Imethylene blue kuphando lwestroke nokuncipha kokuhamba kwegazi engqondweni: oko kuboniswa ziimodeli ezintathu

Umthambo wegazi ovalekileyo, iiseli ezikhuliswe elebhu zavinjwa izondlo, nempuku enemithambo esentanyeni ecutheneyo zinokuvakala ngathi ziindlela ezintathu zovavanyo olunye. Azinjalo. Nganye ibuza umbuzo owahlukileyo, yaye imethylene blue inika impendulo eyahlukileyo kuyo nganye. Xa uzibhidanisa, uncwadi lophando lubonakala luziphikisa. Xa uzahlula, kuvela umkhwa ocacileyo, oxhomekeke kakhulu kwixesha lokuyinika.

Oko kwahlula yeyona njongo yolu phononongo. Iimodeli ezintathu zistroke esiqala ngesiquphe nesigxile kwindawo enye, ukuvinjwa kweoksijini neglucose kulandelwe kukubuyiselwa kweoksijini kwiiseli ezikhuliswe elebhu, kunye nokuhamba kwegazi engqondweni okuphantsi iiveki ezininzi. Indlela ecetywayo ezidibanisayo inxulumene nemitochondria, kodwa iziphumo ziyahluka kuba iimeko zemetabolism ziyahluka.

Iimodeli ezintathu ziphendula imibuzo eyahlukeneyo

Istroke esiqala ngesiquphe nesigxile kwindawo enye kwiimpuku sidla ngokwenziwa ngokuvala umthambo wegazi ophakathi wengqondo, indlela eshunqulelwa ngokuthi yiMCAO. Ukuvaleka okufana nehlwili kudala umbindi one-ischemia ojikelezwe yipenumbra, izicubu ezisemngciphekweni kodwa ezinokuhlangulwa ukuba ukuhamba kwegazi kuyabuya. Umbuzo apha ngowokuba ungenelelo luyakucothisa na ukukhula kwendawo yezicubu ezifileyo okanye lugcine ukusebenza ngexesha lokubuyiselwa kokuhamba kwegazi.

Ukuvinjwa kweoksijini neglucose, okushunqulelwa ngokuthi yiOGD, kusebenza kumlinganiselo owahlukileyo ngokupheleleyo. Iiseli zengqondo ezikhuliswe elebhu zibekwa kwimeko eneoksijini ephantse ingabikho, kungekho glucose, zize zibuyiselwe kulwelo lwesiqhelo lokuzikhulisa. Akukho hlwili, akukho kujikeleza kwegazi ngezinye iindlela, akukho xinzelelo lwegazi, yaye akukho majoni omzimba. Umbuzo ungoweeseli kuphela: kwenzeka ntoni kuphefumlo lweeseli, kwiATP, nasekusindeni kwazo xa izinto ezifunekayo kwimetabolism ziphela zize zibuye.

Imodeli yokuhamba kwegazi engqondweni okuphantsi ixesha elide isebenzisa ukuvalwa okusisigxina kwemithambo yecarotid kumacala omabini kwiimpuku, ebizwa ngokuba yimodeli ye2VO. Ukuhamba kwegazi ukuya kwinxalenye yangaphambili yengqondo kuyehla kuze kuhlale kuphantsi iiveki ezininzi. Akukho kufa kwezicubu ngequbuliso kwindawo enye, yaye akukho kubuyiselwa kokuhamba kwegazi okungxamisekileyo. Umbuzo ngowokuba inkxaso yemetabolism enikwa iiveki ezininzi iyayigcina na imithambo yegazi, imitochondria, nenkumbulo ngexesha lokuhamba kwegazi okuphantsi ixesha elide.

Ngoko ukuphucuka kwenkumbulo emva kwenyanga enye yonyango kwimodeli ye2VO akuthethi nto ngokuthe ngqo ngokuhlangula ingqondo yomntu ngexesha lokususwa kwehlwili okungxamisekileyo. Lo mahluko ubalulekile kuba izishwankathelo ezininzi ezinethemba ziyawutyeshela.

