zaug (PSE)

ii. tau npaj los kho cov teeb meem thib ob ntawm MS (piv txwv li, spasticity, qaug zog)

iii. uas tau tshawb xyuas ua ke nrog lwm cov tshuaj yog tias lwm yam tshuaj tsis raug pom zoo los ntawm European Medicines Agency (EMA) / US Food and Drug Administration (FDA) rau kev kho mob ntawm MS.

Yog tias cov kev tshawb fawb tau ua nyob rau hauv pawg nrog ob qho tib si rov qab los ntawm MS lossis mob optic neuritis (AON) thiab cov neeg mob MS zuj zus, qhov sib xyaw tau raug xa mus rau pawg twg uas muaj ntau tus lej.

Cov kev tshawb nrhiav tau xa rov qab 6656 cov ntaub ntawv, 21 ntawm qhov ntawd, nrog rau tag nrho ntawm 15 tus neeg sawv cev sib txawv, tau ua raws li peb cov txheej txheem suav nrog (rau cov ntsiab lus ntawm kev tshawb nrhiav lub tswv yim saib daim duab 1; rau cov ntsiab lus ntawm ib tus neeg sib txuas saib Table 1).

3 Kev Kho Mob Tsis Zoo hauv Kev Kho Mob Kho Mob Mob Neuritis thiab Relapsing Multiple Sclerosis

3.1 Neuroprotective Approaches

Rau qee qhov, MS tuaj yeem nkag siab tias yog kev sib tham ntawmneuroinflamationthiabneurodegeneration[10]. Yog li, dhau ntawm kev kho immunomodulatory, muaj qhov xav tau ceev ceevneuroprotectivekho mob kom ameliorateneurodegenerativecov txheej txheem thiab ncua kev xiam oob qhab hauv MS.NeuroprotectionMuaj ntau ntau ntawm cov txheej txheem xws li kev txhawb nqa ntawm trophic yam thiab kev tiv thaiv excitotoxicity nrog rau oxidative kev nyuaj siab rau kev kho ntawm mitochondrial muaj nuj nqi [7, 8]. Vim qhov no ntau hom phiaj, ib tug dav spectrum ntawmneuroprotectivecov neeg ua haujlwm tau raug sim hauv kev sim tshuaj.

3.1.1 Atorvastatin

3.1.1.1 Tom qab Hydroxymethylglutaryl-CoA reductase inhibitors (ntawm no hu ua statins) tau dav siv.

Cov tshuaj tiv thaiv dyslipidemia. Dhau li ntawm inhibition ntawm txoj kev mevalonate, statins tau pom tias tiv thaiv excitotoxicity [11], induce lub secretion ntawm neurotrophic yam [12], thiab txo qhov tso tawm ntawm dawb radicals vim yog inhibition ntawm inducible nitric oxide synthase [13]. Tshaj lineurotiv thaiv, statins nthuav tawm cov cuab yeej immunomodulatory. Ntawm cov no yog txwv kev nthuav qhia antigen [14], inhibition ntawm leukocyte migration hla cov ntshav-hlwb barrier (BBB) ​​[15], thiab induction ntawm kev hloov ntawm inflammatory teb rau T helper 2 (TH2) hlwb [16]. Xav txog cov noneuroprotectivethiab cov teebmeem immunomodulatory, kev kho mob statin unsurprisingly proven convincing kev ua tau zoo nyob rau hauv kev sim autoimmune encephalomyelitis (EAE) [15, 16]. Ntxiv mus, ntau qhov kev tshawb fawb me me qhia tau hais tias muaj txiaj ntsig ntawm statins hauv RRMS, ib leeg lossis ua ke nrog interferon- [17-21].

