Methylene blue mutsvakurudzo yesitiroko nekuyerera kweropa kushoma muuropi: zvinonyatsoratidzwa nemamodheru matatu

Tsinga yeropa yakavharika, masero akakuriswa murabhoritari achinyimwa zvinovapa simba, uye gonzo rine tsinga dzemutsipa dzakatetepa zvinganzwika semhando nhatu dzechiedzo chimwe chete. Hazvisi izvo. Chimwe nechimwe chinobvunza mubvunzo wakasiyana, uye methylene blue inopa mhinduro yakasiyana mune chimwe nechimwe. Ukazvisanganisa, zvinyorwa zvetsvakurudzo zvinoita sezvinopikisana. Ukazvipatsanura, patani yakajeka inooneka, inonyanya kutungamirirwa nenguva yainopiwa.

Kupatsanura uku ndiko chinangwa chikuru cheongororo iyi. Mamodheru matatu aya isitiroko inoerekana yatanga muchikamu chimwe cheuropi, kushayiswa okisijeni neglukosi kuchiteverwa nekudzorerwa kweokisijeni mumasero akakuriswa murabhoritari, uye kuyerera kweropa kushoma muuropi kwemavhiki. Maitiro anofungidzirwa kuti anoabatanidza ane chekuita nemitochondria, asi migumisiro inosiyana nokuti mamiriro ekushandurwa kwezvinovaka muviri kuita simba anosiyana.

Mamodheru matatu anopindura mibvunzo yakasiyana

Sitiroko inoerekana yatanga muchikamu chimwe cheuropi mumakonzo inowanzogadzirwa nekuvhara tsinga inonzi middle cerebral artery, zvichipfupikiswa kunzi MCAO. Kuvharika kwakafanana negwamba reropa kunogadzira nzvimbo yepakati isingawani ropa yakakomberedzwa nepenumbra, nyama iri mungozi asi ingangoponeswa kana kuyerera kweropa kukadzoka. Mubvunzo pano ndewokuti kupindira kunononotsa here kukura kwenzvimbo ine nyama yakafa kana kuti kunochengetedza kushanda kweuropi panguva yekudzorerwa kwekuyerera kweropa.

Kushayiswa okisijeni neglukosi, kunopfupikiswa kunzi OGD, kunoshanda pachiyero chakasiyana zvachose. Masero europi akakuriswa murabhoritari anoiswa mune okisijeni inenge isipo uye musina glukosi, ozodzorerwa mumushonga wekukurisira masero wakajairika. Hamuna gwamba reropa, hamuna dzimwe nzira dzinogona kutenderedza ropa, hamuna BP, uye hamuna masoja emuviri. Mubvunzo uyu ndewemasero chete: chii chinoitika pakufema kwemasero, paATP, uye pakurarama kwawo kana zvinhu zvinoshandiswa kugadzira simba zvikanyangarika zvobva zvadzoka.

Modheru yekuyerera kweropa kushoma muuropi kwenguva refu inoshandisa kuvharwa zvachose kwetsinga dzecarotid kumativi ose mumakonzo, ichinzi modheru ye2VO. Kuyerera kweropa kuchikamu chepamberi cheuropi kunodzikira uye kunoramba kwakaderera kwemavhiki. Hapana kufa kwenyama kunoerekana kwaitika panzvimbo imwe uye hapana kudzorerwa kwekuyerera kweropa kwechimbichimbi. Mubvunzo ndewokuti kutsigira kugadzirwa kwesimba kwemavhiki kunochengetedza here tsinga, mitochondria, uye ndangariro panguva yekuyerera kweropa kushoma kunoramba kuripo.

Saka kuvandudzika kwendangariro mushure memwedzi mumwe wekurapwa mumodheru ye2VO hakutauri chinhu chakananga nezvekuponesa uropi hwemunhu panguva yekubviswa kwegwamba reropa kwechimbichimbi. Musiyano uyu unokosha nokuti pfupiso zhinji dzine tarisiro huru dzinouusiya.

