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Pls nyem qhov no mus rau Ntu 2

Cistanche herba muaj cov nyhuv neuroprotective zoo heev

4 Cov Kev Kho Mob Ua Tsis Tau Zoo hauv Kev Txhim Kho Ntau Yam Sclerosis

4.1 Neuroprotective Approaches

4.1.1 Acid-Sensing Ion Channels-Amiloride

4.1.1.1 Keeb kwm

Ib pawg ntawm ion channel txuas nrog Na ntxiv - thiab Ca2 ntxiv - nyob ntawm kev raug mob neuroaxonal yog tsev neeg ntawm cov kua qaub-sensing ion channels (ASICs). Cov no yog cov proton-gated cationic channel qhib los ntawm acidic pH ua rau muaj kev nkag mus ntawm Na plus thiab Ca2 ntxiv ions [175]. Amiloride, paub zoo tias yog diuretic, tau dhau los ua ib qho kev txwv tsis pub muaj ntawm ASICs thiab twb tau ua pov thawj ua tau zoo hauv cov qauv tsiaj ntawm PD [176], stroke [177], thiab Huntington's disease [178]. Raws li txoj cai, amiloride-inducedneurotiv thaivalleviated axonal degeneration nrog rau cov tsos mob ntawm tus mob EAE [179, 180]. Qhov tseem ceeb tshaj, kev kho mob amiloride kuj tau kho cov tsos mob ntawm EAE ua nyob rau hauv Biozzi ABH nas, tus qauv zoo li cov yam ntxwv ntawm kev loj hlob MS [179, 180]. Txawm hais tias ASICs kuj tau hais tawm ntawm ntau lub cev tiv thaiv kab mob (xws li, B hlwb, T hlwb, thiab macrophages), cov pov thawj qhia tau hais tias cov txiaj ntsig zoo ntawm amiloride hauv EAE tau kho nws tus kheej los ntawm immunomodulation [180].

Tshaj li kev nkag siab sau los ntawm kev sim tsiaj, kuj tseem muaj cov ntaub ntawv kho mob uas txhawb nqa qhov kev xav ntawm kev koom tes ntawm ASICs hauv MS pathophysiology. Ua ntej, SNPs nyob rau hauv ib tug gene coding rau ASICs yog txuam nrog enhanced susceptibility rau MS [181]. Ntxiv mus, axonal ASIC kev qhia yog upregulated ntawm ciam teb ntawm mob MS lesions [179]. Qhov tseem ceeb, kev kho amiloride twb tau sim nyob rau hauv ib qho kev tshawb nrhiav tsis muaj kev tswj xyuas hauv PPMS [182]. Nyob ntawd, nws ua rau lub hlwb atrophy qeeb thiab txo qis ntawm cov ntaub so ntswg puas tsuaj cuam tshuam nrog cov cim ntawm DTI.

cistanche cograu AD

4.1.1.2 Kev Kawm

Amiloride hauv AON Hauv kev sim ACTION, amiloride tau soj ntsuam hauv cov neeg mob nrog thawj ntu ntawm unilateral AON [183]. Hauv qhov kev tshawb nrhiav ob-dig muag Phase II no, 48 tus neeg mob tau muab tso rau hauv kev kho txhua hnub nrog 10 mg amiloride lossis placebo. Kev kho mob tau pib nyob rau hauv 28 hnub tom qab cov tsos mob tshwm sim thiab txuas ntxiv rau tsib lub hlis. Kev kho mob steroid tom qab AON pib tau tso cai tab sis tsis tas yuav tsum tau ua. Lub pSE ntsuas qhov hloov pauv ntawm peri-papillary RNFL thickness tom qab rau lub hlis. Txawm li cas los xij, qhov kawg no tsis tau mus txog. Tsis tas li ntawd, kev soj ntsuam ntawm cov ntsiab lus thib ob, suav nrog cov qauv tsim, pom, thiab cov txheej txheem electrophysiological, tsis pom qhov zoo ntawm kev kho amiloride. Cov neeg mob ntawm pab pawg kho mob txawm tias ua rau lub sijhawm ntev tshaj plaws ntawm VEPs.

Amiloride hauv SPMS Tom qab tau txais txiaj ntsig zoo ntawm kev tshawb nrhiav kev sim hauv PPMS [182], qhov ua tau zoo ntawm kev kho amiloride hauv SPMS tau raug sim hauv ntau lub caj npab, ob-dig muag Phase IIb sim, nyob rau tib lub sijhawm rau fluoxetine thiab riluzole (MS-SMART. Ib.) [184]. Rau lub sijhawm 96 lub lis piam, 223 tus neeg mob tau suav nrog kom tau txais 10 mg / hnub amiloride lossis placebo. Txawm li cas los xij, kev kho mob amiloride tsis ua rau muaj qhov sib txawv ntawm pSE, piv txwv li, PBVC tom qab 96 lub lis piam. Ntxiv mus, theem nrab MRI (PBVC tom qab 24 lub lis piam, tshiab lossis loj T2 qhov txhab tom qab

96 lub lis piam) thiab cov ntsiab lus kawg ntawm kev kho mob (xws li, kev hloov hauv EDSS) tsis tau raws li.

4.1.1.3 lus

Dhau li ntawm qhov txiaj ntsig tsis zoo ntawm ACTION thiab MS-SMART kev sim, cov kev tshawb fawb loj-raws li kev tshawb fawb tsis tuaj yeem tshawb pom kev sib koom ua ke ntawm kev kho mob amiloride thiab txo qis kev pheej hmoo rau MS lossis MS-txog kev mus pw hauv tsev kho mob, nug ntxiv txog kev ua tau zoo ntawm amiloride hauv MS [185] .

Ntxiv mus, raws li cov pathophysiology ntawm AON feem ntau yog kho los ntawm cov txheej txheem inflammatory [186], xaiv lub hom phiaj ntawm kev poob neuroaxonal yam tsis muaj kev cuam tshuam rau cov tshuaj tiv thaiv kab mob yuav tsis txaus. Qhov tseem ceeb, 20 feem pua ​​​​ntawm cov neeg mob hauv cov placebo tab sis tsuas yog 5 feem pua ​​​​hauv pab pawg kho mob tau txais cov tshuaj steroids tom qab AON pib hauv txoj kev tshawb fawb ACTION [183]. Xav txog kev txhim kho ntawm kev pom kev ua haujlwm los ntawm kev kho corticosteroid hauv AON [187], ntau zaus ntawm kev tswj hwm steroid tuaj yeem cuam tshuam cov txiaj ntsig ntawm pawg placebo. Qhov kev sib txuas no tseem ceeb tshwj xeeb tshaj yog muab lub sijhawm ncua ntawm kev kho mob tsis pub dhau 28 hnub tom qab pib, vim qhov kev puas tsuaj tseem ceeb tau tshwm sim ua ntej pib kho [183]. Cov kev tshawb fawb yav tom ntej yuav tsum, yog li ntawd, tshawb xyuas kev kho mob amiloride hauv kev sib koom ua ke nrog cov koob tshuaj IVMPS sai sai tom qab AON pib. Concomitant immunosuppressive tswv yim yuav, piv txwv li, txhim khu kev ua tau zoo ntawm amiloride los ntawm ameliorating lub inflammatory milieu thiab tiv thaiv kab mob-mediated neuroaxonal raug mob.

Qhov tseem ceeb, kuj tseem muaj qhov tsis paub meej txog cov txheej txheem ntawm kev ua ntawm amiloride hauv MS. ASIC qhib yog kho los ntawm ib puag ncig acidic. Strikingly, extra-cellular acidosis tsuas yog pom nyob rau hauv infanta-tory lesions hauv EAE [180]. Hauv MS, acidosis tsuas yog xav tau, raws li cov kab mob inflammatory tau nthuav tawm ntau dua lactate concentration [188]. Txawm li cas los xij, qhov nce ntawm lactate zoo li cuam tshuam nrog qib ntawm kev ua tsis zoo thiab twb tau txo qis hauv cov plaques uas tsis muaj zog, ntxiv kev tsis ntseeg txog qhov cuam tshuam ntawm amiloride tshwj xeeb tshaj yog nyob rau hauv MS. Nyob rau hauv txoj kab nrog rau qhov no, ASIC qhia hauv MS cov kab mob tau pom ua ntej ntawm cov kab mob ciam teb, uas cuam tshuam nrog ntau qhov mob milieu [179]. Ib txoj kev tshawb fawb tsis ntev los no tau ntsuas qhov ntsuas pH hauv lub hlwb ntawm cov neeg mob MS thiab tuaj yeem ua rau pom qhov teeb meem no [189].

4.1.2 Fluoxetine

4.1.2.1 Keeb kwm

Selective serotonin reuptake inhibitors (SSRIs) yog cov kws kho mob paub zoo rau kev kho mob hlwb [190]. Ib qho ntawm SSRIs yog fluoxetine. Txawm hais tias nws siv ib txwm siv, ib daim ntawv tshaj tawm xyoo 1991 tau hais

20 MS cov neeg mob uas tau ntsib kev kho mob zoo nyob rau hauv kev kho mob fluoxetine [191]. Yog li, SSRIs tau rov ua dua hauv thaj chaw ntawmneuroinflamationthiab neurodegeneration. Kev rov ua dua ntawm SSRIs tau txhawb ntxiv los ntawm kev nkag siab los ntawm EAE kev sim. Nyob ntawd, ob qho tib si prophylactic thiab kho daim ntawv thov ntawm fluoxetine alleviated soj ntsuam EAE kev loj hlob thiab txhim kho cov kab mob remission [192, 193]. Ob peb lub tswv yim hauv qab EAE amelioration tau tham txog. Feem ntau, aneuroprotectivehom kev txiav txim yog xam. Fluoxetine tau pom tias yuav txhawb nqa astrocytic glycogenolysis thiab lactate tso tawm, yog li muab lub zog rau cov neurons [194, 195]. Tsis tas li ntawd, fluoxetine txhim kho kev tsim cov neurotrophic yam [196] thiab inhibits voltage-gated calcium [197] nrog rau sodium channels [198]. Ua li no, fluoxetine tiv thaiv Ca2 ntxiv - thiab Na ntxiv -induced neurotoxicity [197, 198]. Tshaj lineurotiv thaiv, ntau tus qauv qhia tias muaj kev ruaj ntseg ntawm fluoxetine ntawm BBB los ntawm kev rov ua kom nruj hlwv molecules [199, 200]. Thaum kawg, fluoxetine muaj ob peb yam cuam tshuam txog kev mob inflammatory teb. Ntawm cov no yog ib qho inhibited microglial activation [200], impaired glial antigen kev nthuav qhia [201], thiab tom qab ntawd, txo qis kev tso tawm pro-inflammatory cytokines los ntawm T hlwb [202].

