Methylene blue yeMS: tsananguro yetsvakurudzo yeEAE mumhuka

Tsvaga methylene blue yeMS uye unowana mapepa anoita seari kupindura mubvunzo mumwe chete. Haasi kudaro. Rimwe pepa rakapa mbeva dzairwara methylene blue sekurapa. Rimwe harina kumborapa mhuka nayo. Rakashandisa methylene blue sedhayi rebhuruu pazvimedu zvitete zvemuzongoza kuitira kuti nyanzvi inoongorora zvirwere munyama yemuviri ione myelin nemaikorosikopu.

Iyi ndiyo pfungwa iri shure kwechinyorwa chose. Dhayi iri rine mabasa maviri muzvidzidzo zvezvinhu zvipenyu, uye mabasa aya haana chaanogovana kunze kwebhodhoro. Parinoyedzwa kuti ringazova mushonga, rinopiwa kumhuka mhenyu uye mubvunzo ndewekuti chirwere chinoshanduka here. Parinoshandiswa kudhaya, rinoiswa panyama yemuviri yakafa yakachengetedzwa kuti isashanduka mushure mekuyedza, uye mubvunzo ndewekuti nyama yacho yaitaridzika sei. Kana ukasanzwisisa musiyano iwoyo, unoverenga chikamu chenzira dzekuongorora zvirwere munyama sokunge chiri mugumisiro wekurapa.

EAE chii, nemashoko ari nyore

Experimental autoimmune encephalomyelitis, inowanzopfupikiswa ichinzi EAE, ndiyo nzira yakajairika yekushandisa mhuka kumiririra zvimwe zvinhu zvemultiple sclerosis. Muongorori anobaya mbeva inokwanisa kubatwa nechirwere ichi nechimedu chepuroteni yemyelin pamwe nechinhu chine simba chinosimudzira mhinduro yemas oja ekudzivirira muviri. Masoja ekudzivirira muviri anobva arwisa hurongwa hwemhuka yacho hwepakati hwetsinga. Mbeva inova nekushaya simba kunokwira kubva pasi, kuri nyore kupa zvibodzwa pachiyero che0 kusvika 5, kubva pamuswe usina simba kusvika pakuoma mitezo yemakumbo ekumashure.

Kureruka ikoko kwekupa zvibodzwa kunotsanangura kuti nei EAE ichishandiswa zvakanyanya uye kuti nei ichigonawo kutsausa. MS yevanhu inotanga yoga, inosanganisira zvinhu zvakawanda uye zvisina kunyatsotsanangurwa zvinorwiswa nemasoja ekudzivirira muviri, uye inokonzera zviratidzo zvekuona, kunzwa, kufunga, mashandiro echikamu cheuropi chinoronga kufamba nekuenzana kwemuviri, uye kufamba kwemhasuru, muchirwere chinodzoka kana chinoramba chichiwedzera. EAE inodzokorora dzimwe nzira dzakasarudzwa dzakadai sekuzvimba, kurasika kwemyelin, uye kukuvara kwemaaxon mumamiriro anodzorwa. Haidzokorori MS muchimiro chidiki. Vaverengi vanoda kunzwisisa maonero akazara vanogona kutanga vaongorora kuti methylene blue inofungidzirwa kushanda sei pamasero vasati vatonga chero chirevo pamusoro pechirwere chimwe chete.

Mapepa maviri ari pasi apa akashandisawo maantigen akasiyana eEAE, uye izvi zvinokosha. Ong ororo yekurapa yakakonzera chirwere neMOG35-55, peptide pfupi inobva mumyelin oligodendrocyte glycoprotein. Ong ororo yezvirwere munyama yakakonzera chirwere neMP4, mubatanidzwa wezvikamu zvemyelin basic protein neproteolipid protein. Kusarudzwa kwerudzi rwembeva neantigen kunoshandura nzvimbo dzinoonekwa kukuvara uye maitiro ekuzvimba, saka ongororo mbiri idzi hadzisi kudzokorora kuyedza kumwe chete kaviri.

Mepu: kubva pamuenzaniso kuenda kumubvunzo nemiganhu

Ramba wakavhura tafura iyi. Ndiyo hwaro hwechinyorwa ichi. Mutsara wega wega unotaura mubvunzo wekurapa vanhu unogona kupindurwa nemuenzaniso wacho, zvakayerwa chaizvo, uye panoperera kushandisa zvakawanikwa kuvanhu.

