I-methylene blue ekulimaleni kobuchopho: ukuqonda ubufakazi bangaphambi kocwaningo kubantu

Ukushayeka ekhanda, ukuvaleka komthambo wegazi, nesifo esiqhubeka kancane sokuwohloka kwezinzwa kungagcina kuholele enkingeni efanayo: ubuchopho abusakwazi ukuthola amandla okwenza umsebenzi wabo. Leso siphetho esifanayo yisona esenza into eyodwa yamakhemikhali ihlale ivela ocwaningweni lwazo zontathu lezi zimo. Kodwa ukuba nesiphetho esifanayo akusho ukuhlola umqondo ofanayo. Ukwelashwa okunikezwa ngaphambi kokulimala, okunikezwa ehoreni ngemva kwakho, nokuhlolwa imiphumela yakho ezinyangeni kamuva kuhlola imibono ehlukene, noma umjovo uqukethe uketshezi olufanayo oluluhlaza okwesibhakabhaka.

Lesi sihloko silandela ingxenye yalolo cwaningo ephathelene nokulimala. Sibuyekeza ukuthi ukusetshenziswa kwe-methylene blue ekulimaleni kobuchopho kusho ukuthini ekuhlolweni ezilwaneni, sehlukanise ukulimala ngenxa yokushayeka ne-stroke kanye nokuwohloka kwezinzwa okuqhubekayo, futhi sibonise ukuthi kungani isikhathi sokunikeza umthamo sichaza umehluko omningi phakathi kwezifundo.

Izinhlobo ezintathu zokulimala, ukwehluleka okukodwa kokukhiqiza amandla

Indlela yokusebenza exhumanisa la mamodeli ingaphakathi kwama-mitochondria. Ngokuvamile, ama-electron adlula ochungechungeni lokuthuthwa kwama-electron ukuze kukhiqizwe i-ATP, futhi uchungechunge olusebenza kahle lugcina izinhlobo zomoya-mpilo ezisebenza kakhulu ngaphansi kolawulo. Ngemva kokulimala, izingxenye zalolu chungechunge ziyantengantenga, ukukhiqizwa kwe-ATP kwehle, futhi ukukhiqizwa kwama-radical amahhala kunyuke. Ukubuyekezwa kwe-Molecular Neurobiology kwango-2018 kuchaza i-methylene blue njengomunye umthwali wama-electron: yamukela ama-electron avela ku-NADH bese iwadlulisela ku-cytochrome c, okwandisa ukusebenza kwe-complex IV futhi kubuyisele ukwakhiwa kwe-ATP ngisho nalapho ingxenye yokuqala yochungechunge ingasebenzi kahle.

Izinombolo ezibikiwe ziqondile. Emasampuleni amaseli nezingcezu zezicubu ezilungiselelwe ukuhlolwa, ukusebenza kwe-complex IV kwenyuka ngamaphesenti angu-30 kuya ku-100, kanti ukusetshenziswa komoya-mpilo kwenyuka ngokuhambisana nakho. Lokhu kubonisa ukuthi ama-electron angeziwe enza umsebenzi owusizo kunokuba aphume ochungechungeni njengama-radical. Kumodeli ye-stroke kumagundane amakhulu, ukukhiqizwa kwe-ATP endaweni ethintekile kwakuphakeme cishe ngamaphesenti angu-30 emahoreni angu-24 ngemva kokwelashwa uma kuqhathaniswa nezilwane ezingelashiwe. Ukubuyekezwa kwe-Biochemistry (Moscow) kwango-2022 kunezela imiphumela elandelayo: ukuncipha kwengcindezi yokulimala okubangelwa ukusabela komoya-mpilo, ukuvuvukala kwezicubu zezinzwa okuncane, ukuncipha kokufa kwamaseli okuhleliwe, kanye nemiphumela ku-monoamine oxidase, nitric oxide synthase, ukwakheka kwama-mitochondria amasha, ukuzigaya kwamaseli, nokuhlangana kwamaprotheni asongwe ngendlela engafanele.

Ngakho umqondo ulula. Ukulimala kuphazamisa indlela evamile yama-electron, kanti i-methylene blue inikeza enye indlela yokudlula. Konke okulandelayo kumayelana nokuthi yiluphi uhlobo lokulimala, inikezwa nini, nokuthi imiphumela ilinganiswa kanjani.