Cistanche tubulosa muaj cov nyhuv neuroprotective zoo heev

4.1.2.2 Kev Kawm

Pib xyoo 2012, ib qho kev sim randomized, ob-dig muag Phase II ntsuam xyuas qhov cuam tshuam ntawm fluoxetine ntawm kev kis tus kab mob hauv 77 PPMS thiab 55 SPMS cov neeg mob (FLUOX- PMS) [203]. Cov neeg koom nrog tau txais 40 mg / hnub fluoxetine lossis placebo tshaj 108 lub lis piam. Lub pSE ntsuas lub sijhawm rau 12-lub lim tiam tau lees paub tias nce 20 feem pua ​​​​hauv T25FW lossis 9HPT. Txawm li cas los xij, tsis muaj kev txhim kho tseem ceeb hauv kev tsom xam ntawm lub hom phiaj tseem ceeb thiab theem nrab (xws li kev ntsuam xyuas kev txawj ntse thiab MRI cov qauv).

Fluoxetine tau tshawb xyuas ntxiv hauv qhov tau piav qhia ntau lub caj npab Phase IIb MS-SMART kev sim ntawm koob tshuaj 40 mg / hnub [184]. Ib puas thiab kaum ib tus neeg mob SPMS tau faib rau pawg fluoxetine, thiab 112 tau txais cov placebo. Txawm li cas los xij, fluoxetine tsis tuaj yeem cuam tshuam rau pSE, uas yog PBVC, tom qab 96 lub lis piam. Ntawm qhov tsis sib xws, PBVC txawm tias muaj txiaj ntsig zoo dua piv rau cov placebo tom qab 24 lub lis piam. Hais txog lub hom phiaj thib ob, kev kho mob fluoxetine txo tus naj npawb ntawm cov kab mob tshiab lossis loj dua T2. Lwm cov ntsiab lus thib ob (piv txwv li, kev hloov pauv hauv EDSS) tsis tau ntsib.

4.1.2.3 lus

Hauv kev xaus, kev kho mob fluoxetine tsis ua rau muaj txiaj ntsig zoo hauv ob qhov kev sim siab II. Thaum txoj kev tshawb fawb MS-SMART tau muaj zog txaus [184], qhov kev poob qis ntawm kev mob tshwm sim tau tshwm sim hauv FLUOX-PMS kev sim, txo qis nws lub zog [203]. Tsis tas li ntawd, ob qhov muag tsis pom kev, kev sim tshuaj placebo hauv 42 tus neeg mob nrog PPMS lossis SPMS tsis tau ua kom pom qhov zoo ntawm kev kho mob fluoxetine [204]. Kev sib koom ua ke ntawm qhov tsis ua tiav ntawm fluoxetine hauv tag nrho peb qhov kev sim, qhov kev ntseeg tau zoo hauv kev loj hlob MS tsis zoo li.

Thaum saib ntawm hom kev ua, qhov pib xav tias predominantneuroprotectiveLub luag haujlwm ntawm fluoxetine tej zaum yuav muaj ntau dua los ntawm nws cov tshuaj tiv thaiv kab mob. Kev kho mob Fluoxetine ua rau muaj ntau yam txheej txheem immunomodulatory, uas tau pom nyob rau hauv ob qho tib si tsiaj thiab tib neeg kev tshawb fawb [193, 205]. Raws li tib cov kab, fluoxetine tau ua pov thawj tias muaj txiaj ntsig zoo hauv cov qauv tsiaj uas muaj zog inflammatory pathophysiology [192, 193]. Kev siv tsiaj cov qauv pom zoo los ntawm kev hais tawm inflammatory pathophysiology kuj tseem piav qhia vim li cas cov ntaub ntawv cog lus ntawm kev kho mob fluoxetine hauv kev sim ua ntej tsis tau txhais mus rau hauv kev sim tshuaj suav nrog cov neeg mob uas muaj MS. Tej zaum, tus qauv tsiaj ntawm kev loj hlob MS, xws li EAE hauv cov nas uas tsis rog rog, yuav tau tsim nyog los kawm txog qhov cuam tshuam ntawm fluoxetine ntawm pathophysiology ntawm cov kab mob hnyav.

Kev txhawb nqa ntxiv rau lub luag haujlwm tseem ceeb ntawm kev tiv thaiv kab mob ntawm fluoxetine muab los ntawm ob qhov kev tshawb fawb soj ntsuam. Ua ntej, escitalopram, lwm SSRI, txo qhov kev pheej hmoo ntawm kev rov qab los piv rau kev tswj hwm hauv kev sim qhib-label [206]. Tsis tas li ntawd, nyob rau hauv ob qhov muag tsis pom kev, cov placebo-tswj txoj kev tshawb fawb hauv RRMS thiab SPMS cov neeg mob, fluoxetine nws tus kheej txo qis kev tsim ntawm GELs [207]. Nyob rau hauv txoj kab nrog kev siv cov fluoxetine nyob rau hauv relapsing MS yog txo T2 qhov txhab nyob rau hauv lub MS- SMART mus sib hais, txawm hais tias qhov kev soj ntsuam no yuav tsum tau paub tseeb tias xav tias tom qab-gadolinium scans ntawm lub hauv paus tsis ploj [184]. Noj ua ke, fluoxetine muaj peev xwm muab cov txiaj ntsig zoo rau cov neeg mob rov qab ua dua dua li MS.

4.1.3 Riluzole

4.1.3.1 Keeb kwm

Glutamate excitotoxicity yog ib qho kev sib tham dav dav uas pab txhawb rau pathophysiology ntawm neurodegeneration [208]. Cov txheej txheem hauv qab ntawm glutamate excitotoxicity koom nrog axonal kev puas tsuaj thiab neuronal cell tuag [209, 210]. Tsis tas li ntawd, glutamate excitotoxicity ua rau oligodendrocyte puas thiab demyelination tom qab [208]. Yog li, glutamate antagonists tau txais txiaj ntsig zoo lineuroprotectivekev kho mob.

Ib tug paub zoo glutamate antagonist yog riluzole, uas yog feem ntau siv rau hauv kev kho mob ntawm amyotrophic lateral sclerosis [211]. Dhau li ntawm inhibiting qhov tso tawm ntawm glutamate los ntawm cov hlab ntsha terminals, riluzole stabilizes sodium raws nyob rau hauv lub xeev inactivated [211]. Hauv kab, EAE kev sim tau qhianeuroprotectiveCov teebmeem tshwm sim los ntawm daim ntawv thov riluzole [210]. Tsis tas li ntawd, kev tshawb nrhiav kev sim ua nyob rau hauv 16 cov neeg mob uas muaj kev vam meej MS tau pom tias txo qis ntawm lub ncauj tsev menyuam atrophy vim kev kho mob nrog riluzole [212].

4.1.3.2 Kev Kawm

Ua raws li cov lus piav qhia kev sim hauv kev nce qib MS, riluzole tau tshawb xyuas ntxiv hauv ntau lub caj npab Phase IIb MS-SMART sim [184]. Ob puas thiab nees nkaum-peb tus neeg mob SPMS tau suav nrog kom tau txais 100 mg / hnub riluzole lossis placebo rau lub sijhawm 96 lub lis piam. Txawm li cas los xij, pab pawg kho mob ua tsis tau raws li pSE (PBVC tom qab 96 lub lis piam) thiab tag nrho cov txiaj ntsig thib ob (xws li kev hloov pauv hauv EDSS lossis MSFC).

4.1.3.3 lus

Dhau li ntawm qhov kev sim MS-SMART thiab kev sim ua haujlwm, riluzole tau raug tshuaj xyuas ntxiv nrog rau kev tswj hwm txhua lub limtiam interferon- 1a [213]. Qhov randomized placebo-tswj Phase II sim no suav nrog 43 tus neeg mob uas muaj RRMS lossis kev kho mob cais tawm. Nco ntsoov, kev kho mob nrog riluzole tsis txo lub hlwb atrophy hauv txoj kev tshawb no. Nyob rau hauv txoj kab nrog cov txiaj ntsig ntawm riluzole, kev kho mob nrog NMDA antagonist memantine ua tsis tiav los txhim kho kev paub tsis meej hauv cov neeg mob rov qab los thiab nce qib MS [214]. Muab qhov tsis muaj qhov cuam tshuam ntawm riluzole thiab memantine kev kho mob ntawm ob qho tib si CNS atrophy thiab qhov chaw kho mob tsis zoo, cov lus nug tshwm sim rau qhov twg glutamate excitotoxicity cuam tshuam rau cov txheej txheem neurodegenerative hauv MS. Ntawm qhov tod tes, tus naj npawb siab ntawm glutamate-dependent cell lub hom phiaj thiab cov txheej txheem ntawm kev txiav txim ua rau pleiotropic los ntawm cov glutamate antagonists [208]. Thaum kawg, kev txheeb xyuas ntxiv ntawm cov teeb meem cuam tshuam txog kev koom nrog, ua ke nrog kev tsim cov ntsiab lus tshwj xeeb, tuaj yeem ua rau peb nkag siab txog lub luag haujlwm ntawm glutamate excitotoxicity hauv neurodegeneration thaum MS.