3.1.1.2 Kev Kawm Hauv 2016, cov txiaj ntsig ntawm ARIANNA txoj kev tshawb fawb tau luam tawm [22].

Kev tso npe rau 154 tus neeg mob RRMS, atorvastatin tau soj ntsuam ntawm koob tshuaj 40 mg / hnub raws li kev kho ntxiv rau interferon- 1b tshaj 24 lub hlis hauv ob qhov muag tsis pom kev, randomized, tswj cov placebo. Atorvastatin ua tsis tiav los txhim kho pSE, piv txwv li, kev hloov pauv ntawm lub paj hlwb. Tsis tas li ntawd, cov ntsiab lus thib ob, suav nrog kev kho mob (xws li Expanded Disability Status Scale [EDSS] [23], txhua xyoo relapse tus nqi [ARR]), kev txawj ntse (Rao roj teeb test [24]), thiab magnetic resonance imaging (MRI) cov qauv (xws li, gadolinium-enhanced lesions [GELs]) tsis tau ntsib.

3.1.1.3 Tawm tswv yim Qhov kev poob siab ntawm txoj kev tshawb fawb ARI- ANNA yog ua raws li qhov ua tsis tiav ntawm ntau yam kev sim tshuaj ntsuam xyuas lub luag haujlwm ntawm statins hauv RRMS [25–28, 33].

Feem ntau, cov txiaj ntsig ntawm qhov kev sim loj tshaj plaws hauv cov ntsiab lus no, txoj kev tshawb fawb SIMCOMBIN, yog qhov zoo kawg nkaus [29]. Hauv Phase IV qhov kev sim no, kev kho mob nrog simvastatin ua ib qho kev kho ntxiv rau interferon- 1ib qho ua tsis tau tej yam txiaj ntsig. Tsis tas li ntawd, ob qhov kev tshuaj ntsuam xyuas meta tau lees paub tias kev kho mob statin tsis txhim kho kev kho mob lossis MRI tsis zoo hauv RRMS [30, 31]. Qee qhov kev sim txawm hais tias muaj qhov nce ntawm T2 qhov txhab lossis txhim kho kev kho mob kev ua haujlwm hauv cov neeg mob tau txais statins [18, 28–30, 32, 33]. Cov kev soj ntsuam no yuav nyob ntawm seb cov txheej txheem cuam tshuam los ntawm statin. Cov txheej txheem no tej zaum yuav muaj peev xwm txawm ua rau mob neuronal- zog thiab degeneration. Cov txheej txheem hauv qab no suav nrog kev txhim kho kev tso tawm ntawm cov cytokines pro-inflammatory cytokines [34] nrog rau kev txo qis ntawm OPCs thiab oligodendrocytes, yog li cuam tshuam cov remyelination [35].

Tsis tas li ntawd, statins kuj tseem cuam tshuam cov teebmeem cuam tshuam lawv kev sib xyaw nrog interferon-. Ntawm cov no yog qhov inhibition ntawm interferon-induced phosphorylation ntawm cov teeb liab transducer thiab activator ntawm transcription (STAT) 1 [36] thiab kev tawm tsam ntawm interferon-mediated suppression ntawm matrix metalloproteinases (MMPs) [37]. Muab cov kev tawm tsam no, statins yuav zoo dua ua ke nrog lwm yam kev kho kab mob-hloov kho (DMTs) los tsim kev sib koom ua ke. Txij li thaum lub mechanism ntawm kev txiav txim ntawm interferon- kev kho mob yog multifactorial thiab tseem tsis tau to taub tag nrho

[38], kev tshawb fawb ntawm cov cog lus cog lus raws li cov tshuaj ntxiv rau interferon- yuav tsum tau nug txog feem ntau. Hloov chaw ntawm interferon-, kev sib xyaw ua ke nrog cov tshuaj tiv thaiv kab mob zoo heev uas tau pom los ntawm lub tswv yim meej ntawm kev ua haujlwm zoo li tsim nyog los ntsuas qhov cuam tshuam ntawmneurotiv thaivthiabneuroregeneration.