Ukulimala ngenxa yokushayeka akuyona i-stroke

Kumodeli yokulimala kobuchopho ngenxa yokushayeka, amandla okushaya afika ngesikhathi esisodwa. Umonakalo wokuqala ubangelwa ukushayeka uqobo: izicubu ziyadabuka, imithambo iqhume, futhi umgoqo ophakathi kwegazi nobuchopho uvuleke emizuzwini embalwa. Lokho i-methylene blue engase ikuthinte ngokunengqondo yigagasi lesibili elilandela emahoreni nasezinsukwini ezilandelayo, lapho ama-mitochondria ezicutshini ezisindile ehluleka, ukuvuvukala kusabalala, futhi kuqoqana uketshezi olubangela ukuvuvuka. Izilinganiso zemiphumela kulezi zifundo zibonisa lokho kulandelana: umthamo wendawo eyonakele, inani lamanzi ebuchosheni, ukusinda kwamaseli ezinzwa eduze kwendawo eshayekile, nokuziphatha kamuva njengokululama kokunyakaza noma ukufunda ukuhamba endaweni enemizila ephambanayo.

Kumodeli ye-stroke noma yokuntuleka kokugeleza kwegazi ebuchosheni bonke, ukulimala kuqala ngendlela ephambene. Ukugeleza kwegazi kuyama, ukwehluleka kokukhiqiza amandla kulandele emizuzwini embalwa, futhi ukubuyiselwa kokugeleza kuletha owakho umonakalo. Lapha ukunikezwa komthamo kuqondaniswa nesenzakalo somthambo, ngokuvamile kungakapheli imizuzu ngemva kokuvaleka noma ukubuyiselwa kokugeleza kwegazi. Izilinganiso zemiphumela zihlola ukuthi kwenzekani ezicutshini ngokushesha, emahoreni kuya osukwini olulodwa noma ezimbili: ubukhulu bendawo yezicubu ezifile ngenxa yokuntuleka kwegazi, ukugeleza kwegazi, nokululama kokuqala kokusebenza. Enye indlela evela ocwaningweni lwe-stroke ukwelashwa kusengaphambili, lapho izilwane zinikezwa umthamo ngaphambi kokuvalwa komthambo. Lokhu kuhlola ukuvimbela ngendlela okungekho ukuhlolwa kokulimala ekhanda okungayiphinda kubantu ngokuhambisana nezimiso zokuziphatha zocwaningo.

Imiphumela ye-stroke inamandla kakhulu ocwaningweni lokulimala, futhi ihlanganisa nomphumela ocace kakhulu wokungabi nomehluko. Amagundane amakhulu anikezwa i-methylene blue lapho kubuyiselwa ukugeleza kwegazi ngemva kwehora elilodwa lokuvalwa komthambo ophakathi wobuchopho aba nezindawo zezicubu ezifile ezincane ngamaphesenti angu-30 ngosuku 2, kwasinda ingxenye enkulu yomnyombo osengozini nendawo ewuzungezile, i-penumbra (Shen, 2013). Ucwaningo lokuvalwa komthambo unomphela lwathola ukuthi izicubu ezisengozini zaziguquka kancane zibe izicubu ezifile, kodwa alutholanga ukuncipha komthamo wokugcina wendawo yezicubu ezifile emahoreni angu-24 kunoma yimuphi wemithamo emibili eyahlolwa (Rodriguez, 2014). Ucwaningo lwesithathu lokuvalwa komthambo lwehlisa ubukhulu bendawo yezicubu ezifile cishe ngesigamu ngomthamo ophakathi, futhi lwabhala ngokuqondile ukwakheka okuningiliziwe kwama-mitochondria nokugaywa kwama-mitochondria, i-mitophagy, ebuchosheni obuntula ukugeleza kwegazi. Ngesikhathi esifanayo lwabika imininingwane ephambene nalokho obekungalindelwa: ukufa kwamaseli okuhleliwe okwakulinganisiwe kwenyuka njengoba ukufa kwezicubu okungalawulwa kwehla (Di, 2015). Ekuntulekeni kokugeleza kwegazi ebuchosheni bonke, ukufakwa okuqhubekayo komthamo ophansi kwabuyisela ukusebenza kwe-cytochrome c oxidase, amazinga e-ATP, nomehluko kagesi kulwelwesi lwama-mitochondria endaweni esengozini ye-CA1 ye-hippocampus, kwagcina lawo maseli ezinzwa ephila futhi kwavikela inkumbulo yezindawo (Lu, 2016). Kuyafaneleka ukuma kancane kuleso silinganiso se-CA1: idatha eqondile ye-ATP nochungechunge lokuphefumula kwamaseli evela ngaphakathi kobuchopho obulimele, okuyinto ucwaningo lwe-TBI oluvame ukuyicabangela ngokususela kweminye imiphumela kunokuba luyilinganise.