4.1.4 Ubiquinone-Idebenone

4.1.4.1 Keeb kwm

Ubiquinone (CoQ) yog ib qho tshuaj tiv thaiv oxidant thiab lipophilic electron cab kuj nyob rau hauv mitochondrial electron thauj saw. Txawm li cas los xij, tsis muaj dej solubility ua rau CoQ impracticable rau kev kho mob daim ntawv thov [215]. Idebenone, ib qho dej-soluble luv-chain analog ntawm CoQ [216], yog siv los kho Friedreich's ataxia thiab Leber's hereditary optic neuropathy, ob qho tib si tshwm sim los ntawm mitochondrial dysfunction [217]. Ib yam li CoQ, idebenone kev tswj hwm tau pom tias tshem tawm cov dawb radicals thiab inhibit lipid peroxidation [218]. Ntxiv mus, kev kho mob nrog idebenone regenerates mitochondrial muaj peev xwm los ntawm kev kho cov electron ntws siv ib tug bypass mechanism [219, 220]. Raws li oxidative kev nyuaj siab thiab mitochondrial dysfunction kuj ua rau muaj kev puas tsuaj rau neuroaxonal hauv neuroinflammation thiab neurodegeneration [8], idebenone yog suav tias yog tus neeg sawv cev hauv MS [215].

Tshaj nwsneuroprotectiventa, idebenone kuj muaj peev xwm tiv thaiv kev ua phem. Nyob rau hauv microglia, nws suppressed zus tau tej cov pro-inflammatory yam (xws li, interleukin (IL) -1 , qog necrosis factor- ) thiab induced hloov mus rau ib tug M2 phenotype uas muaj feem xyuam rau kev tiv thaiv infammation thiab regeneration [221] . Muab rauneuroprotectivethiab immunomodulatory zog, idebenone tuaj yeem yog cov tshuaj cog lus hauv MS.

4.1.4.2 Kev Kawm

Hauv ob qhov muag tsis pom kev, cov placebo-tswj Phase I / II sim, idebenone tau soj ntsuam hauv 77 tus neeg mob PPMS (IPPoMS) [222]. Ib lub sijhawm 1- xyoo ua ntej kev kho mob tau ua raws li theem ua haujlwm ntawm 2 xyoos nrog kev siv txhua hnub ntawm 2250 mg idebenone. Lub pSE tau tshawb xyuas qhov kev hloov pauv hauv Combinatorial Weight-Adjusted Disability Score (CombiWISE) uas muaj EDSS, T25FW, 9HPT, thiab Scripps Neurological Disability Scale [223]. Txawm li cas los xij, kev kho mob tsis muaj kev cuam tshuam rau CombiWISE. Tsis tas li ntawd, kev soj ntsuam ntawm cov hom phiaj thib ob, suav nrog kev hloov pauv ntawm qhov loj ntawm lub ventricular ntim nrog rau qhov sib txawv ntawm ib pawg ntawm CombiWISE, tsis tau qhia txog kev txhim kho tseem ceeb uas tau tshwm sim los ntawm idebenone.

Tom qab ntawd, txhua tus neeg mob uas tau ua tiav qhov kev sim IPPoMS tau raug caw mus rau qhov kev tshawb nrhiav qhib-daim ntawv txuas ntxiv [224]. Nyob ntawd, txhua tus neeg mob yuav tsum tau txais idebenone rau 1 xyoos ntxiv. Hmoov tsis zoo, kev tshaj tawm ntawm kev tshawb fawb txuas ntxiv yog ploj lawm.

4.1.4.3 lus

Qhov tsis txaus ntawm cov ntaub ntawv kho mob tam sim no cuam tshuam qhov kev soj ntsuam ntawm lub luag haujlwm ntawm idebenone hauv MS. Tsis tas li ntawd, kev nkag siab ua ntej kev kho mob tsis tshua muaj. Idebenone tau sim ib zaug hauv EAE, tsis ua rau muaj kab mob tshwm sim, pib, thiab mob hnyav [225]. Ntxiv mus, idebenone tsis muaj kev cuam tshuam rauneuroinflamationlos yog axonal kev puas tsuaj.

Nws tuaj yeem kwv yees tias qhov tsis ua haujlwm ntawm idebenone muaj feem xyuam rau qhov kev vam khom ntawm nws txoj haujlwm ntawm cytoplasmic NAD (P) H: quinone oxidoreductase 1 (NQO1). NQO1 catalyzes txo cov idebenone rau hauv idebenone [220]. Thaum idebenone nws tus kheej nthuav tawm cov khoom oxidative [226] thiab ua rau cov saw hlau thauj hluav taws xob tsis zoo [227], cov kev ua tau zoo raug ntaus nqi rau idebenone [215]. Hmoov tsis zoo, NQO1 kev qhia yog tsuas yog txwv rau astrocytes thiab ib feem ntawm oligodendrocytes, thaum nws tsis tshua muaj nyob rau hauv neurons [228]. Yog li ntawd, lub peev xwm rau ncaj qhaneurotiv thaivtxwv tsis pub [229]. Txawm li cas los xij, raws li NQO1 qhia yog inducible, ua ke nrog cov neeg ua hauj lwm xaiv upregulating NQO1 nyob rau hauv neurons yuav tswj idebenone kev kho mob nyob rau hauv neurodegeneration [229].

Qhov tseeb, qhov tsis txaus ntseeg ntawm cov ntaub ntawv cuam tshuam qhov kev xav ntawm qhov cuam tshuam ntawm idebenone rauneuroinflamation. Txawm li cas los xij, qhov ua tsis tau zoo hauv IPPoMS kev sim thiab kev nkag siab tau los ntawm kev sim tsiaj txhu tawm tsam lub luag haujlwm muaj txiaj ntsig ntawm idebenone hauv PPMS, tsawg kawg thaum siv los ua monotherapy.

cistanche tshuaj xyuas : Cistanche muaj cov nyhuv neuroprotective zoo heev

4.2 Neuroregenerative Approaches

4.2.1 Erythropoietin Cov

4.2.1.1 Keeb kwm

Erythropoietin (EPO) yog ib qho tshuaj hormone stimulating erythropoiesis. Qhov zoo siab, kev tshawb fawb cov ntaub so ntswg tau txheeb xyuas EPO thiab nws cov receptor (EPOR) hauv cov neurons, glial, thiab cov hlwb endothelial ntawm CNS [230–232]. Cov pov thawj tshwm sim piav qhia txog EPO-EPO-R- axis ua ib qho endogenousneuroprotectiveLub kaw lus tau txais kev ua haujlwm hauv kev teb rau kev puas tsuaj neuronal hais txog hypoxia, kev ntxhov siab hauv metabolic, lossis kev ua tsis zoo, ib yam li tau pom hauv EAE [233, 234]. Raws li, exogenously tswj EPO ameliorated soj ntsuam cov cim ntawmneuroinflamationhauv nas [235–237]. Kev txhim kho kho mob nyob ntawm tsawg kawg yog ib feem ntawm qhov induction ntawm remyelination. Hauv vitro, piv txwv li, EPO txhawb kev sib txawv ntawm OPC thiab oligodendrocyte maturation [230, 238]. Tsis tas li ntawd, nws txhim kho qhov kev qhia ntawm myelin cov cim tom qab cuprizone-induced demyelination thiab proliferation ntawm OPCs thaum lub sij hawm EAE [239, 240].

Dhau li ntawm remyelination, EPO tiv thaiv cov cim sib txawv ntawm autoimmuneneuroinflamation, xws li BBB breakdown lossis axonal raug mob [235–237]. Lub hauv paus mechanisms ntawmneurotiv thaivkoom nrog neurotrophic [241], anti-oxidative [242], thiab anti-apoptotic txheej txheem [243]. Tsis tas li ntawd, EPO modulates cov lus teb inflammatory, ua rau muaj kev nthuav dav ntawm kev tswj T hlwb thiab suppressed sib txawv ntawm TH 17 hlwb [236].

Ntxiv nrog rau cov kev soj ntsuam ua ntej tau hais tseg, ib qho kev tshawb nrhiav me me qhib-label Phase I / IIa sim ntawm kev kho mob siab EPO tau pom tias muaj kev nce ntxiv hauv kev taug kev mus ntev thiab txhim kho kev paub tsis meej hauv PPMS thiab SPMS [244]. Kev kho mob ntev EPO tau raug soj ntsuam ntxiv hauv ib qho kev tshawb fawb me me hauv SPMS pawg, qhia txog cov txiaj ntsig zoo ntawm EPO nyob rau hauv cov ntsiab lus ntawm cov txheej txheem neurophysiological (xws li, nce intracortical kev yooj yim) thiab cov qauv ntawm ameliorated qaug zog [245].