	Ong ororo yekurapa (MOG EAE)	Ong ororo yezvirwere munyama (MP4 EAE)
Pepa	Ong ororo yekurapa EAE yakakonzerwa neMOG peptide	Ong ororo yezvirwere munyama yeMP4 nekufamba kwenguva
Basa remethylene blue	Chinhu chakapiwa mbeva mhenyu kuyedza kuchinja chirwere	Dhayi rakaiswa pazvimedu zvemuzongoza zve1 micrometer zvakachengetedzwa kuti zvisashanduka
Mubvunzo wekurapa vanhu wainogona kupindura	Kupa chinhu ichi kunochinja here kukomba kweEAE nekutumirana kwezviratidzo mumasoja ekudzivirira muviri	Kurasika kwemyelin nekukuvara kwemaaxon zvinoshanduka sei mumwedzi mitanhatu
Zviyero zvemigumisiro	Zvibodzwa zvezviratidzo zvechirwere zvezuva nezuva, masero akapinda mumuzongoza, kurasika kwemyelin, kukuvara kwemaaxon, kutumirana kwezviratidzo kweAMPK neSIRT1, kushanda kweNF-kB, kuenzana kweTh17 neTreg	Ukuru hwenzvimbo yakakuvadzwa, zviyero zvekuzvimba nekuungana kwemvura munyama, kuwanda kwetambo dzarasikirwa nemyelin, g-ratio inoyerwa nemaikorosikopu yemaerekitironi, kuparara kwemaaxon, kuzvimba kwemitochondria, chinhambwe pakati peneurofilaments
Mug anhu wekushandisa zvakawanikwa kuvanhu	Rudzi rwembeva rumwe chete, hadzi kana hono imwe chete, nguva pfupi yemazuva 30, kuwirirana kwete humbowo hwenzira inoshanda nayo	Hapana kurapa kwakayedzwa, kutorwa kwenyama kubva kumapoka akasiyana panguva dzakasiyana, nzvimbo dzakakuvadzwa dzakatorwa zvikuru muchikamu chemuzongoza chepazasi pemusana

Munhu wese ari kuongorora musoro wenhau unotevera anogona kushandisazve makoramu mamwe chete achibatsirwa nema verengero etsvakurudzo inoitwa kusati kwaedzwa kurapa vanhu: bvunza rudzi rwemhuka neantigen, basa rechinhu chakashandiswa, zviyero zvemigumisiro, uye kana mugumisiro wacho uri kufamba kwechirwere kana kuti mamiriro enyama pane imwe nguva chete.

Mugumisiro wekurapa: zvakachinjwa nekupa methylene blue

Ong ororo yekurapa ya2016 muJournal of Neuroimmunology yakashandisa mbeva hadzi dzeC57BL/6, dzaiva nemavhiki anenge 8 kusvika 10, dzakabaiwa ne250 micrograms yeMOG35-55 pambeva imwe neimwe. Mushure mekukonzera chirwere, mhuka dzeEAE dzakakamurwa nemukana chete kuita boka remethylene blue kana boka reEAE risina kurapwa, uye zvibodzwa zvezviratidzo zvechirwere zvakateverwa kusvika pazuva rinenge 30.

Zvibodzwa zvezviratidzo zvechirwere zvaiva zvakaderera zvine musiyano wakakosha pane zviverengero mumbeva dzakarapwa kupfuura mumbeva dzeEAE dzisina kurapwa kubva pazuva 15 kusvika pazuva 30, paP iri pasi pe0.01. Kuongorora muzongoza kwakaratidzawo izvozvo, paine kupinda kushoma kwemasero ekuzvimba, kurasika kushoma kwemyelin, uye kurasika kushoma kwemaaxon mumhuka dzakarapwa.

Chikamu chakanga chakasiyana ndechezviyero zvekutumirana kwezviratidzo. Kurapa kwakawedzera kumutswa kweAMPK nekugadzirwa kweSIRT1 uye kwakadzvinyirira kumutswa kweNF-kB, iyo ine basa guru pakutanga kuzvimba. Kudivi remasoja ekudzivirira muviri anodzidza kupindura zvinhu zvaanosangana nazvo, kwakaderedza mhinduro yeTh17 uye kwakasimbisa mhinduro yeTreg. Saka nhevedzano yakakurudzirwa ndeyekuti methylene blue inokanganisa AMPK neSIRT1, izvo zvinoderedza kutumirana kwezviratidzo kweNF-kB, zvichichinja kubva kuTh17 inokurudzira kuzvimba kuenda kuTreg inodzora mhinduro yemas oja ekudzivirira muviri, zvichitungamirira kukukuvara kushoma kwenyama uye kuzvibodzwa zvakaderera.