Qhov tseem ceeb, simvastatin tau pom tias txo qis lub hlwb atrophy los ntawm 43 feem pua ​​​​hauv ob qhov muag tsis pom kev, cov tshuaj placebo-tswj, suav nrog 140 tus neeg mob nrog SPMS (MS-STAT) [39]. Qhov kev cia siab no tau pib qhov kev sim ua ntu III txuas ntxiv [40]. Cov txiaj ntsig zoo ntawm simvastatin hauv SPMS tsa cov lus nug ntawm seb qhov twgneuroprotectiveCov txiaj ntsig ntawm statins tuaj yeem tshaj lawv cov peev xwm tiv thaiv kab mob. Qhov tseem ceeb yog qhov kev tshawb fawb tsis ntev los no uas suav nrog cov neeg mob los ntawm kev sim ARIANNA thiab lwm txoj kev tshawb fawb uas tau soj ntsuam qhov cuam tshuam ntawm atorvastatin ntawm RRMS raws li kev siv tshuaj ntxiv rau interferon- 1a [41]. Plaub caug-ob tus neeg mob uas tau muab faib rau cov placebo thiab 27 tus neeg koom uas tau txais atorvastatin hauv kev tshawb fawb thawj zaug tau ua raws li 8 xyoo. Zoo kawg nkaus, pawg atorvastatin pom qhov txo qis ntawm EDSS kev loj hlob; Txawm li cas los xij, tsis muaj qhov tseem ceeb amelioration ntawm tus nqi rov qab.

Hauv kev xaus, statins tsis tuaj yeem muab cov txiaj ntsig zoo rau cov neeg mob RRMS hauv lub sijhawm luv. Txawm li cas los xij, kev cuam tshuam mus sij hawm ntev thiab kev siv hauv SPMS yuav tsum tau soj ntsuam ntxiv kom paub meej tias thawj qhov txiaj ntsig zoo.

3.1.2 Lipoic acid

3.1.2.1 Keeb kwm

Lipoic acid (LA) yog ib qho endogenously tsim antioxidant, uas yog siv, piv txwv li, rau kev kho mob ntshav qab zib peripheral neuropathy [42]. Anti-oxidative functions nyob ntawm ntau yam txheej txheem. Nrog nws daim ntawv txo qis, dihydrolipoic acid, LA tsim ib lub zog redox ob peb [43]. Ua ke, lawv rov tsim dua lwm cov tshuaj tiv thaiv oxidative [44], ua haujlwm chelators ntawm hlau ions [45], thiab txhim kho mitochondrial kev ua haujlwm [43]. Los ntawm kev tshem tawm cov dawb radicals [44], LA tiv thaiv cov pa oxygen reactive hom-mediated dysfunction ntawm BBB thiab transendothelial monocytic migration [46]. Tsis tas li ntawd, LA txo cov cytokine secretion, proliferation, thiab central nervous system (CNS) nyob rau hauv lub traction ntawm T hlwb [47, 48]. Qhov cuam tshuam ntawm T hlwb zoo li tau kho los ntawm kev nce hauv lub cell ntawm cyclic adenosine monophosphate (cAMP) [49]. Ob peb ntawm cov teebmeem uas tau hais los twb tau pom hauv MS cov neeg mob tau txais LA [50–52]. Muab qhov cuam tshuam rau cov txheej txheem o thiab cov txheej txheem oxidative, nws tsis yog qhov xav tsis thoob tias EAE cov kev sim ua kom pom qhov ua tau zoo ntawm LA hauvneuroinflamationthiabneurodegeneration[47, 48].

cistanche tubulosarau AD

3.1.2.2 Kev Kawm

Ua tiav xyoo 2016, ob qhov muag tsis pom kev, tshuaj placebo-tswj, randomized Phase I sim tshuaj xyuas qhov cuam tshuam ntawm LA hauv 31 tus neeg mob kuaj pom nrog kev sim AON [53]. Kev kho mob nrog 1200 mg / hnub LA lossis placebo tau pib ua ntej 14 hnub tom qab kuaj pom thiab siv sijhawm li 6 lub lis piam, tom qab ntawd los ntawm 18- lub lis piam soj ntsuam. Lub pSE ntsuas qhov cuam tshuam ntawm LA ntawm retinal paj fiber txheej (RNFL) tuab tom qab 24 lub lis piam piv rau hauv paus. LA ua tsis tiav los txhim kho RNFL rov tsim dua tshiab. Strikingly, pawg LA txawm pom qhov sib txawv ntawm kev txhim kho RNFL poob piv rau cov placebo. Nyob rau sab saum toj ntawm qhov ntawd, cov txheej txheem thib ob (piv txwv li, RNFL thickness tom qab 12 lub lis piam, kev hloov pauv hauv qhov qis- thiab siab qhov pom kev pom zoo [VA]) tsis tau raws li.