4.2.1.2 Kev Kawm

Ua raws li cov txiaj ntsig tau txais txiaj ntsig zoo tshaj plaws, kev sim ua ob qhov muag tsis pom qhov thib ob tau ua tiav hauv 18 PPMS thiab 34 SPMS cov neeg mob (tsis muaj kev rov ua dua hauv 2 xyoo dhau los) [246]. Qhov nruab nrab tus kab mob ncua sij hawm sib txawv ntawm 16.7 xyoo hauv EPO thiab 14.9 xyoo hauv pawg placebo. Cov neeg koom nrog tau txais 48,000 IU EPO lossis placebo rau 24 lub lis piam (hauv ib nrab ntawm lub lim tiam, tom qab ob lub lis piam) ua raws li lub sijhawm 24- lub lis piam soj ntsuam. IVMPS 1 g tau siv ua ntej frst thiab thib ob infusion ntawm EPO lossis placebo. Lub pSE tau tshawb xyuas qhov kev hloov pauv ntawm cov qhab nia sib xyaw uas muaj qhov siab tshaj plaws ntawm kev tawm mus.

tance, tes dexterity, thiab kev paub tom qab 24 lub lis piam. Cov neeg mob kho nrog EPO pom tau tias nce me ntsis ntawm cov qhab nia sib xyaw, qhia txog kev txhim kho kev kho mob. Txawm li cas los xij, qhov kev hloov no tsis tseem ceeb thiab tsis tuaj yeem pom tom qab 48 lub lis piam. Kev soj ntsuam ntawm qhov chaw kho mob (piv txwv li, EDSS thiab MSFC), kev soj ntsuam MRI (piv txwv li, T2 lesion ntim thiab PBVC) nrog rau cov txiaj ntsig tau tshaj tawm rau tus neeg mob (36-Cov Ntawv Tshawb Fawb Txog Kev Noj Qab Haus Huv Short-Form [247]) tsis tau nthuav tawm ib qho qhov zoo ntawm EPO kev kho mob. Hais txog kev nyab xeeb profle, feem ntau cov neeg mob hauv pab pawg kho mob xav tau kev tso ntshav vim yog nce hematocrit thiab muaj kev mob siab ntau dua.

4.2.1.3 lus

Thaum ib qho kev tshawb nrhiav frst pilot txoj kev tshawb fawb qhia txog kev txhim kho nyob rau hauv EPO kev kho mob, tshwj xeeb tshaj yog nyob rau hauv cov nqe lus ntawm lub cev muaj zog functions [244], cov txiaj ntsig no tsis tuaj yeem rov ua dua tshiab hauv qhov kev tshuaj xyuas Phase II, txawm tias muaj kev pom zoo [246]. Ib qho laj thawj rau kev ua tsis tiav tej zaum yuav yog tus kab mob ntev tshaj 16 xyoo. Tseeb, remyelination poob nrog MS lub sijhawm thiab tsis tshua muaj nyob rau hauv cov kab mob ntev [6, 87]. Yog li, cov neeg ua haujlwm txhawb nqa remyelination tuaj yeem ua tau zoo dua hauv cov kab mob pob ntseg, vim tias muaj kev cuam tshuam rau cov kab mob ntev ntev, tsis ua haujlwm tsis zoo. Nyob rau hauv txoj kab nrog qhov kev xav no, ib qho kev tshawb fawb me me ob qhov muag tsis pom kev txhawb nqa kev ua tau zoo ntawm EPO-kev kho mob hauv cov neeg mob RRMS nrog qhov mob hnyav [248]. Cov txiaj ntsig zoo tshaj plaws ntawm EPO hauv AON hauv kev sim tshuaj placebo-tswj theem II ntxiv txhawb qhov kev xav no [249]. Qhov tseeb, kev xaiv cov neeg mob nyob rau theem siab ntawm kev kis tus kab mob tuaj yeem tau npog qhov muaj txiaj ntsig zoo ntawm kev kho EPO.

Txawm li cas los xij, qhov muaj peev xwm siv EPO hauv MS yog cuam tshuam los ntawm kev cuam tshuam sab. Kev tswj hwm ntawm EPO tsis yog tsuas yog ua rau erythropoiesis tab sis muaj ob peb lwm yam cuam tshuam xws li vasoconstriction lossis thrombocythemia, yog li ua kom muaj kev pheej hmoo rau cov xwm txheej thromboembolic thiab kub siab [233]. Yog li, cov neeg mob uas muaj kab mob plawv, keeb kwm ntawm cov xwm txheej thromboembolic, lossis kev tsis tuaj yeem raug tshem tawm los ntawm kev sim tshuaj [246, 249, 250]. Ntxiv mus, EPO tuaj yeem ua rau tsis tshua muaj tab sis muaj peev xwm ua rau tuag taus dawb huv cell aplasia [251]. Raws li kev qhia ntawm EPO thiab EPO-R ntawm ntau cov qog nqaij hlav malignant [252] thiab cov lus ceeb toom ntawm cov qog nthuav dav hauv EPO kev kho mob [253, 254], cov neeg mob uas muaj keeb kwm ntawm malignancy yuav tsum tsis txhob tau txais cov tshuaj no. Muab ua ke, ib qho txiaj ntsig zoo ntawm cov neeg mob, tshwj xeeb tshaj yog tias kev txom nyem los ntawm ntau tus neeg mob, yuav tsis tsim nyog rau kev kho mob txawm tias EPO yuav ua tau zoo hauv MS.

Ntawm qhov tod tes, cov txheej txheem tiv thaiv cov ntaub so ntswg yuav tsis tsuas yog kho los ntawm classical EPO-R. Qhov tseem ceeb tshaj plaws, cov txiaj ntsig zoo li no tau tshwm sim los ntawm kev sib cuam tshuam ntawm thaj chaw EPO sib txawv nrog lub heteromeric receptor uas muaj ib qho EPO-R subunit thiab cov saw-kev sib koom los ntawm cov tswv cuab ntawm IL-3 receptor tsev neeg [233, 255] . Yog li, derivates ntawm EPO tau pom los ua pov thawjneurotiv thaivtsis cuam tshuam rau erythropoiesis [235]. Ntawm cov derivates no yog JM-4 [256]. Qhov peptide no tiv thaiv cov nas los ntawm demyelination thiab txo cov lus teb tsis zoo, yog li amelio- ntsuam xyuas cov tsos mob ntawm EAE [256]. Tau kawg, txoj kev tshawb fawb Theem I thaum ntxov tau pib los ntsuas kev nyab xeeb thiab kev ua tau zoo ntawm JM-4 hauv cov ntsiab lus ntawm MS [257].

4.2.2 Carboxylase Enzymes-Biotin

4.2.2.1 Keeb kwm

Biotin yog ib qho dej-soluble vitamin nyob thoob plaws hauv lub ntiaj teb, ua ib qho tseem ceeb co-enzyme rau ntau carboxylase [258]. Raws li cov ntaub ntawv qhia txog kev ua tau zoo ntawm biotin hauv SPMS, cov kev tshawb fawb frst tau qhia los ntsuas biotin raws li lub hom phiaj muaj peev xwm hauv MS [259]. Kev txo qis ntawm biotin pom nyob rau hauv cov kua cerebrospinal (CSF) thiab cov ntshav ntawm MS cov neeg mob tau nce ntxiv mus rau repurpose biotin hauv cov ntsiab lus ntawmneuroinflamation[260]. Tsis tas li ntawd, qhov tsis txaus ntawm biotinidase, ib qho enzyme xav tau rau biotin recycling [261], ua rau demyelination thiab cov tsos mob ntawm lub paj hlwb uas piv rau MS [262].

Qhov laj thawj tom qab siv biotin yog raws li kev xav ntawm 'virtual hypoxia' hauv MS [258]. Nws yog assumed tias mitochondrial tsis ua hauj lwm thiab xav tau ntau zog vim demyelination ua rau ib tug mismatch ntawm lub zog mov thiab xav tau. Yog li ntawd, qhov kev tsis sib haum xeeb no yuav ua rau raug mob neuroaxonal. Biotin muaj peev xwm hais txog ob qho tib si txo qis kev tsim hluav taws xob thiab kev xav tau ntau ntxiv. Ua ntej, ua ib qho tseem ceeb co-enzyme ntawm peb carboxylase koom nrog hauv lub voj voog tricarboxylic acid, ntau ntxiv ntawm biotin tuaj yeem txhawb nqa neuronal ATP mov [263]. Qhov thib ob, bio-tin yog xav tau hauv oligodendrocytes rau kev ua haujlwm ntawm ob lub carboxylase uas tsim cov substrate ntawm fatty acid synthesis [263]. Nyob rau hauv txoj kev no, biotin tuaj yeem txhim kho remyelination vim nce qib ntawm cov fatty acids, uas yuav tsum tau rau kev tsim myelin [264]. Los ntawm kev rov ua kom cov ntsev ua kom muaj ntsev thiab yog li, txwv tsis pub cov membrane excitation rau ntawm Ranvier, biotin yuav txo tau lub zog thov [265].

Cov pov thawj ntxiv txhawb nqa lub luag haujlwm muaj txiaj ntsig ntawm bio-tin hauv MS muab los ntawm kev tshawb fawb me me, tsis muaj kev tswj hwm hauv 23 PPMS thiab SPMS cov neeg mob, qhia txog kev txhim kho kev pom thiab lub cev muaj zog hauv yuav luag txhua tus neeg mob [266]. Ua raws li qhov kev sim no, kev sim frst Phase III hauv 154 PPMS thiab SPMS cov neeg mob (SPI) tau pom tias txo qis kev tsis taus los ntawm kev kho biotin [267].