Sitiroko inoerekana yatanga: kudzivirirwa pakudzorerwa kwekuyerera kweropa, kunonotswa kana kusingadzorerwi

Mugumisiro wakajeka zvikuru wesitiroko inoerekana yatanga unobva paMCAO yenguva pfupi ichiteverwa nekudzorerwa kwekuyerera kweropa. Tsinga dzemakonzo dzakavharwa kwemaminitsi 60, ndokuzopiwa mwero wakaderera wemethylene blue kuburikidza netsinga yeropa kutangira pakudzorerwa kwekuyerera kweropa, nemimwe miyero pamaawa 3 uye pazuva 2. MRI yakaratidza kuti nzvimbo yakakuvara muboka rakapiwa mushonga wekutakurisa usina methylene blue yakakura neinenge 19 percent pazuva 2, ukuwo nzvimbo yakakuvara muboka rakarapwa yakaderera neinenge 17 percent, nzvimbo dzekupedzisira dzine nyama yakafa dziri diki neinenge 30 percent uye zvibodzwa zvekuongorora mashandiro etsinga zviri nani pamazuva 2 na7. Kurarama kwenyama yepakati neye penumbra sezvakaratidzwa pamifananidzo kwakavandudzika. Zvinyorwa zvakakura pamusoro pekudzivirirwa kwetsinga zvinoisa kudzivirirwa uku kunopiwa panguva yekudzorerwa kwekuyerera kweropa pamwe chete nezvakawanikwa pakushayikwa kweropa muuropi hwose nekukuvara.

Mamiriro acho anochinja kana tsinga ikaramba yakavharika. Muchiedzo cheMCAO yekuvharwa zvachose, methylene blue yakapiwa ropa richiri kusasvika zvakakwana yakanonotsa kuwedzera kwenzvimbo yakakuvara yairatidzwa nemifananidzo yediffusion uye yakawedzera kwenguva pfupi nguva yekusawirirana kweperfusion nediffusion, kuyerera kweropa munzvimbo yacho kuri nani zvishoma, asi ukuru hwekupedzisira hwenzvimbo ine nyama yakafa pamaawa 24 hwakanga husina musiyano wakakosha maererano nenhamba dzetsvakurudzo. Yakanonotsa kuchinja kwenyama iri mungozi kuita nyama yakafa, asi haina kutsiva kuvhurwazve kwetsinga.

Chidzidzo chechitatu chesitiroko inoerekana yatanga chinowedzera tsananguro yemaitiro nemisiyano yemwero. Mwero mumwe wakabaiwa mukati medumbu pakarepo mushure mekuvharwa kwetsinga wakaratidza kuderera kukuru kwenzvimbo ine nyama yakafa, kunenge 50 percent, pamwero wepakati we5 mg/kg pane pa1 kana 10 mg/kg, pamwe chete nezvibodzwa zviri nani zvekushanda kwekunzwa nekufamba. Vanyori vakabatanidza izvi nekuchengetedzwa kwechimiro chemitochondria uye kuwedzera kwemitophagy, kubviswa kwemitochondria yakakuvara ichisarudzwa. Saka mwero, nzira yokupa, uye chirongwa chenguva zvinokosha, uye miyero yemakonzo yemg/kg haisi miyero yokurapa sitiroko muvanhu.

Masero akakuriswa murabhoritari: mushonga mumwe chete unobatsira kana kukuvadza zvichienderana nenguva yaunosvika

Chiedzo chemaastrocyte ndicho chinodzidzisa zvikuru uye chinowanzotaurwa zvisiri izvo. Maastrocyte ekutanga akatorwa mucortex yembeva akashayiswa zvinovapa simba zvakanyanya kwemaawa 6 paokisijeni ye0.1 percent mumushonga wekukurisira masero usina glukosi, pyruvate, kana serum, zvichiteverwa nemaawa 24 ekudzorerwa kweokisijeni nezvinhu zvinoshandiswa kugadzira simba. Inenge hafu yemasero yakafa, izvo zvinopa chiyedzo mukana wekuratidza kubatsira kana kukuvadza.

Methylene blue payaivapo panguva yekushayiswa uku, kurarama kwemasero kwakawedzera kuipa, kwete kuvandudzika. Payakaunzwa panguva yekudzorerwa kweokisijeni pachinzvimbo chacho, uwandu hwakaderera hunoyerwa nemicromolar hwakavandudza kurarama kwemasero uye hwakawedzera kushandiswa kweokisijeni, kupinzwa kweglukosi, nekugadzirwa kweATP. Mumamiriro akajairika, uwandu humwe chete hwakawedzera kupinzwa kweglukosi neinenge 89 percent pa0.1 micromolar uye neinenge 200 percent pa1 micromolar, glycogen nekushanda kwehexokinase zvichichengetedzwa mushure mekukuvara uye pasina kuwedzera kwesuperoxide kwakayerwa.