3.1.2.3 Lus Qhia Cov txiaj ntsig los ntawm qhov kev tshuaj xyuas yuav tsum tau muab txhais nrog kev ceev faj vim muaj cov neeg koom nrog tsawg thiab lub sijhawm luv luv [53]. Txawm li cas los xij, qhov txiaj ntsig tsis txaus ntseeg ntawm qhov kev sim no yog qhov tsis sib xws rau cov txiaj ntsig ua ntej kev kho mob. Ntawm ntau EAE cov kev tshawb fawb tau ua, txawm li cas los xij, tsuas yog ob qho kev tshawb fawb los ntawm AON. Ua ntej, Chaudhary thiab al tau qhia txog kev txo qis ntawm axonal raug mob ob qho tib si tom qab prophylactic thiab kev kho mob nrog LA [54]. Kev tiv thaiv ntawm retinal ganglion hlwb (RGCs) kuj tau pom los ntawm Dietrich li al [55]. Txawm li cas los xij, txoj kev tshawb fawb tom kawg tau tshaj tawm tias qhov kev tiv thaiv no tsuas yog txhim kho qhov pom kev ua haujlwm thaum LA tau tswj hwm ua ntej kev kho mob tshwm sim tab sis ua tsis tiav thaum thov tom qab pib mob. Tsis tas li ntawd, tsis zoo li kev kho mob prophylactic, kev tswj hwm kev kho mob kuj ua tsis tau zoo los tiv thaiv cov txheej txheem sab hauv retinal los ntawm degeneration thiab ameliorate inflammatory infiltration rau hauv cov hlab ntsha optic. Yog li ntawd, kev kho mob LA hauv AON tsuas yog tsim nyog thaum siv tam sim ntawd tom qab qhov tsos mob tshwm sim. Hmoov tsis zoo, cov ntaub ntawv ntawm lub sijhawm nruab nrab ntawm thawj koob tshuaj LA tsis tau muab rau hauv qhov kev tshuaj xyuas [53].

Tom ntej no, cov yam ntxwv pharmacokinetic ntawm LA kuj cuam tshuam nws txoj kev siv hauv kev kho mob. Tsis tsuas yog luv luv ib nrab-lub neej tab sis, tseem ceeb tshaj, muaj zog interindividual variabilities nyob rau hauv lub concentration siab tshaj plaws thiab bioavailability nyuaj tswj kev kho mob [52, 56, 57]. Sib nrug los ntawm kev sib txawv ntawm tus kheej, kev siv cov qauv sib txawv ntawm LA ua rau cov lus teb sib txawv [50, 56]. Hmoov tsis zoo, tsis muaj cov ntaub ntawv qhia txog cov qauv siv hauv kev kawm tau piav qhia [53].

Tshaj li pharmacokinetics, kev txiav txim siab ntawm pharmacodynamics tseem ceeb hauv cov ntsiab lus no. Cov lus teb rau LA cov thawj coj zoo li txawv ntawm ntau hom MS [51]. Kev nce cAMP cov lus teb ntawm peripheral ntshav mononuclear hlwb (PBMCs) raws li kev tswj hwm LA tau pom hauv cov neeg mob SPMS. Txawm li cas los xij, kev kho mob ntawm cov neeg mob RRMS ua rau txo qis cAMP qib. Cov lus teb ntawm cov neeg mob AON rau LA hais txog cAMP tsis paub. Muab qhov LA-induced nce ntawm cAMP hauv SPMS, nws yuav tsum tau hais tias daim ntawv thov LA txo qhov feem pua ​​​​ntawm cov paj hlwb hloov pauv (PBVC) txhua xyoo los ntawm 68 feem pua ​​​​hauv cov neeg mob SPMS piv rau cov placebo hauv ob qhov muag tsis pom kev sim [58]. Yog li ntawd, Phase II txoj kev tshawb fawb hauv cov neeg mob uas muaj kev vam meej MS tau pib hauv 2018 [59]. Yog li, kev tshawb fawb ntawm LA zoo li yuav txhawb nqa ntau dua rau cov neeg mob uas muaj kev vam meej MS es tsis yog AON.