Nhevedzano iyoyo itsananguro yezvakawanikwa, kwete nhevedzano yakaratidzwa kuti chimwe chinokonzera chinotevera. Ong ororo inoratidza kuti mushonga, kuchinja kwezviratidzo zvinotumiranwa, uye kuvandudzika kwechirwere zvakaitika pamwe chete. Hairatidzi kuti AMPK neSIRT1 ndizvo zvinounza kubatsira kwose, uye zvinyorwa zvinowanikwa muruzhinji mumadatabase hazviratidzi zvakajeka zvakakwana chipimo chaicho chemilligram pakilogram, nzira yekupa mushonga, zuva rekutanga, kana nguva yawakapiwa, kuti nzira yekurapa idzokororwe pachishandiswa pfupiso chete. Ona nhamba ipi neipi yechipimo inotaurwa nezvepepa iri papeji rekutengesa seisina kusimbiswa kunze kwekunge ichinongedzera kuchikamu chenzira dzakashandiswa chiri muzvinyorwa zvizere. Muunganidzwa wakafara weumbowo hwemethylene blue muvanhu ndiyo nzvimbo yekutarisa kana chiratidzo ichi chekutanga chemasoja ekudzivirira muviri chakazombosvika pakupa mashoko kubva muongororo dzevarwere.

Mugumisiro wekuongorora zvirwere munyama: zvakaratidzwa nenyama mumwedzi mitanhatu

Ong ororo yeMP4 ya2015 muPLoS ONE yakashandisa mbeva hadzi dzeC57BL/6 dzakabaiwa ne200 micrograms yeMP4 iri mucomplete Freund adjuvant pamwe nepertussis toxin pazuva rekubaiwa uye zvakare mushure memaawa 48. Hapana mhuka yakapiwa methylene blue semushonga. Mushure mekuchengetedza nyama kuti isashanduka nekuiisa muchinhu chinotsigira kuchekwa kwayo, zvimedu zvemuzongoza zvakachekwa zvakachinjika zvine ukobvu hwemicrometer imwe zvakadhayiwa nemethylene blue kuti zviongororwe nemaikorosikopu yechiedza, uye nzira yetsinga iri nechepamberi neparutivi pemuzongoza yakaongororwa nemaikorosikopu yemaerekitironi kuti paonekwe zvinhu zvidiki zvakadzama.

Nyama yakatorwa pamatanho matatu: pakukomba kukuru kwekutanga nembeva 7, mwedzi mitatu mushure mekutanga kwechirwere nembeva 5, uye mwedzi mitanhatu mushure mekutanga kwechirwere nembeva 10. Avhareji yezvibodzwa zvezviratidzo zvechirwere pamatanho iwayo yaitaridzika yakada kufanana, iri pedyo ne1.7 kusvika 1.8 pachiyero che0 kusvika 5. Nyama yakaratidza zvakasiyana. Kukuvara kwemyelin chete kwakakwira kubva patambo dzinenge 569,000 pasquare millimeter pakukomba kukuru kwekutanga kusvika padzinenge 1,496,000 pamwedzi mitanhatu, uye kuenzanisa danho rekutanga nenguva yakareba kwakaratidza musiyano wakakosha pane zviverengero paP yakaenzana ne0.027. Kukuvara kwemyelin pamwe nemaaxon kwakawedzera zvakada kusvika kaviri pamwedzi mitanhatu. Tambo dzakanga dzichivakazve myelin dzakaramba dziri pasi pechikamu chimwe chete kubva muzana padanho rega rega, chinova chinhu chinoda kufungwa nezvacho pakutarisira kugadziriswa kwekukuvara.

Kukuvara kwemaaxon kwakatevera chimiro cheU: kwakanga kwakawanda pakukomba kukuru kwekutanga, kushoma pamwedzi mitatu, uye kwakanyanya pamwedzi mitanhatu; kwaienderanawo nekuzvimba kwemitochondria uye kuderera kwechinhambwe pakati peneurofilaments. Vaiongorora vakanga vasingazivi zvibodzwa kana danho rechirwere, izvo zvinosimbisa dudziro yekuti zvibodzwa zvezviratidzo zvechirwere zvairatidza kukuvara kushoma pane kwainge kuri kuramba kuchiitika muchimiro chenyama.

Kusawirirana ikoko ndiko kubatsira chaiko kweongororo iyi kumuverengi ari kufarira MS. Kusachinja kwechibodzwa chekuremara kwaisareva kuti nyama yakanga isingachinji. Zvinoratidzawo kuti nei pepa iri risingagoni kutsigira chero chirevo chekushandisa methylene blue kurapa MS. Rakaedza kuchinja nekufamba kwenguva, kwete kurapa.