4.2.2.2 Kev Kawm

Kev sim thib ob ob qhov muag tsis pom Phase III tau pib hauv 2016 (SPI2) [268], nyob rau hauv uas 227 PPMS thiab 415 SPMS cov neeg mob uas tsis muaj kev rov qab los hauv 2 xyoo dhau los tau muab tso rau 300 mg / hnub biotin lossis placebo. Txhua tus neeg mob tseem nyob hauv ob qhov muag tsis pom kev, cov placebo-tswj theem ntawm qhov kev sim mus txog rau thaum tus neeg koom nrog zaum kawg mus txog Lub Hlis 15. Lub sijhawm ntawd, txhua tus neeg mob tau hloov mus rau kev kho mob biotin ntawm kev mus ntsib tom ntej. Yog li ntawd, cov placebo-tswj ib feem ntawm txoj kev tshawb no tau nyob nruab nrab ntawm 15 thiab 27 lub hlis (lub sijhawm nruab nrab: 20.1 lub hlis). Kev txuas ntxiv ntawm kev kho mob nrog DMTs tau tso cai thoob plaws tag nrho cov kev sim. Lub pSE ntsuas qhov sib txawv ntawm qhov sib faib ntawm cov neeg mob nrog kev paub tseeb tias kev txhim kho hauv EDSS tus qhab nia lossis T25FW tom qab 12 lub hlis. Hmoov tsis zoo, biotin ua tsis tau zoo los txhawb cov txiaj ntsig tseem ceeb ntawm pSE. Tsis tas li ntawd, txoj kev tshawb no tsis tau raws li qhov kawg theem nrab (piv txwv li, lub sijhawm rau EDSS kev nce qib, hloov hauv T25FW).

Ntxiv rau qhov kev sim SPI2, ob txoj kev tshawb fawb tau ua nyob rau hauv qhov chaw tiag tiag. Qhov frst tau ua nyob rau hauv xya PPMS thiab 36 SPMS cov neeg mob, suav nrog cov neeg mob rov qab los [269]. Siv cov qauv qhib-daim ntawv lo, txhua tus neeg mob tau txais 300 mg / hnub biotin rau 1 xyoo raws li cov tshuaj ntxiv rau hauv rooj plaub ntawm DMT uas twb muaj lawm. Ib feem peb ntawm cov neeg mob tau tshaj tawm cov ntsiab lus tsis zoo ntawm MS, ua rau nce EDSS cov qhab nia hauv ob kis. Tsuas yog ob tus neeg koom tau ntsib kev txhim kho kho mob, uas yog, txawm li cas los xij, tsis txaus los txo EDSS. Strikingly, tsuas yog 24 ntawm 43 tus neeg mob ua tiav tag nrho cov sijhawm kawm. Cov laj thawj tseem ceeb ntawm kev tshem tawm suav nrog kev ua tsis tau zoo thiab ua rau cov tsos mob tsis zoo.

Qhov thib ob qhib-label kawm nyob rau hauv lub ntiaj teb no qhov chaw muaj xws li 84 PPMS thiab 94 SPMS cov neeg mob [270]. Concomitant intake ntawm DMTs tau tso cai. PSE tau soj ntsuam kev txhim kho kev tsis taus tom qab 12 lub hlis ntawm kev kho mob bio-tin siab, ntsuas los ntawm kev txo qis hauv EDSS. Kev txo qis ntawm EDSS tau pom nyob rau hauv tsuas yog rau tus neeg mob. Cov txiaj ntsig thib ob, txheeb xyuas kev xiam oob qhab, kev ua haujlwm nrawm, thiab kev ua haujlwm hluav taws xob, qhia tsis muaj txiaj ntsig zoo dua li kev txhim kho qhov mob thiab qhov tsis xis nyob hauv daim ntawv nug tus neeg mob. Txawm hais tias ARR tsis tau ua kom zoo dua piv rau lub sijhawm ua ntej kev kho biotin, MRI kev soj ntsuam tau pom tias muaj kev cuam tshuam hluav taws xob hauv kwv yees li 30 feem pua ​​​​ntawm cov neeg mob nrog MRI scans.

4.2.2.3 lus

Tsis tsuas yog ua tsis tiav hauv kev sim tshuaj tab sis tseem tsis txaus ntseeg ntawm lub luag haujlwm ntawm biotin hauv kev tiv thaiv kab mob tiv thaiv kab mob neuroinflammation lo lus nug ntxiv. Kev txhim kho kev kho mob los ntawm kev hloov pauv biotin nyob rau hauv cov ntaub ntawv ntawm biotinidase deficiency zoo nkaus li zoo ib yam nyob rau hauv lub teeb ntawm hnyav shortness ntawm biotin. Txawm li cas los xij, nws zoo li tsis zoo li qhov nce ntawm cov roj fatty acid txhim kho cov txheej txheem nyuaj ntawm remyelination hauv MS. Tsis tas li ntawd, cov ntaub ntawv kho mob ua ntej tsis ntev los no muab pov thawj cuam tshuam txog kev cuam tshuam zoo ntawm biotin ntawm autoimmune neuroinflamation. Buonvicino thiab al qhia tias biotin ua tsis tau kom nce qib ATP hauv murine cortical neurons [271]. Tsis tas li ntawd, biotin tsis tuaj yeem tiv thaiv cov neurons los ntawm glutamate-induced excitotoxicity thiab oligodendrocytes los ntawm cuprizone-mediated raug mob. Tsis tas li ntawd, kev kho biotin tsis cuam tshuam rau EAE kev loj hlob hauv cov nas uas tsis rog ntshav qab zib, zoo ib yam li MS [271]. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, biotin kuj tseem tsis tau pom los txhawb nqa remyelination hauv vitro lossis hauv vivo. Muab qhov tsis muaj txiaj ntsig zoo ntawm kev kho biotin ntawm lub paj hlwb atrophy thiab cov qib ntshav hauv cov ntshav hauv SPI2 sim [268],neuroprotectiveefect kuj tsis zoo li.

Dhau li ntawm kev tsis ntseeg txog nws cov txheej txheem ntawm kev ua, qee qhov kev tshawb fawb tau tshaj tawm tias muaj cov kab mob rov qab thiab MRI nyob rau hauv kev kho mob biotin siab txawm tias nyob hauv cov neeg mob uas tsis tau rov ua dua yav dhau los [267, 269, 270, 272–276]. Qhov ua tau biotin-mediated cawv ntawm BBB kev ncaj ncees tsis tau raug soj ntsuam. Tsis tas li ntawd, cov teebmeem immunomodulatory ntawm cov koob tshuaj biotin tsis txaus qhia meej. Kev soj ntsuam ntawm PBMCs tau txais los ntawm biotin-kho cov neeg mob nrog kev kho mob lossis MRI qhov ua tsis zoo qhia tau tias muaj kev hloov pauv hauv lub cev tiv thaiv kab mob ntau zaus [277]: kev txo qis ntawm tag nrho cov lymphocytes, txo CD4 ntxiv nrog rau CD8 ntxiv rau T hlwb, thiab nce ntxiv. chav kawm-hloov lub cim xeeb IgD-CD27 ntxiv rau B hlwb tau tshaj tawm. Hmoov tsis zoo, subpopulations ntawm CD4 ntxiv rau T hlwb tsis tau ntxiv tus cwj pwm, txwv kev txiav txim siab txog biotin-mediated los ntawm cov lus teb inflammatory.

Txawm li cas los xij, qhov kev sim SPI2 tsis tau lees paub qhov kev ntshai ntawm tus nqi rov qab ntau dua [268]. Tsis tas li ntawd, ib qho kev tshawb nrhiav loj (IPBio-SeP) tshawb xyuas qhov tshwm sim ntawm relapses hauv cov neeg mob biotin-kho [278]. Kev soj ntsuam nruab nrab ntawm 1279 biotin-tau txais cov neeg mob thiab 483 kev tswj tsis tau qhia qhov sib txawv ntawm qhov zaus ntawm kev rov qab los tom qab 16 lub hlis.

Ib qho laj thawj rau cov txiaj ntsig sib txawv ntawm kev kho biotin hauv SPI piv rau SPI2 kev sim yuav yog qhov ntau dua cov placebo teb tus nqi hauv SPI2 mus sib hais kom txo tau lub zog ntawm txoj kev tshawb no [268]. Txawm li cas los xij, muab cov neeg mob ntau dua hauv qhov kev sim SPI2, nws muaj feem ntau tias cov txiaj ntsig zoo tau pom hauv SPI kev sim ua los ntawm hom 1 yuam kev [268]. Tsis tas li ntawd, tus nqi ntawm kev xiam oob qhab tau txo qis hauv ob pawg ntawm SPI2 mus sib hais. Qhov no, nyob rau hauv lem, tej zaum yuav ua rau lub sij hawm soj ntsuam yuav luv luv rau depict lubneuroregenerativecuam ​​tshuam. Lub ntsiab lus tseem ceeb hauv kev tsim qauv ntawm SPI2 mus sib hais yog pSE raws li nws tau soj ntsuam kev txhim kho kev tsis taus. Txawm li cas los xij, kev ncua ntawm tus kab mob kev loj hlob zoo li yuav muaj tseeb ntau dua li kev txhim kho tseem ceeb ntawm cov tsos mob.

Ua ke, muab cov txiaj ntsig tsis zoo ntawm SPI2 mus sib hais thiab ob txoj kev tshawb fawb hauv qhov chaw tiag tiag, qhov txiaj ntsig zoo ntawm biotin hauv kev nce qib MS tsis zoo li.