Ukuwohloka kwezinzwa okuqhubekayo kwehlukile kuzo zombili. Amamodeli ezifo ze-Alzheimer, Parkinson ne-Huntington anikeza izilwane imithamo amasonto noma izinyanga, bese elinganisa ukuhlangana kwamaprotheni, ukusetshenziswa kwe-dopamine, noma ukwehla kancane kwamakhono okuqonda. Lezo zilinganiso cishe azihlangene nendawo eyonakele elinganiswa ezinsukwini ngemva kokushayeka. Abafundi abasusa umphumela kwesinye isigaba bawuse kwesinye badlulisa okutholakele ngaphesheya komngcele ukuhlolwa okungazange kuwuwele. Umhlahlandlela wethu wocwaningo lokuwohloka kwezinzwa ugcina lezo zifundo ezithatha isikhathi eside emkhakheni wazo, futhi ukuqhathanisa nobufakazi be-stroke kuphela kwehlukanisa ngokuningiliziwe izindlela zokuhlola ukuvaleka kwemithambo nalezo zokushayeka.

Lokho amamodeli e-TBI akwenza ngempela

Akukashicilelwa ukuhlolwa kubantu kwe-methylene blue ekulimaleni kobuchopho ngenxa yokushayeka. Lonke ulwazi lwe-TBI luvela emsebenzini owenziwe ezilwaneni, ikakhulukazi amagundane amakhulu namancane, futhi lugxile eqoqweni elincane lokuhlolwa okufanele kubalulwe, ngoba imininingwane yako yehlukile ngezindlela ezivame ukulahleka ezifingqweni.

Ucwaningo lokuqala lokushayeka okulawulwayo koqweqwe lobuchopho lwanikeza amagundane amakhulu u-1 mg/kg ngomthambo wegazi ihora elilodwa ngemva kokushayeka okuncane, kwase kulandela u-0.5 mg/kg emahoreni amathathu (Watts, 2014). Umthamo wendawo eyonakele owalinganiswa nge-MRI wahlala uphansi ezilwaneni ezelashiwe phakathi namasonto amabili okulandelela. Amaphutha okunyathela ekuhlolweni kokuhamba ehla ngokuphawulekayo ngezinsuku 1, 2, no-7 kodwa hhayi ngosuku 14. Ekuhlolweni ngesibonakhulu ngosuku 14, amaseli ezinzwa ayeqhubeka nokonakala oqweqweni lobuchopho olwalulimele ayengu-270 uma kuqhathaniswa nangu-368 endaweni ngayinye yokubuka, kanti ukudayeka kwe-Nissl okungajwayelekile kwakungu-41 uma kuqhathaniswa no-73. Ngamanye amazwi, kwaba nokuvikeleka ekuqaleni, kodwa inzuzo ekuziphatheni yaphela ngesonto lesibili.

Indlela yokuhlola ukulimala okusabalele yasebenzisa ukushaywa yingcindezi yoketshezi emgqeni ophakathi ekhanda kumagundane amancane, kanye nomthamo owodwa ongu-2 mg/kg ngomthambo wegazi kungakapheli isigamu sehora (Fenn, 2015). Izilwane ezelashiwe zabonisa ukusebenza okuthambile kofuzo oluhlobene nokuvuvukala, ama-microglia ambalwa avuvukele, ukuqoqana koketshezi okwakubonakala kuncane, nokungabi nokuziphatha okufana nokudangala ngosuku 7. Imiphumela yokungabi nomehluko ibaluleke ngokufanayo: ukulimala ngokwakho kwandisa amanzi ebuchosheni kancane kuphela, futhi i-methylene blue ayizange ivimbele ukwehla kwesisindo somzimba noma ukuntuleka kokuhambisana kahle kokunyakaza. Ukunciphisa ukuvuvukala akufani nokuvikela ngokuphelele.

Izifundo ezimbili kumagundane amancane zasebenzisa uhlelo olufanayo, u-1 mg/kg ngehora elilodwa, u-0.5 mg/kg emahoreni ayisithupha, kwase kuba ukunikezwa komthamo nsuku zonke izinsuku ezintathu, futhi zanweba ukuqonda indlela yokusebenza. Kumodeli yokushayeka koqweqwe lobuchopho, ukwelashwa kwehlisa umthamo wendawo eyonakele emahoreni angu-24, emahoreni angu-72, nangosuku 14, ngesikhathi kugcina amaseli ezinzwa ephila futhi kwandisa izinkomba zokuzigaya kwamaseli (Zhao, 2016). Kumodeli yokushaywa yingcindezi yoketshezi, kwehlisa ukufa okuhleliwe kwamaseli ezinzwa, kwaqinisa umgoqo ophakathi kwegazi nobuchopho owawuvuza, futhi kwathuthukisa amaphuzu okuhlola ukusebenza kwezinzwa phakathi namasonto amabili (Shen, 2019). Nokho, inani lamanzi ebuchosheni alizange libonise umehluko emahoreni angu-72 ocwaningweni lukaZhao, futhi ukusebenza ekuhlolweni ngenduku ezungezayo, i-rotarod, akuzange kubonise umehluko ngezinsuku 1 no-3 ocwaningweni lukaShen. Izilinganiso zendawo eyonakele nokusinda kwamaseli zashintsha; ukuvuvuka nezilinganiso zokuqala zokunyakaza azizange zilandele njalo.