3.1.3 Flupirtine Maleate

3.1.3.1 Keeb kwm

Flupirtine maleate (ntawm no hu ua flirting) yog cov tshuaj uas tsis yog opioid analgesic [60]. Cov txiaj ntsig tau txais los ntawm cov qauv tsiaj ntawm Parkinson's disease (PD) [61] thiab Alzheimer's disease (AD) [62] nrog rau kev sim tshuaj rau cov neeg mob uas kuaj pom muaj Creutzfeldt-Jakob dis-ease [63] qhia.neuroprotectivecov khoom ntawm tus neeg sawv cev no. Flupirtine zoo li ua kom ruaj khov ntawm daim nyias nyias muaj peev xwm thiab txo qis excitability los ntawm kev ua kom KCNQ-type- [64] thiab G protein-coupled inwardly rectifying potassium channels [65]. Indirect antagonistic cuam tshuam ntawm N-Methyl-D-aspartate (NMDA) receptor kev ua haujlwm [66] thiab gating ntawm -aminobutyric acid (GABA)A receptors [64] zoo li ntxiv txhawb rauneurotiv thaiv. Thaum kawg, flupirtine-inducedneurotiv thaivkuj tau pom nyob rau hauv cov qauv tsiaj. Thaum lub sij hawm sim AON, piv txwv li, kev kho mob flupirtine alleviated degeneration ntawm RGCs thiab txhim kho qhov pom kev ua haujlwm thaum siv los ua tshuaj ntxiv rau interferon- 1a [67].

3.1.3.2 Kev tshawb fawb suav nrog 30 tus neeg mob RRMS, txoj kev tshawb fawb FLO- RIMS tau ua raws li kev sim ob qhov muag tsis pom kev II [60]. Cov neeg koom nrog tau txais flupirtine ntawm ib hnub noj ntawm 300 mg lossis placebo rau 1 xyoos, ob qho tib si raws li kev kho mob ntxiv rau interferon- 1b. Thaum qhov kev sim siab tau npaj ua ntej nrog 80 tus neeg mob, tsuas yog 30 tus neeg mob tau randomized vim tsis muaj teeb meem nrhiav neeg ua haujlwm. Thaum kawg, tsuas yog 12 tus neeg mob rau ib pawg ua tiav qhov kev sim. Vim qhov kev tshawb nrhiav tus cwj pwm ntawm txoj kev tshawb no, tsis muaj pSE tau txhais. Kev kho mob nrog flupirtine ua rau muaj txiaj ntsig zoo dua li cov placebo txog kev kho mob tsis zoo xws li tus lej ntawm kev rov qab los lossis EDSS kev loj hlob. Ntxiv mus, pab pawg kho mob nquag kuj tau pom qhov txo qis ntawm GELs. Txawm li cas los xij, tsis muaj ib qho ntawm cov kev soj ntsuam no tseem ceeb. Hais txog kev nyab xeeb profile, tsib tus neeg mob hauv pab pawg flupirtine tau nthuav tawm lub siab enzymes ua rau kev txiav tawm hauv ob kis.