4.3 Lwm txoj hauv kev

4.3.1 Glycogen Synthase Kinase-3-Lithium

4.3.1.1 Keeb kwm

Ua ib qho ntawm frst FDA-pom zoo tshuaj, lithium yog lub siab-stabilizer tseem ceeb rau kev kho mob ntawm kev puas siab puas ntsws bipolar [279]. Cov ntaub ntawv kho mob ua ntej tau txais los ntawm ntau tus qauv EAE ua rau muaj kev siv lithium hauv cov mob neuroinflammatory [280, 281]. Txawm hais tias lithium cuam tshuam rau ntau lub hom phiaj, amelioration ntawmneuroinflamationzoo li feem ntau yog kho los ntawm kev tawm tsam ntawm glycogen synthase kinase-3 (GSK-3) [280]. Inhibition of GSK-3, piv txwv li, cuam tshuam rau tiam ntawm TH 1 [282] thiab TH 17 hlwb [283]. Kev txwv ntawm GSK-3 kuj tseem tuaj yeem khaws BBB kev ncaj ncees los ntawm kev tswj hwm ntawm WNT/ -catenin txoj kev [284]. Muaj cov pov thawj ntxiv rau kev koom tes ntawm lithium thiab GSK-3 hauv MS raws li cov qib ntshav lithium raug txo qis hauv cov neeg mob RRMS [285], thaum qhia txog GSK-3 tau tswj hwm hauv cov neeg mob uas muaj PPMS [286] .

4.3.1.2 Kev Kawm

Ua raws li cov txiaj ntsig tau txais txiaj ntsig ua ntej kev kho mob, ib qho qhib-daim ntawv sau npe, ntsuas qhov muag tsis pom kev rau theem I / II sim tau ua hauv 3 PPMS thiab 20 SPMS cov neeg mob [287]. Tus kab mob lub sij hawm txawv ntawm 3 mus rau 43 xyoo. Txoj kev tshawb no tau ua nyob rau hauv ib tug cross-over tsim, nrog random assignment rau lithium kev kho mob nyob rau hauv lub xyoo frst los yog thib ob. Lithium koob tshuaj sib txawv ntawm 150 thiab 300 mg / hnub. Kev kho mob ib txhij nrog DMTs (natalizumab, interferon-, GA) tau tso cai. Daim ntawv thov ntawm lithium ua rau muaj qhov zoo tab sis tsis tseem ceeb rau pSE, piv txwv li, PBVC. Ntxiv mus, lithium kev kho mob ua tsis tau tejyam cuam tshuam rau lwm yam kev kho mob lub hom phiaj (xws li, hloov nyob rau hauv EDSS, MSFC) tab sis tseem ceeb heev txhim kho cov neeg mob-reported tshwm sim nyob rau hauv cov nqe lus ntawm lub hlwb domains ntawm MS Quality of Life-54 questionnaire [288].

4.3.1.3 lus

Dhau li ntawm qhov qhib-label tsim, heterogenous lub hauv paus tus yam ntxwv nyob rau hauv cov nqe lus ntawm divergent dis-ease duration thiab ib txhij thov ntawm DMTs nyob rau hauv ib co neeg mob cuam tshuam kev txhais cov ntsiab lus. Hmoov tsis zoo, tsis muaj cov ntaub ntawv hais txog kev sib raug zoo ntawm cov txiaj ntsig tau tshwm sim thiab kev noj DMT lossis cov neeg mob cov qib lithium serum, uas tej zaum yuav tau nthuav tawm cov koob tshuaj tsawg.

Tsis tas li ntawd, vim muaj ntau lub hom phiaj cuam tshuam, lithium-induced aggravation ntawm neuroinflamation tsis tuaj yeem raug cais tawm. Ntawm cov txheej txheem muaj feem cuam tshuam yog WNT / -catenin-mediated dysfunction ntawm remyelination [289]. Lwm qhov piv txwv yog kev ua kom cov pro- kinase Akt-1 los ntawm lithium, raws li cov ntaub ntawv tsis ntev los no qhia tau tias muaj kev cuam tshuam lub luag haujlwm ntawm Akt-1 hauv EAE [290]. Nyob rau hauv txoj kab nrog qhov no, kev tshuaj xyuas rov qab ntawm kev kho lithium suav nrog 101 US cov qub tub rog nrog txhua hom MS tau qhia txog qhov nce rov qab. Qhov tsis zoo ntawm EDSS, txawm li cas los xij, tau qeeb qeeb [291].

Muab cov neeg koom nrog tsawg, cov txheej txheem kev txwv, thiab tsis muaj lwm yam kev sim yav tom ntej, lub luag haujlwm ntawm lithium hauv MS tseem tsis pom.

5 Kev sib tham

Hauv kev tshuaj xyuas no, peb muab qhov hloov tshiab ntawm kev sim tshuaj ntsuam xyuas cov tswv yim txhawb nqa remyelination,neuroprotectivekev kho mob, thiab lwm txoj hauv kev uas ua tsis tau lossis raug cuam tshuam rau lwm yam laj thawj. Yog li peb txuas ntxiv peb cov kev tshuaj xyuas yav dhau los ntawm kev sim ua tsis tiav hauv cov ntsiab lus ntawm MS [292–295]. Ntawm cov ntawv ceeb toom, qhov hloov tshiab tam sim no ntawm kev ua tsis tiav lossis cuam tshuam cov kev tshawb fawb ntawm cov neeg ua haujlwm tiv thaiv kab mob tsis ntev los no tau muab rau hauv ib tsab xov xwm cais [9].

Cov lus qhia tseem ceeb tshaj plaws uas tau kawm los ntawm kev sim ua tsis tiav yog qhov kev thov rau kev tshawb fawb ntxiv. Muaj ntau txoj kev koom nrog tau paub. Txawm li cas los xij, peb tsis nkag siab qhov kawg ntawm lawv qhov kev sib cuam tshuam uas ua rau remyelination thiab, qhov tseem ceeb tshaj, cov txheej txheem hauv qab nws qhov tsis txaus [6]. Tsis muaj kev nkag siab txog vim li cas remyelination tsis ua haujlwm hauv qee cov neeg mob, thaum lwm tus pom muaj feem ntau ntawm cov kab mob remyelinated [87]. Kev nkag siab ntxiv rau cov txheej txheem tseem ceeb ntawm remyelination yuav tsum tau hais txog lawv txaus. Raws li, muab qhov heterogeneity ntawm qhov txhab, ntau yam kab mob kev kawm, thiab qhov nyuaj ntawm MS, nws zoo li tsis zoo li kev tsom mus rau ib txoj hauv kev yuav ua tau zoo [296]. Yog li ntawd, kev sib koom ua ke ntawm cov txheej txheem uas txhawb nqa tsis yog OPC kev loj hlob thiab kev sib txawv nkaus xwb tab sis kuj tsim kom muaj ib puag ncig zoo microenvironment zoo li yuav muaj kev vam meej [297]. Tsis tas li ntawd, kev sib xyaw ua ke nrog cov tshuaj tiv thaiv kab mob yuav ua rau muaj kev mob tsawg dua tab sis muaj txiaj ntsig zoo dua milieu txhim kho remyelination thiab muab cov txiaj ntsig ntxiv los ntawm tackling MS pathophysiology ntau dua. Ntawm cov tshuaj tshuaj xyuas uas tau sim ua ke nrog cov tshuaj tiv thaiv kab mob, feem ntau cov neeg ua haujlwm raug tshuaj xyuas raws li kev kho mob ntxiv rau interferon- [22, 60, 71, 98, 120, 169]. Vim muaj ntau ntau ntawm interferon-mediated mechanisms, txawm li cas los xij, muaj kev pheej hmoo siab rau (tsis tau pom dua) kev sib cuam tshuam [38]. Xav txog cov kev sib cuam tshuam tsis tuaj yeem, kev siv cov tshuaj sib xyaw ua ke nrog interferon- yuav ua rau muaj kev cuam tshuam tsis zoo. Nyob rau hauv cov ntaub ntawv ntawm atorvastatin, piv txwv li, ua ke siv nrog interferon- muaj peev xwm antagonized interferon-mediated suppression ntawm MMPs thiab phosphorylation ntawm STAT 1 [36, 37]. Qhov no tej zaum yuav txo tau cov txiaj ntsig kev kho mob zoo hauv pab pawg kho mob. Ntawm qhov tod tes, kev sib xyaw ua ke ntawm interferon- nrog cov khoom sib txuas uas ua rau cov txheej txheem sib piv yuav suav nrog qhov sib txawv ntawm kev kho mob thiab pab pawg tswj hwm, raws li tau piav qhia rau inosine (saib 3.1.4) thiab minocycline (saib 3.3.2). Hauv qhov sib piv, cov tshuaj tiv thaiv monoclonal xws li natalizumab tuaj yeem yog lwm txoj hauv kev tsim nyog, vim lawv muab ntau yam zoo dua li interferon-. Ua ntej, cov kev xaiv ntau dua ntawm kev ua haujlwm pab txhawb kev sib txuas nrog cov lus cog tseg txij li kev sib cuam tshuam ntawm qib molecular yog qhov yooj yim rau kwv yees [298]. Thib ob, kev kho mob monoclonal antibody muab qib siab ntawm kev tswj hwm kab mob nrog rau kev tiv thaiv kev ua kom muaj zog ua rau lawv ua tus khub zoo hauv kev tshawb fawb ntxiv nrog.neuroregenerativecov neeg sawv cev [299].

Peb kuj tau pom ib qho kev hloov pauv rau cov kev kho mob paub zoo uas tau tso cai rau lwm yam kab mob hauv cov ntsiab lus ntawm autoimmune.neuroinflamation. Yog li ntawd, cov neeg tshawb xyuas tsis tsuas yog txo qis qhov kev pheej hmoo ntawm qhov tsis pom qhov tshwm sim tsis zoo tab sis kuj txo cov nqi thiab ua kom muaj kev vam meej los ntawm cov theem sib txawv ntawm kev sim tshuaj mus rau hauv kev ua lag luam. Txawm li cas los xij, tsis muaj ib qho ntawm cov tshuaj no tau ua tiav zoo [22, 142, 169, 183, 184, 203, 222, 246, 287]. Nrog rau qhov tsis muaj txiaj ntsig, qee qhov xwm txheej, qhov qhia thawj zaug rau kev pom zoo dhau los ua rau muaj kev cuam tshuam sab nraud txwv kev siv hauv MS, raws li pom rau EPO [233]. Txawm li cas los xij, qhov piv txwv yav dhau los qhia tau hais tias kev tsim qauv tshiab thiab ntau qhov tshwj xeeb derivates tej zaum yuav yog ib txoj hauv kev los txo cov kev mob tshwm sim tab sis tseem tau txais txiaj ntsig los ntawm thawj qhov laj thawj.