Istroke esiqala ngesiquphe: ukhuseleko xa kubuyiselwa ukuhamba kwegazi, ukulibaziseka xa kungabuyiselwa

Esona siphumo sicacileyo kwimeko eqala ngesiquphe sivela kwiMCAO yethutyana elandelwa kukubuyiselwa kokuhamba kwegazi. Imithambo yeempuku yavalwa kangangemizuzu eyi60, zaza zanikwa idosi ephantsi yemethylene blue emthanjeni ukususela ngexesha lokubuyiselwa kokuhamba kwegazi, zalandelwa zezinye iidosi kwiiyure ezi3 nangosuku lwe2. IMRI yabonisa ukuba indawo yomonakalo kwiqela elanikwa isithwali ngaphandle kwechiza yakhula malunga ne19 yeepesenti ngosuku lwe2, ngoxa indawo yomonakalo kwiqela elanyangwayo yancipha malunga ne17 yeepesenti, kunye neendawo zokugqibela zezicubu ezifileyo ezazincinane malunga ne30 yeepesenti namanqaku angcono okuhlolwa kwemithambo-luvo ngeentsuku ze2 ne7. Ukusinda kwezicubu zombindi nezepenumbra okuboniswe yimifanekiso kwaphucuka. Uncwadi olubanzi ngokhuseleko lwemithambo-luvo lubeka olu khuseleko luxhomekeke kwixesha lokubuyiselwa kokuhamba kwegazi ecaleni kweziphumo ze-ischemia echaphazela ingqondo yonke nezokwenzakala.

Umfanekiso uyatshintsha xa umthambo uhlala uvalekile. Kuvavanyo lweMCAO esisigxina, imethylene blue enikwe ngexesha le-ischemia eqhubekayo yacothisa ukwanda kwendawo yomonakalo eboniswa yimifanekiso yokusasazeka kwamanzi, yaza yandisa okwexeshana ukungangqinelani phakathi kwemifanekiso yokuhamba kwegazi neyokusasazeka kwamanzi, kunye nokuhamba kwegazi okungcono kancinane kuloo ndawo, kodwa umthamo wokugqibela wezicubu ezifileyo kwiiyure ezingama24 wawungahlukanga ngokubalulekileyo. Yalibazisa ukuguquka kwezicubu ezisemngciphekweni zibe zizicubu ezifileyo ngaphandle kokuthatha indawo yokuvulwa kwakhona komthambo.

Uphononongo lwesithathu lwemeko eqala ngesiquphe longeza iinkcukacha zendlela esebenza ngayo kunye nedosi. Idosi enye enikwe ngaphakathi kumngxuma wesisu kwangoko emva kokuvaleka yabonisa okona kuncipha kukhulu kwezicubu ezifileyo, malunga ne50 yeepesenti, kwidosi ephakathi ye5 mg/kg endaweni ye1 okanye ye10 mg/kg, kunye namanqaku angcono emisebenzi yokuziva nokushukuma. Ababhali bakunxulumanisa oku nokugcinwa kobume bemitochondria nokwanda kwemitophagy, ukususwa okukhethayo kwemitochondria eyonakeleyo. Ngoko idosi, indlela yokuyinika, neshedyuli zibalulekile, yaye amaxabiso eempuku e-mg/kg ayizizo iidosi zestroke zabantu.

Iiseli ezikhuliswe elebhu: ichiza elifanayo liyanceda okanye lenzakalise ngokuxhomekeke kwixesha elifika ngalo

Uvavanyo lwee-astrocyte lolona lufundisa kakhulu nolona ludla ngokucatshulwa ngendlela engachanekanga. Ii-astrocyte zokuqala ezivela kwi-cortex yeempuku zafakwa kwiiyure ezi6 zokuvinjwa kakhulu kwioksijini eyi0.1 yeepesenti, kulwelo olungenayo iglucose, ipyruvate, okanye iserum, kwalandela iiyure ezingama24 zokubuyiselwa kweoksijini kunye nezinto ezifunekayo kwimetabolism. Malunga nesiqingatha seeseli safa, nto leyo enika uvavanyo ithuba lokubonisa nokuba sisiphumo esiluncedo okanye esiyingozi.