Maitiro acho ari nyore kunzwisisa kana achienzaniswa nejenareta rinoshandiswa pakushaikwa kwemagetsi. Methylene blue inoshanda seimwe nzira yekutakura maerekitironi inogamuchira reducing equivalents yoaendesa kucytochrome c necomplex IV, izvo zvinotsigira kuyerera kwemaerekitironi nekugadzirwa kweATP zvichideredza kubuda kwemaerekitironi pamatanho ekutanga. Panguva yekushayiswa kwakanyanya, kukurudzira uku kunova dambudziko, nokuti kunowedzera kudiwa kwezvinhu zvinogadzira simba apo okisijeni neglukosi zvinenge zvisipo, izvo zvinogona kupedza zvakachengetwa zvekupedzisira nokukurumidza. Kana zvinhu zvinoshandiswa kugadzira simba zvadzoka, chimiro chimwe chete ichi chinova chinobatsira, nokuti chinobatsira mitochondria yakakuvara kushandisa okisijeni neglukosi zvakadzorerwa nemazvo. Ndokusaka zvinowanika muzvinyorwa zvinotsanangura kutamiswa kwemaerekitironi mumitochondria zvichifanira kutaurwa pamwe chete nemamiriro ekushayiswa uku.

Chinhu chimwe chekuchenjerera: mutemo uyu wenguva une chekuita nemaastrocyte akagadzirirwa chiyedzo ichocho. Chimwe chidzidzo chemasero chaienderana nacho, chakashandisa rumwe rudzi rwemasero, kushayiswa kusina kunyanya kusimba, uye uwandu hwakaderera, chakawana kudzivirirwa kunyange methylene blue ichipiwa panguva yekushayiswa. Rudzi rwesero, okisijeni yasara, uwandu hwemushonga, uye nzira yechiyedzo ndizvo zvinotara kana mugumisiro uri kubatsira kana kukuvadza.

Kuyerera kushoma kwenguva refu: ndangariro, cytochrome oxidase, uye tsinga mumavhiki

Zviedzo zvenguva refu zvakashandisa kurapwa nemwero wakaderera zuva nezuva kwemavhiki, kwete mwero mumwe mukuru wechimbichimbi. Muchidzidzo chekutanga, makonzo aive netsinga dzecarotid dzakavharwa zvachose akapiwa 4 mg/kg zuva nezuva kwemwedzi mumwe, zvichiitwa mushure mechikamu chimwe nechimwe chekudzidziswa kwezuva iroro kuitira kunangana nekusimbiswa kwezvakadzidzwa pane kugona kwepakarepo. Mhuka dzaive netsinga dzakavharwa dzaidzidza mabasa ekusiyanisa zvinhu nezvadzinoona zvishoma nezvishoma uye dzaiita zvakashata pabvunzo yakaoma yendangariro, asi kugona kushambira, kufamba kwemuviri, uye kuziva hwema hazvina kuchinja. Kurapwa zuva nezuva kwakaderedza kushomeka pakudzidza nendangariro pasina kuchinja maitiro ekufamba kwemuviri zvawo.

Chidzidzo chakatevera chakaratidza kushanda kwecytochrome oxidase, inova mitochondrial complex IV, munzvimbo 44 dzeuropi mushure mechirongwa chimwe chete chemwedzi mumwe. Kuvharwa kwetsinga kwakaderedza kushanda kweenzyme mucortex inoona, yepamberi, neperirhinal, pamwe chete nehippocampus neamygdala, uye kwakaderedza kuwirirana kwekushanda pakati pecortex inoona nehippocampus. Kurapwa kwakachengetedza kushanda kweenzyme munzvimbo dzakasiyana uye kwakasimbisa kuwirirana kwekugadzirwa kwesimba pakati penzvimbo idzodzo, uye kushanda kwakachengetedzwa kwaifambirana nekugona kuita basa zviri nani. Kuwirirana uku kunotsanangura kushanda kwakabatana kwemaenzyme anobatanidzwa mukugadzirwa kwesimba, kwete kuyerwa kwakananga kwekubatana kwekushanda kweuropi hwevanhu, pfungwa inobatsirwa kujekeswa neongororo dzekugadzirwa kwesimba muuropi.

Chimwe chidzidzo chevhiki rimwe chakashandisa 2 mg/kg zuva nezuva uye chakawedzera chinovhara nzira yekutumira masaini kuti chiedze maitiro acho. Nekurapwa, kuyerera kweropa muuropi kwakakwira kubva paanenge 60 kusvika paanenge 100 mL pa100 g paminiti, uye kuwanda kwetsinga muhippocampus kwakakwira kubva paanenge 15.1 kusvika pa23 percent. Kuwedzera kwose uku kwakadzokera shure zvishoma pakavharwa nzira yePI3K/Akt inotsigira kurarama kwemasero, uye Akt yakanga yawedzerwa phosphate yakawedzera nek urapwa. Zvakawanikwa pakuyerera kweropa, kuwanda kwetsinga, chipingamupinyi, uye masero etsinga zvinonongedzera kukudzivirirwa kwetsinga dzeropa nemasero europi kwakabatana nemasaini ePI3K/Akt, kwete mugumisiro wekugadzirwa kwesimba chete.