Muab qhov tsis txaus ntseeg ntawm txoj hauv kev uas tau ua pov thawj ua tau zoo hauv kev sim ua ntej, nws pom tseeb tias cov qauv tsiaj pab kawm tshwj xeeb ntawm CNS autoimmunity tab sis tsis tuaj yeem zoo li tag nrho cov intricacy ntawm MS. Tus qauv cuprizone, piv txwv li, muab kev nkag siab zoo rau cov txheej txheem ntawm remyelination tab sis tsis saib xyuas qhov cuam tshuam inflammatory [110]. Lwm qhov cuab yeej siv tau zoo rau kev kawm txog kev muaj peev xwm neuroregenerative yog tus qauv siv kev txhaj tshuaj ntawm cov teeb meem dawb gliotoxin lysolecithin [300]. Qhov kev raug mob hnyav no nyob rau hauv ib cheeb tsam tso cai rau kev soj ntsuam remyelination thaum tsis muaj cov ntaub so ntswg tsis tu ncua [301]. Txawm li cas los xij, qhov kev raug mob no tshwm sim yam tsis muaj kev koom tes ntev ntawm lymphocytes [296]. EAE, ntawm qhov tod tes, qhia ntau yam kev tiv thaiv kab mob thiab histological nrog MS. Tseem, qhov kev siv ntawm cov lus teb tsis tu ncua tuaj yeem cuam tshuam qhov kev tshawb nrhiav ntawm remyelination [296].

Tsis tas li ntawd, nws tseem ceeb heev rau xaiv cov qauv tsiaj raws li qhov xav tau ntawm kev ua haujlwm ntawm cov tshuaj ntsuam xyuas. Piv txwv li, cov neeg ua haujlwm kho mob neurodegeneration yuav tsum tau kawm hauv cov qauv uas qhia txog cov yam ntxwv ntawm pathophysiological ntawm kev loj hlob MS, xws li EAE hauv cov kab mob ntshav qab zib tsis rog MS nas [271, 302]. Txawm li cas los xij, cov neeg cog lus yuav tsum tau soj ntsuam tsis yog ib qho qauv tsiaj xwb tab sis txawv hauv vivo thiab hauv vitro mus kom ze, suav nrog ntau yam kev koom tes hauv MS.

Lwm qhov tseem ceeb suav nrog cov teeb meem uas nquag pom txog kev rov ua dua ntawm cov ntaub ntawv ua ntej kho mob ntawm cov chaw kuaj mob sib txawv. Cov teeb meem no yog ib feem los ntawm kev vam khom ntawm kev sim ntawm yam xws li hom kab mob lossis caj ces keeb kwm ntawm cov tsiaj, ib puag ncig, lossis kev noj haus [303]. Ib txoj hauv kev cia siab los txhim kho kev rov tsim dua tshiab ntawm kev nkag siab tau txais los ntawm kev sim tsiaj tej zaum yuav yog qhov kev sim ua ntej kev soj ntsuam randomized tswj (pRCTs) uas tau ua nyob rau hauv ntau lub chaw soj nstuam sib txawv raws li tus qauv [304]. Cov RCTs no tuaj yeem muab qib siab dua ntawm kev sib piv thiab siv tau ntawm cov ntaub ntawv ua ntej kho mob. Yog li, cov pRCTs no tuaj yeem yog kauj ruam tseem ceeb los txuas qhov sib txawv ntawm cov kev tshawb fawb ua ntej thiab Phase I kev sim tshuaj.

Tsis tas li ntawd, nws yuav tsum tau sib tham txog seb qhov sib xyaw ua ke hauv kev sim tshuaj thaum ntxov yuav tsum tau soj ntsuam tsuas yog los ntawm kev ua tiav ntawm qhov tseem ceeb ntawm cov ntsiab lus ntawm kev kawm. Qee qhov xwm txheej, xws li GSK239512 [120], qhov loj me me yuav raug kwv yees. Yog li ntawd, tej zaum kuj nyob rau hauv lub teeb ntawm tus nqi siab uas twb muaj lawm, ntau cov kev tshawb fawb tau zoo li underpowered. Txawm li cas los xij, cov kev tshawb fawb no tuaj yeem muab cov kev nkag siab tseem ceeb rau hauv cov txheej txheem ntawm kev ua ntawm cov tshuaj ntsuam xyuas. Qhov tseem ceeb tshaj, kev txheeb xyuas pawg pab pawg tuaj yeem siv los xaiv cov neeg mob uas yuav tau txais txiaj ntsig los ntawm kev kho mob hauv kev sim tshuaj tom ntej. Yog li ntawd, cov neeg sib tw cog lus yuav tsum tsis txhob muab pov tseg vim lawv ua tsis tau raws li pSE.

6 Cov lus xaus

Qhov kev txiav txim tseem ceeb yog qhov tseem ceeb ntawm cov qauv kev kawm tsim nyog. Qhov tseem ceeb tshaj plaws, tseem yuav tsum muaj kev ntseeg siab thiab muaj txiaj ntsig cov txiaj ntsig tsis zoo hauv kev sim tshuaj xyuasneuroregenerativekev kho mob. Txog rau tam sim no, tsis muaj ib qho cim uas tuaj yeem paub qhov txawv ntawm qhov muaj nyob rau hauv pre-muaj thiab remyelinated myelin [6]. Tsis tas li ntawd, nws tsis paub meej tias yuav ua li cas kom muaj nuj nqis ntawm remyelination. Ntau hom kev yees duab, suav nrog MTR, DTI, lossis positron emission tomography, tau tshwm sim thiab twb tau ua pov thawj los piav txog qhov ntawm remyelination [305-307]. Txawm li cas los xij, cov txheej txheem no tsis tau siv dav lossis siv tau txaus [308]. Hauv kev sim tshuaj xyuas, tsuas yog txoj kev tshawb fawb ntawm GSK239512 tau siv ib qho ntawm cov txheej txheem no raws li [120]. Lwm txoj hauv kev los txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau tshuaj yog qhov ua kom pom tseeb yog qhov ntsuas ntawm multifocal VEPs. Nyob rau hauv txoj kev no, multifocal VEPs muab cov qib siab dua ntawm kev nkag siab thiab qhov tshwj xeeb hauv kev tshawb nrhiav kev rov tsim dua tshiab ntawm txoj kev pom sab hauv piv rau cov pa VEPs [309].

Nyob rau hauv cov nqe lus ntawm kev tshawb nrhiavneuroprotectivetxoj hauv kev, kev sim siab yav tom ntej kuj tseem suav nrog kev ntsuas kev ntsuas neurofilament light chain (NFL). Neurofilaments yog ib feem ntawm cov neuronal cytoskeleton thiab tshwj xeeb tshaj yog enriched hauv axons. Yog li, neurofilaments raug tso tawm rau hauv CSF thiab cov ntshav qab zib neuroaxonal raug mob [310] ua rau kev ntsuas NFL yog ib qho kev cog lus elucidating.neuroprotectivecuam ​​tshuam. Txawm hais tias tsis yog MS-specifc, NFL tau pom tias yog biomarker ntawm cov kab mob kev ua haujlwm thiab kev kwv yees ntawm cov txiaj ntsig ntev hauv MS taug qab ob qho tib si neuroinflammatory thiab neurodegenerative puas tsuaj [310-312].

Ntxiv nrog rau cov kev txwv no, qhov kev thov rau cov txheej txheem kho mob kom zoo yog qhov tseem ceeb dua. Cov tshuaj yuav tsuas yog ua tiav cov kev xaiv kho mob rau cov neeg mob yog tias lawv tsis tsuas yog txhim kho paraclinical tsis tab sis muab cov txiaj ntsig cuam tshuam rau cov neeg mob. Yog li ntawd, cov ntsiab lus kho mob rhiab heev uas qhia txog qhov cuam tshuam ntawm neuroregeneration (xws li, kev txhim kho ntawm kev paub txog cov tsos mob) yog qhov yuav tsum tau ceev. Tshwj xeeb, cov qhab nia kho mob sib xyaw ua ke cuam tshuam txog qhov sib txawv ntawm qhov chaw kho mob, raws li siv hauv SYNERGY [98] thiab IPPoMS trials [222], zoo li muaj txiaj ntsig zoo rau kev soj ntsuam cov txiaj ntsig ntawm kev kho mob.neuroprotectivethiabneuroregenerativetus neeg sawv cev.

Tsis tas li ntawd, cov txiaj ntsig zoo ntawmneurotiv thaivFeem ntau yog los ntawm kev rov tsim dua los ntawm kev raug mob axonal thiab txo qis kev puas tsuaj ntawm neuronal thaum lub sijhawm [6]. Yog li, cov teebmeem kev kho mob tsis zoo li yuav tshwm sim tom qab ib zaug rov qab los. Tej zaum lawv yuav pom zoo tom qab xyoo ntawm kev ncua kev xiam oob khab thiab kab mob, yog li thov rau kev sim mus ntev [308]. Txawm li cas los xij, feem ntau ntawm cov kev sim siab tam sim no tsis ua tau raws li qhov xav tau no rau lub sijhawm taug qab ntev.