Xa imethylene blue yayikho ngexesha lokuvinjwa, ukusinda kwaba kubi ngakumbi, akuzange kuphucuke. Xa yafakwa ngexesha lokubuyiselwa kweoksijini endaweni yoko, amanqanaba asezantsi e-micromolar aphucula ukuphila kweeseli aza andisa ukusetyenziswa kweoksijini, ukufunxwa kweglucose, nokuveliswa kweATP. Phantsi kweemeko eziqhelekileyo, loo manqanaba afanayo andisa ukufunxwa kweglucose malunga ne89 yeepesenti kwi0.1 micromolar kwaye malunga ne200 yeepesenti kwi1 micromolar, ngoxa iglycogen nokusebenza kwehexokinase zagcinwa emva kokwenzakala, kwaye akuzange kulinganiswe ukwanda kwesuperoxide.

Indlela esebenza ngayo kulula ukuyiqonda ngokuyifanisa nejenereyitha esetyenziswa xa umbane ungekho. Imethylene blue isebenza njengesinye isithwali see-electron esamkela izinto ezinikezela ngee-electron size sizidlulisele ngasecytochrome c nakwicomplex IV, nto leyo exhasa ukuhamba kwee-electron nokuveliswa kweATP ngoxa inciphisa ukuvuza kwee-electron kumanyathelo angaphambili. Ngexesha lokuvinjwa kakhulu, olo khuthazo luyingxaki kuba lwandisa iimfuno zemetabolism xa ioksijini neglucose ziphantse zangabikho, nto leyo enokuphelisa ngokukhawuleza oovimba bokugqibela. Emva kokuba izinto ezifunekayo kwimetabolism zibuyile, olo phawu lunye luba luncedo kuba lunceda imitochondria eyonakeleyo isebenzise ngokufanelekileyo ioksijini neglucose ezibuyiselweyo. Kungenxa yoko le nto iziphumo ezivela kwiinkcazelo zokudluliselwa kwee-electron kwimitochondria kufuneka zihambe nomxholo wokuvinjwa.

Isilumkiso esinye: lo mgaqo wexesha lokuyinika ubhekisa kwelo lungiselelo lee-astrocyte. Uphononongo lweeseli olwaluhamba nalo, olusebenzisa uhlobo olwahlukileyo lweeseli, ukuvinjwa okungekho ngqongqo kangako, nenqanaba elisezantsi, lwafumanisa ukhuseleko nangona ichiza lalikho ngexesha lokuvinjwa. Uhlobo lweseli, ioksijini eseleyo, inqanaba lechiza, nenkqubo yovavanyo zigqiba ukuba isiphumo siluncedo okanye siyingozi.

Ukuhamba kwegazi okuphantsi ixesha elide: inkumbulo, icytochrome oxidase, nemithambo kwiiveki ezininzi

Iimvavanyo zexesha elide zasebenzisa unyango lwedosi ephantsi yonke imihla kangangeeveki, hayi idosi enye ekhawulezileyo yexesha likaxakeka. Kuphononongo lokuqala, iimpuku ezinemithambo yecarotid evaleke ngokusisigxina zanikwa i4 mg/kg yonke imihla kangangenyanga enye, emva kweseshoni nganye yoqeqesho yemihla ngemihla, ukuze kujoliswe ekuqinisweni kwenkumbulo kunokuba kujoliswe ekusebenzeni kwangoko. Izilwanyana ezinemithambo evalekileyo zafunda ngokucothayo ukusombulula iingxaki zokwahlula izinto ezibonwayo, zaza zenza kakubi ngakumbi kuvavanyo olunzima lwenkumbulo, ngoxa ukukwazi ukuqubha, ukushukuma, nokuqaphela ivumba kwakungachaphazelekanga. Unyango lwemihla ngemihla lwanciphisa ukusilela ekufundeni nakwinkumbulo ngaphandle kokutshintsha indlela eqhelekileyo yokushukuma.