3.1.3.3 Tawm tswv yim Txawm hais tias qee qhov kev hloov pauv tsis tseem ceeb qhia tau tias muaj txiaj ntsig me me, FLORIMS sim tsis tau ntxiv qhov kev nkag siab zoo rau hauvneuroprotectivemuaj peev xwm ntawm flupirtine vim muaj tsawg tus neeg mob tuaj koom. Qhov tsis txaus ntawm cov neeg tuaj koom no yog tshwm sim los ntawm cov teeb meem ntawm kev nrhiav neeg ua haujlwm thiab txo lub zog rau 59 feem pua ​​​​ntawm cov kev hloov hauv EDSS [60]. Hmoov tsis zoo, cov laj thawj hauv qab kev cuam tshuam rau kev nrhiav neeg ua haujlwm tsis tau piav qhia ntxiv tab sis yuav muaj feem cuam tshuam nrog cov lus ceeb toom ntawm cov mob hnyav ntawm flupirtine-induced hepatotoxicity [68]. Cov tshuaj ua rau lub siab raug mob ua rau muaj kev pom zoo tshem tawm ntawm flupirtine los ntawm EMA hauv xyoo 2018. Cov txheej txheem ntawm flupirtine-mediated hepatic puas yog tsis to taub tag nrho. Kev koom nrog caj ces nrog rau chav kawm II tib neeg leukocyte antigen haplotype tau pom, qhia txog qhov tsis tsim nyog T cell teb [69]. Ntawm qhov tod tes, kev tsim cov tshuaj muaj zog heev thiab hepatotoxic metabolites tau tham txog [70].

Ntxiv mus, tseem muaj qhov tsis paub meej txog lub luag haujlwm ntawm flupirtine hauvneuroinflamation. Piv txwv li, kev kho mob ntxiv nrog flupirtine thaum lub sij hawm EAE, piv txwv li, tsis tau qhia qhov zoo dua piv rau ib leeg interferon- 1kev tswj hwm [67]. Raws li qhov kev soj ntsuam no, flupirtine tsis tau kho cov tsos mob EAE thaum siv ib leeg. Tsis tas li ntawd, qhov hais txog kev tiv thaiv ntawm kev kho mob flupirtine ntawm RGCs thaum lub sij hawm sim AON tau kho nws tus kheej los ntawm cov txheej txheem inflammatory. Yog li, kev xaiv ntawm RRMS pawg rau qhov kev tshuaj xyuas yuav tsum tau tshuaj xyuas. Txawm li cas los xij, tom qab kev pom zoo tshem tawm los ntawm EMA, kev tshawb fawb ntxiv txog kev kho flupirtine hauv MS raug cuam tshuam.

Cistanche herba muaj cov nyhuv neuroprotective zoo heev

3.1.4 Uric Acid-Inosine

3.1.4.1 Keeb kwm

Uric acid (UA) yog purine metabolite nrog kev tiv thaiv oxidative muaj peev xwm [71]. Txij li thaum qhov ncauj supplementation tsis ua kom cov ntshav concentration ntawm UA txaus, nws precursor inosine tuaj yeem siv los nce qib UA [72]. UA-mediated anti-oxidation feem ntau yog ntaus nqi rau kev tshem tawm ntawm peroxynitrite [73]. Peroxynitrite yog ibneuro-tshuaj lom neeg uas ua rau muaj kev puas tsuaj rau oligodendrocytes [74] thiab ua rau muaj kev cuam tshuam BBB [75]. Ntxiv mus, peroxynitrite yog txuam nrog kev tsim cov quav hniav hauv MS [76]. Nco ntsoov, inosine thiab UA tau ua pov thawj tias muaj txiaj ntsig zoo hauv ntau qhov kev sim EAE, raws li kev kho mob txo qhov mob hnyav [77, 78].

Tsis tas li, cov ntaub ntawv kho mob qhia txog kev koom tes ntawm UA hauv MS. Ua ntej, txawm tias muaj cov lus ceeb toom tsis sib xws, kev tshuaj ntsuam xyuas meta tau pom tias cov qib ntshav ntawm UA tau txo qis hauv MS [79]. Qhov zoo siab, qhov qis tshaj plaws tau pom hauv cov neeg mob SPMS. Qhov thib ob, cov kev tshawb fawb ntxaib pom tau tias txo UA qib hauv cov menyuam ntxaib kuaj pom nrog MS [80]. Thaum kawg, kev soj ntsuam ntawm ntau dua 20 lab tus neeg mob cov ntaub ntawv tau qhia tias tus naj npawb ntawm cov neeg mob raug kev txom nyem los ntawm MS thiab gout, uas yog tus cwj pwm los ntawm kev nce siab ntawm UA, qis dua qhov xav tau, qhia txog lub luag haujlwm tiv thaiv UA hauvneuroinflamation[77].