Lwm qhov tseem ceeb hais txog kev tsim qauv, tshwj xeeb tshaj yog ntawm kev kho mob remyelinating, yog lub hnub nyoog ntawm cov neeg mob suav nrog. Siv cov kev tshuaj ntsuam xyuas pab pawg ntawm RENEW txoj kev tshawb fawb ua piv txwv, qhov sib txawv ntawm hnub nyoog raws li qhov ua tau zoo ntawm cov txheej txheem remyelinating tau pom tseeb [106]. Remyelination peev xwm, piv txwv li, poob nrog hnub nyoog [107]. Cov kev tshawb fawb yav tom ntej yuav tsum tau qhia, seb qhov kev poob qis no ua rau txo qis ntawm kev kho cov tshuaj remyelinating los yog tej zaum, ntawm qhov tsis sib xws, kom tau txais txiaj ntsig zoo ntawm kev kho mob remyelinating vim qhov kev nthuav dav ntawm kev txhim kho. Yog li ntawd, lub hnub nyoog ntawm cov neeg koom yuav tsum tau txiav txim siab nyob rau hauv txoj kev tshawb fawb tsim ntawm cov kev kho mob no nyob rau hauv daim ntawv ntawm kev txwv lub hnub nyoog txwv thiab hnub nyoog sib piv mus kom ze. Ntxiv nrog rau qhov cuam tshuam ntawm lub hnub nyoog, tus kab mob ntev kuj zoo li muaj kev cuam tshuam loj rau kev ua tau zoo ntawmneuroregenerativezoo lineuroprotectivekev kho mob. Cov laj thawj hauv qab zoo li cuam tshuam txog kev puas tsuaj ntawm cov txheej txheem neuroaxonal. Ua ntej, lub xub ntiag ntawm kev ua haujlwm tsis zoo axons yog qhov yuav tsum tau ua ua ntej rau remyelination [6]. Qhov thib ob, kev ncaj ncees ntawm cov xov tooj neuronal zoo li tau txo qis hauv cov theem siab ntawm tus kab mob, txo qhov muaj peev xwm ua tiav ntawmneuroprotectivekev ua si [111]. Yog li ntawd, kev txiav txim siab kom raug ntau dua ntawm cov kab mob ntev yog qhov tseem ceeb rau kev kawm tsim qauv ntawm kev sim yav tom ntej.

Kev sib piv cov txiaj ntsig ntawm tib tus neeg sawv cev hauv cov kab mob sib txawv, raws li pom hauv kev sim ntawm atorvastatin (saib 3.1.1) lossis EPO (saib 4.2.1), qhia txog qhov tseem ceeb ntawm kev sib cais nruj ntawm cov chaw hauv kev tshawb fawb soj ntsuam. Ua ke nrog qhov sib txawv ntawm cov tswv yim sib txawv ntawm cov kab mob pathophysiological hauv qab cov kab mob [3], qhov kev soj ntsuam no qhia txog qhov tseem ceeb ntawm kev ua tib zoo xaiv cov neeg mob uas tsim nyog rau kev ua tiav ntawm kev sim tshuaj.

Thaum kawg, nws qhov kev tshuaj xyuas ntxiv hais txog qhov xav tau ntawm kev tshaj tawm cov kev tshawb fawb soj ntsuam ua tsis tiav. Txawm hais tias cov kev sim no tsis ntsuas raws li qhov kev cia siab, lawv tseem muab cov ntaub ntawv tseem ceeb ntawm MS pathophysiology. Tsis tas li ntawd, lawv pab kom nkag siab txog cov teeb meem hais txog kev txhais lus ntawm kev nkag siab tau txais los ntawm kev tshawb fawb preclinical thiab yog qhov tseem ceeb rau kev nce qib hauv kev tsim qauv. Yog li ntawd, cov kws tshawb nrhiav thiab cov ntawv xov xwm yuav tsum tau txhawb ntxiv kom tshaj tawm cov txiaj ntsig tsis zoo.

Cistanche muaj cov nyhuv neuroprotective zoo heev

Cov lus tshaj tawm

Kev Pab Nyiaj Qhib Kev Siv Nyiaj tau qhib thiab tsim los ntawm Projekt DEAL.

Kev tsis sib haum xeeb ntawm kev txaus siab Niklas Huntemann: tshaj tawm tsis muaj kev tsis sib haum xeeb ntawm kev txaus siab. Leoni Rolfes tshaj tawm tias tsis muaj kev cuam tshuam ntawm kev txaus siab. Marc Pawlitz-ki: tshaj tawm tsis muaj kev cuam tshuam ntawm kev txaus siab. Tobias Ruck: tau txais tus nqi ntawm tus kheej los ntawm Alexion, Biogen, Merck Serono, Sanofi-Genzyme, Roche, thiab Teva, nyiaj pab los ntawm Alexion thiab Sanofi-Genzyme, thiab kev txhawb nqa tsis yog nyiaj txiag los ntawm Merck Serono. Stefen Pfeufer: tau txais cov nyiaj them rov qab mus ncig los ntawm Sanofi Genzyme thiab Merck Serono, honoraria rau kev qhia los ntawm Sanofi Genzyme, Biogen, thiab Mylan Healthcare, thiab kev tshawb fawb txhawb nqa los ntawm Merck Serono, Diamed, thiab German Multiple Sclerosis Society North Rhine-Westphalia. Heinz Wiendl: tau txais nyiaj pab los ntawm German Ministry rau Kev Kawm thiab Kev Tshawb Fawb

(BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, European Union, Hertie Foundation, NRW Ministry of Education thiab Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, Biogen, Glaxo- SmithKline GmbH, Roche , thiab Sanofi-Genzyme; kev sab laj nqi los ntawm AbbVie, Actelion, Argenx, Biogen, EMD Serono, Idorsia, IGES, Immunic, Merck, Novartis, Roche, Sanofi-Aventis, Swiss Multiple Sclerosis Society, thiab UCB; kev txhawb nqa rau kev mus ncig rau cov rooj sib tham rau lwm lub hom phiaj los ntawm Alexion, Biogen, Cognome, F. Hofmann-La Roche Ltd., Hertie Foundation, Merck Serono, Novartis, Roche, Genzyme, Teva, thiab WebMD Global; cov nqi rau kev koom tes hauv kev tshuaj xyuas cov haujlwm xws li cov ntaub ntawv saib xyuas cov ntaub ntawv los ntawm Polpharma Biologics; them nyiaj rau kev qhuab qhia los ntawm Alexion, Biogen, Cognome, F. Hofmann-La Roche Ltd., Hertie Foundation, Merck Serono, Novartis, Roche, Genzyme, Teva, thiab WebMD Global; Honorarium rau cov kws tshaj lij cov lus pov thawj los ntawm Lub Tsev Haujlwm Saib Xyuas Tshuaj ntawm German Medical Association. Sven G. Meuth: tau txais honoraria rau kev hais lus thiab kev them nyiaj rov qab mus rau kev mus koom cov rooj sib tham los ntawm Almirall, Amicus Therapeutics Lub Tebchaws Yelemees, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, thiab Teva. Nws cov kev tshawb fawb yog nyiaj txiag los ntawm German Ministry for Education thiab Re- tshawb nrhiav (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology thiab Alexion, Almirall, Amicus Therapeutics Lub Tebchaws Yelemees, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, thiab Teva.

Muaj cov ntaub ntawv thiab cov khoom siv Tsis siv tau.

Kev pom zoo Ethics Tsis siv tau.

Kev tso cai los koom Tsis tau.

Kev tso cai rau kev tshaj tawm Tsis siv tau.

Code muaj tsis tau.

Tus sau kev koom tes NH: kawm lub tswv yim thiab tsim qauv, tau txais cov ntaub ntawv, kev tshuaj xyuas thiab kev txhais cov ntaub ntawv, sau cov ntawv sau. LR: kawm lub tswv yim thiab tsim qauv, tau txais cov ntaub ntawv, sau cov ntawv sau. MP: Kev hloov kho tseem ceeb ntawm cov ntawv sau rau cov ntsiab lus kev txawj ntse. TR: Kev hloov kho tseem ceeb ntawm cov ntawv sau rau cov ntsiab lus kev txawj ntse. SP: Kev hloov kho tseem ceeb ntawm cov ntawv sau rau cov ntsiab lus kev txawj ntse. HW: Kev hloov kho tseem ceeb ntawm cov ntawv sau rau cov ntsiab lus kev txawj ntse. SGM: kawm lub tswv yim thiab tsim qauv, kev hloov kho tseem ceeb ntawm cov ntawv sau rau cov ntsiab lus kev txawj ntse.

Qhib Kev Nkag Mus Tsab Ntawv no tau tso cai raws li Creative Commons Attribution-NonCommercial 4.0 Daim ntawv tso cai thoob ntiaj teb, uas tso cai rau kev siv tsis yog lag luam, sib qhia, hloov kho, faib, thiab luam tawm hauv ib qho nruab nrab lossis hom ntawv, tsuav koj muab credit tsim nyog rau tus thawj kws sau ntawv thiab qhov chaw, muab qhov txuas mus rau Creative Commons daim ntawv tso cai, thiab qhia seb puas tau hloov pauv. Cov duab lossis lwm yam khoom siv thib peb hauv tsab xov xwm no suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai tshwj tsis yog tau qhia lwm yam hauv kab qiv nyiaj rau cov khoom siv. Yog tias cov ntaub ntawv tsis suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai thiab koj qhov kev npaj siv tsis raug tso cai los ntawm txoj cai lij choj lossis tshaj qhov kev tso cai siv, koj yuav tsum tau txais kev tso cai ncaj qha los ntawm tus tuav ntaub ntawv. Txhawm rau saib daim ntawv theej ntawm daim ntawv tso cai no, mus saib http://creativecommons.org/licenses/by-nc/4.0/.