Nei pasina imwe yeongororo idzi inoratidza kubatsira kuvarwere

Funga nezvepepa rimwe nerimwe serinopindura zvakanaka mubvunzo wakamanikana asi risingapinduri zvachose mubvunzo une chekuita nevarwere.

Chekutanga, chinokonzera chirwere chakasiyana. EAE inokonzerwa nemaune neantigen yakanyatsotsanangurwa nechinhu chinosimudzira mhinduro yemas oja ekudzivirira muviri. MS yevanhu inokura yoga iine mashandiro akafara emasoja ekudzivirira muviri anosanganisira masero eT, masero eB, dziviriro yemuviri yekuzvarwa nayo, uye masero eglia anogara mutsinga. Chinhu chinoshandura mhinduro inonyanya kunanga kuMOG mumbeva hachirevi kuti chinoshandurawo mhinduro yakafara iyoyo muvanhu.

Chechipiri, maitiro anooneka echirwere akasiyana. Kushaya simba kunokwira kubva kumuswe kuenda kumakumbo ekumashure kwembeva chinhu chiri nyore kuyera. Kunomanikidza kusiyana kwakawanda kweMS yevanhu kuita nhamba imwe chete yekufamba kwemhasuru. Mishonga inowanzoshandura zvibodzwa zveEAE zvenguva pfupi isingashanduri kufamba kwechirwere muvanhu, ndokusaka EAE iri chishandiso chekutanga chekuongorora uye chekudzidza nzira dzinoshanda nadzo zvinhu, kwete kiriniki diki.

Chechitatu, kuti muviri unosangana nemushonga wakawanda sei uye nguva yekuupiwa hazvisati zvagadziriswa. Kupa mushonga nguva dzose kubva pakutanga mukuyedza mbeva kwemazuva 30 hakusi kushandisa mushonga unonwiwa kwenguva refu mumunhu ane chirwere chakatosimba, uye hapana imwe yeongororo idzi yakayera huwandu hwemushonga muhurongwa hwetsinga. Pasina kubatana ikoko, hapana nzira yekubatanidza huwandu hwechinhu chiri mundiro yerabhoritari kana chipimo chinopiwa mbeva nenzira yekupa mushonga kumunhu.

Chechina, mapepa maviri aya haadzokorori zvakawanikwa nerimwe. Maantigen akasiyana, mibvunzo yakasiyana, zviyero zvemigumisiro zvakasiyana, uye mune imwe hapana kurapa zvachose. Kuataura pamwe chete sokunge ari ongororo mbiri dzakaratidza kubudirira kwekurapa MS kukanganisa kwekuisa zvinhu mumapoka.

Zvinorehwa neizvi kuvaverengi vari kuyera umbowo

Hapana nzira yakasimbiswa yekushandisa methylene blue paMS mumapepa aya. Ong ororo yekurapa inotsigira imwe tsvakurudzo pamusoro peAMPK, SIRT1, NF-kB, uye kuenzana kweTh17 neTreg muMOG EAE. Ong ororo yezvirwere munyama chiyeuchidzo chekuti kukuvara kwenyama kunogona kuramba kuchiwedzera zvibodzwa zvichiita sezvisingachinji, uye kuti methylene blue muchikamu chenzira dzakashandiswa dzimwe nguva inoreva chirongo chedhayi panzvimbo pekabhati yemishonga. Vaverengi vanotevera tsvakurudzo yemultiple sclerosis iri kuenderera mberi vanofanira kuramba vachifunga nezvemusiyano iwoyo pakati pedhayi nemushonga. Mibvunzo yekuchengeteka, kusanganisira njodzi dzine chekuita neropa nekudyidzana nemimwe mishonga, inofanira kukurukurwa nenyanzvi yezvekurapa pamwe chete nemashoko akazara ekuchengeteka kwemethylene blue munhu asati atora danho achivimba nemisoro yenhau yerabhoritari.

Mhedziso yacho inokwana mumutsara mumwe chete. Imwe ongororo yakataurwa yakapa methylene blue kumbeva dzeMOG EAE ikashuma chirwere chisina kunyanya kukomba pamwe nekuchinja kwemas oja ekudzivirira muviri kunoderedza kuzvimba, asi imwe ongororo yakataurwa haina kupa mushonga uye yakashandisa methylene blue kungodhaya muzongoza ichinyora kuwedzera kwekukuvara kwemyelin nemaaxon mumwedzi mitanhatu, saka ongororo mbiri idzi hadziratidzi kuti methylene blue inobatsira paMS yevanhu.