Ukuhlolwa okugqamile mayelana nesikhathi yilokho kokunikeza umthamo sekwephuzile (Watts, 2016). Kusetshenziswa imodeli efanayo yokushayeka, umthamo wokuqala awuzange unikezwe kwaze kwaphela amahora angu-24 ngemva kokulimala. Ngosuku 2, iqembu elanikezwa umthamo sekwephuzile labonisa ukuncipha kwezindawo ezonakele okwakufana nokwezilwane ezelashwa emahoreni okuqala, futhi lokho kuncipha kwaqhubeka ngezinsuku 7 no-14. Inkomba ekuziphatheni yayibuthakathaka: ukuthuthuka kwamaphutha okunyathela eqenjini elathola umthamo sekwephuzile kwakuwumkhuba ongafinyelelanga ekubalulekeni kwezibalo. Ilabhorethri eyodwa, imodeli eyodwa, isikhathi esisodwa samahora angu-24. Lokhu kuwubufakazi bangempela bokuthi isikhathi sokungenelela sidlulela ngale kwamahora okuqala, futhi yibo futhi bonke ubufakazi obukhona balowo mbono. Qaphela ugibe lwegama elithi ukubambezeleka lapho lisetshenziswa kwenye indawo: uchungechunge lwaseRussia olwalunezihloko eziphathelene nokuvikelwa kwezinzwa okubambezelekile lwanikeza umthamo emizuzwini engu-30, futhi lwasebenzisa ukubambezeleka ukubhekisela emiphumeleni ehlala isikhathi eside, hhayi ekuqaleni sekwephuzile.

Ucwaningo oluncane lokulimala okugxile endaweni ethile kumagundane amakhulu luphelelisa isithombe sesikhathi ngakolunye uhlangothi: ukunikezwa komthamo ngokushesha ngaphambi kokulimala nokunikezwa kwawo emizuzwini engu-30 ngemva kwakho kokubili kwehlisa ukungasebenzi kahle kwezitho (Stelmashook, 2019). Ukwelashwa kusengaphambili kusebenza elabhorethri ngenxa yokuthi ilabhorethri iyona ehlela ukuthi ukulimala kuzokwenzeka nini.

Ukuqaphela umthamo kubalulekile lapha. Ukubuyekezwa kuchaza imithamo ephansi njengeshukumisa ukuphefumula kwama-mitochondria, nemithamo ephakeme njengekuvimbelayo, okuyindlela efanayo enezigaba ezimbili ebonakala kuyo yonke imiphumela yemithi ye-methylene blue. Yingakho imiphumela ingenakufundwa ngokuthi ukwanda koketshezi oluluhlaza okwesibhakabhaka kusho ukwanda kokululama. Ucwaningo ngalunye luhlola iphuzu elilodwa ejikeni. Incazelo yokusabela emthameni ilandelela lelo jika emamodelini ahlukahlukene, futhi iphrofayela yokuphepha nemiphumela engemihle ichaza lokho imithamo ephakeme ekwenzayo esikhundleni salokho.

Funda imigqa yalelo thebula: into efanayo yamakhemikhali, izikhathi ezintathu ezihlukene. Ukuvimbela kungokomugqa ophakathi, ukwelashwa ngokushesha kungokwemigqa emibili yokuqala, kanti imiphumela ebonakala kamuva ingeyomugqa wokuqala nowesithathu.

Ukuvimbela, ukwelashwa ngokushesha, imiphumela ebonakala kamuva

Ukuvimbela yisimangalo esiqondwa kabi kalula kunazo zonke. Kumamodeli okuntuleka kokugeleza kwegazi, izilwane ezinikezwa umthamo ngaphambi kokuvalwa komthambo ziba nemiphumela engcono. Ngezinye izikhathi lowo mphumela ucashunwa njengokungathi i-methylene blue ivikela noma yibuphi ubuchopho kunoma yikuphi ukulimala okuzayo. Awubonisi lokho. Ubonisa ukuthi ama-mitochondria alungiselelwe ngenye indlela yokuhamba kwama-electron abekezelela kangcono ukumiswa okuhleliwe kokugeleza kwegazi. Akekho ohlela ukulimala ekhanda.