3.1.4.2 Kev Kawm

Kev nyab xeeb thiab kev ua tau zoo ntawm inosine tau raug soj ntsuam hauv 36 tus neeg mob nrog RRMS hauv Phase II sim [71]. Ino-sine ntawm ib hnub koob tshuaj 3 g los yog placebo tau muab coj los ua ob qhov muag tsis pom kev raws li cov tshuaj ntxiv rau interferon- 1a. Cov neeg mob tau ua raws li 12 lub hlis. PSE tau soj ntsuam AEs thiab kuaj cov txiaj ntsig ntsig txog UA. Unsurprisingly, inosine kev kho mob nce qib UA piv rau cov placebo. Ob tus neeg mob kho nrog inosine tau ntsib UA ntau dua 10 mg / dL thaum muaj mob raum mob. Kaum tus neeg mob ntxiv tau pom tias asymptomatic hyperuricemia. Cov hom phiaj thib ob tau txheeb xyuas qhov chaw kho mob (xws li, tus naj npawb ntawm rov qab los) thiab kev ua haujlwm ntawm cov kab mob hluav taws xob (xws li, tus lej ntawm MRI tshiab). Txawm li cas los xij, inosine ua tsis tau tejyam los cuam tshuam rau cov qauv no.

3.1.4.3 lus

Dhau li ntawm txoj kev tshawb no, ib qho txiaj ntsig ntawm kev kho inosine hauv MS yuav tsum tsis ntseeg ntxiv, muab cov txiaj ntsig los ntawm ob qhov muag tsis pom kev, kev sim tshuaj placebo hauv

159 RRMS cov neeg mob [81]. Nyob ntawd, inosine ua tsis tau tejyam rau ameliorate tus nqi rov qab thiab kev tsis taus. Strikingly, ob qho tib si qhov no thiab cov kev tshawb fawb soj ntsuam tau soj ntsuam inosine raws li kev kho mob ntxiv rau interferon-, txawm hais tias tom kawg paub tias nce qib UA los ntawm nws tus kheej [82]. Yog li ntawd, ib txhij interferon- daim ntawv thov yuav tau them rau cov txiaj ntsig zoo ntawm inosine.

Tsis tas li ntawd, kev xaiv RRMS rau kev soj ntsuam kev kho mob inosine tseem muaj lus nug. Inosine tej zaum yuav ua tau zoo dua nyob rau hauv SPMS pawg, muab hais tias UA theem muaj kev nyuaj siab tshaj plaws hauv cov neeg mob no [79]. Tsis tas li ntawd, xav txog covneuroprotectivemuaj peev xwm ua ib qho tshuaj tiv thaiv oxidant thiab tsis muaj kev tiv thaiv kab mob los ntawm UA hauv EAE [83], cov neeg mob uas muaj kev vam meej MS yuav tau txais txiaj ntsig ntau dua los ntawm kev kho inosine dua li cov neeg mob RRMS.

Txij li cov koob tshuaj ntau dua li siv tau yuav tsim nyog los txhawb qhov tseem ceebneurotiv thaiv, cov kev mob tshwm sim cuam tshuam nrog kev siv tshuaj inosine. Piv txwv li, muaj kev pheej hmoo ntau ntxiv rau cov xwm txheej hauv plawv [84] thiab nephrolithiasis [85] cuam tshuam nrog ntau dua UA ntau dua txwv cov tshuaj inosine.

Nyob rau sab nraud ntawm kev tsim qauv, kev nthuav tawm hom kev ua haujlwm kuj yuav tsum tau nug. Nyob rau hauv lub teeb ntawm qhov nyuaj ntawm MS pathology, hais txog ib qho tshuaj tiv thaiv oxidant yuav tsis ua tau raws li qhov xav tau rau kev txhim kho kev kho mob. Yog li, nws zoo li tsis zoo li inosine monotherapy tuaj yeem pab tau zoo rau cov neeg mob RRMS.