Nei pasina chimwe chezvizvi chakaenzana nekubatsira sitiroko kwechimbichimbi

Kudzorwa kwemamiriro murabhoritari ndicho chikonzero migumisiro iyi isingashandurirwi yakananga pakurapa vanhu. Masero akakuriswa murabhoritari haana gwamba reropa kana mafambiro emushonga mumuviri. Modheru ye2VO kuyerera kweropa kushoma muuropi hwose kunotora nguva refu, kwete gwamba rinoerekana ravhara nzvimbo imwe riine penumbra yangotanga maminitsi mashoma apfuura. Kunyange MCAO yemakonzo inoshandisa mhuka diki dzine utano, mushonga wekutindivadza, kuvharwa kwetsinga kwakafanana, uye kupiwa kwemushonga panguva yakanyatsotarwa, kusiyana nevarwere vakwegura vane magwamba akasiyana-siyana, kuoma nekutetepa kwetsinga, BP yakakwira, chirwere cheshuga, uye nguva isingazivikanwi yakatanga sitiroko.

Hapana chiyedzo chevanhu chakabudiswa, umo vanhu vanopatsanurwa zvisina kurongwa mumapoka, chakasimbisa methylene blue semushonga wechimbichimbi wesitiroko inoerekana yatanga inokonzerwa nekushayikwa kweropa. Chidzidzo chemifananidzo yeuropi muvanhu chinombotaurwa chakapinza vanhu vakuru 26 vane utano, kwete varwere vesitiroko, uye mwero mumwe wakatorwa nemuromo wakachinja masaini europi ane chekuita nebasa, paine kuvandudzika kudiki kwekurangarira mashoko. Izvi zvinoratidza kushanda muuropi, kwete kugona kurapa sitiroko. Nhungamiro dzazvino dzechimbichimbi dzinonyanya kutarisa kudzorerwa nokukurumidza kwekuyerera kweropa kuburikidza nemushonga unonyungudutsa magwamba unopiwa mutsinga kune varwere vanokodzera, uye kubviswa kwegwamba kune kuvharika kwakakodzera kwetsinga huru; nzira dzakajairika dzekubatsira sitiroko yechimbichimbi ndidzo dzinoramba dziri nzira chete dzakasimbiswa. Kubatsira munhu anofungidzirwa kuva nesitiroko hakufaniri kumbononotswa kuti apiwe methylene blue, uye miganhu yekushandurira miyero yetsvakurudzo isati yaitwa muvanhu inotsanangura nei zvirongwa zvemakonzo zvisingagoni kutorwa sezvirongwa zvekurapa vanhu.

Nyaya yekuchengeteka inosimbisa muganhu uyu. Methylene blue inopiwa mutsinga ine yambiro iri mubhokisi pamusoro peserotonin syndrome yakakomba kana inouraya kana ichisanganiswa nemishonga ine chekuita neserotonin, kusanganisira SSRIs, SNRIs, uye zvinovhara MAO, inotorwa nevarwere vakawanda vezera rinowanzobatwa nesitiroko. Haifaniri kushandiswa kune vane kushomeka kweG6PD nokuda kwengozi yekuputsika kwemasero matsvuku eropa. Inovharawo kutumirwa kwemasaini enitric oxide, izvo zvinowedzera kuramba kwetsinga kuyerera kweropa neBP mune mamwe mamiriro, saka haifaniri kungotsanangurwa semushonga unowedzera kuyerera kweropa muuropi. Chirongwa chakabvumirwa che1 mg/kg chinopiwa mutsinga chemethemoglobinemia yakazowanikwa hachisi chirongwa chesitiroko.

Pfupiso yakatendeseka ine muganhu mudiki asi ndeyechokwadi. Panguva yekudzorerwa kwekuyerera kweropa mushure mekushayikwa kweropa kwenguva pfupi muchikamu chimwe cheuropi, methylene blue yemwero wakaderera yakaderedza kufambira mberi kwekukuvara mumakonzo. Kana tsinga yakavharwa zvachose, yakanonotsa asi haina kudzivirira kufa kwenyama. Mumaastrocyte yakakuvadza panguva yekushayiswa kwakanyanya uye yakabatsira pakudzorerwa kweokisijeni. Panguva yekuyerera kweropa kushoma kwenguva refu yakachengetedza cytochrome oxidase, tsinga, uye ndangariro kwemavhiki. Mutakuri mumwe, mamiriro matatu, mhinduro nhatu.