Ukwelashwa ngokushesha yikho lapho ubufakazi be-TBI bugxile khona. Ukunikezwa komthamo emahoreni ngemva kokushayeka kuqondiswe ochungechungeni lokulimala kwesibili lapho lusaqhubeka: ukwehluleka kokukhiqiza amandla, ingcindezi yokulimala okubangelwa ukusabela komoya-mpilo, ukuvuvukala kwezicubu, nokuvuvuka. Izilinganiso zendawo eyonakele nokuqoqana koketshezi ezithuthuka lapha ziyimiphumela yangempela yokwelashwa, kodwa ziwukwelashwa kwenqubo eqhubekayo, hhayi ukubuyisela izicubu ezidabukile esimweni sazo.

Imiphumela ebonakala kamuva ingumqondo wesithathu. Ukuziphatha okulinganiswa emasontweni ngemva kokulimala, noma ukusetshenziswa kwamaprotheni okulinganiswa ezinyangeni ngemva kokuqala kwemodeli yokuwohloka, kuphendula ukuthi ukuvikeleka kokuqala kwaqhubeka yini noma ukuthi izinqubo ezihamba kancane zashintsha yini indlela yazo. Indawo eyonakele encane emahoreni angu-24, umkhuba wokuthuthuka ekuziphatheni ongabalulekile ngokwezibalo ngemva komthamo obambezelwe amahora angu-24, nokuthuthuka ekuhambeni endaweni enemizila ephambanayo ezinyangeni zokunikezwa kwemithamo okuqhubekayo kuyizimangalo ezintathu ezehlukene ezidinga amazinga amathathu ehlukene obufakazi. Okwamanje ngesokuqala kuphela esihlangabezane nezinga laso ngaphezu kwesisodwa.

Lokho lobu bufakazi obungeke bukubonise

Yonke imiphumela engenhla inomngcele ofanayo. Ama-mitochondria ezilwane ezingamagundane asabela ku-methylene blue ngezindlela ezingase zifane nezama-mitochondria abantu, kodwa igundane elinikezwa umthamo ngomthambo wegazi emizuzwini ngemva kokushayeka okulinganiswe ngokucophelela alifani nomuntu ofika emnyangweni wezimo eziphuthumayo emahoreni ngemva kokuwa. Ukubulawa kwezinzwa, ubukhulu bokulimala obulawulwayo, izilwane ezincane eziphilile, nokulandelela kwesikhathi esifushane konke kunciphisa lokho okungadluliselwa kwabanye. Alukho nhlobo ucwaningo lwe-methylene blue ekulimaleni ngenxa yokuqhuma, ngakho uhlobo lokulimala olubaluleke kakhulu kubafundi bezempi yilo olunobufakazi obuncane kakhulu.

Akukho futhi ukuguqulelwa kwemithamo ezilwaneni kube eyabantu okunikezwayo. Ucwaningo ezilwaneni lusebenzisa ukufakwa ngomthambo wegazi nangaphakathi komgodi wesisu ngemithamo ekhethelwe ukulawula ukuhlolwa, hhayi amaconsi aphuzwa ngomlomo athengiswa ezitolo. Akukho kulezi zifundo okusungula uhlelo lokunikeza umthamo kubantu, futhi akukho lapha okuhlola i-methylene blue kanye nokunakekelwa okujwayelekile kokulimala ekhanda.

Ngakho isifinyezo esithembekile singangena esigabeni esisodwa. Ezilwaneni ezingamagundane, i-methylene blue enikezwa ngesikhathi esiseduze nokulimala kobuchopho ngenxa yokushayeka noma ukuntuleka kokugeleza kwegazi igcina ukukhiqizwa kwamandla kwama-mitochondria, futhi lokho kulondolozwa kulandelwa izindawo ezincane zomonakalo namaphuzu angcono okululama. Ucwaningo olulodwa lokushayeka lwagcina ingxenye yomphumela endaweni eyonakele lapho umthamo wokuqala ubambezelwe amahora angu-24. Ukuthi kukhona yini kulokhu okwenzeka ebuchosheni babantu abalimele akukahlolwa, futhi ucwaningo lwe-TBI nolwe-stroke luhlola izikhathi ezehlukene ngokubheka izilinganiso zemiphumela ezehlukene. Noma ubani othengisa isiqiniseko phezu kwalobu bufakazi wengeza isithako ukuhlolwa okungazange kube naso.