Uphononongo olulandelayo lwenza imephu yecytochrome oxidase, eyicomplex IV yemitochondria, kwiindawo ezingama44 zengqondo emva kwaloo nkqubo inye yenyanga enye. Ukuvaleka kwanciphisa ukusebenza kwe-enzyme kwi-cortex yokubona, kwi-cortex engaphambili nakwi-perirhinal cortex, kunye nehippocampus neamygdala, kwaza kwenza buthathaka ukusebenza okulungelelanisiweyo phakathi kwe-cortex yokubona nehippocampus. Unyango lwagcina ukusebenza kwe-enzyme kwiindawo ezithile lwaza lwaqinisa unxulumano lwemetabolism phakathi kwezo ndawo, yaye ukusebenza okwagcinwayo kwakunxulumene nokwenza ngcono imisebenzi. Olu nxulumano luchaza ukusebenza okulungelelanisiweyo kwee-enzyme zemetabolism, hayi imilinganiselo ethe ngqo yonxibelelwano lokusebenza kwengqondo yomntu, into enokucaciswa luphando olushwankathela imetabolism yamandla engqondo.

Uphononongo olwahlukileyo lweveki enye lwasebenzisa i2 mg/kg yonke imihla lwaza longeza isithinteli sendlela yokuthumela imiqondiso ukuze luvavanye indlela esebenza ngayo. Ukuhamba kwegazi engqondweni kwenyuka ukusuka malunga ne60 ukuya malunga ne100 mL nge100 g ngomzuzu ngonyango, yaye ukuxinana kwemithambo yegazi kwihippocampus kwenyuka ukusuka malunga ne15.1 ukuya kwi23 yeepesenti. Zombini ezi mpucuko zancipha ngokuyinxenye xa indlela yokusinda yePI3K/Akt yavalwa, yaye iAkt efakwe iphosphate yanda ngonyango. Iziphumo zokuhamba kwegazi, ukuxinana kwemithambo, umqobo, neeseli zemithambo-luvo zikhomba kukhuseleko lwemithambo yegazi nemithambo-luvo olunxulumene nokuthunyelwa kwemiqondiso kwePI3K/Akt, kunokuba ibe sisiphumo semetabolism kuphela.

Kutheni kungekho nanye kwezi ethetha unyango lwestroke olungxamisekileyo

Ulawulo lweemeko elebhu sisizathu sokuba ezi ziphumo zingadluliselwa ngokuthe ngqo ebantwini. Iiseli ezikhuliswe elebhu azinahlwili okanye iinkqubo zokufunxwa, ukusasazwa, ukuguqulwa nokukhutshwa kwechiza emzimbeni. Imodeli ye2VO imele ukuhamba kwegazi okuphantsi ixesha elide kuyo yonke ingqondo, hayi ukuvaleka ngequbuliso kwendawo enye ngenxa yehlwili elihambileyo, elinepenumbra esandul’ ukuvela kwimizuzu embalwa edlulileyo. Nkqu neMCAO yeempuku isebenzisa izilwanyana eziselula nezisempilweni, amayeza okubulala iintlungu nokulalisa, ukuvaleka okufanayo, nokunikwa kweedosi ngamaxesha achanekileyo, ngokungafaniyo nezigulana ezindala ezinamahlwili ahlukeneyo, i-atherosclerosis, uxinzelelo lwegazi oluphezulu, isifo seswekile, namaxesha okuqala kweempawu angaziwayo.

Akukho luvavanyo lupapashiweyo ebantwini nolwabiwa ngokungenamkhethe oluqinisekise imethylene blue njengonyango olungxamisekileyo lwestroke se-ischemia esiqala ngesiquphe. Uphononongo lwemifanekiso yengqondo yabantu olucatshulwa ngamanye amaxesha lwabandakanya abantu abadala abangama26 abasempilweni, hayi izigulana zestroke, yaye idosi enye ethathwe ngomlomo yatshintsha imiqondiso yengqondo enxulumene nemisebenzi, kunye nokuphucuka okuncinane kokukhumbula. Oko kubonisa ukusebenza kwinkqubo yemithambo-luvo esembindini, hayi ukusebenza kunyango lwestroke. Endaweni yoko, izikhokelo zangoku zonyango olungxamisekileyo zigxile ekubuyiseleni ukuhamba kwegazi ngokukhawuleza ngokunyibilikisa amahlwili ngamayeza afakwa emthanjeni kwizigulana ezifanelekileyo nangokususa amahlwili kwiimeko ezifanelekileyo zokuvaleka kwemithambo emikhulu, yaye iinkqubo ezisemgangathweni zonyango lwestroke olungxamisekileyo zisesona sicwangciso sodwa singqiniweyo. Ukunyanga istroke esikrokrelwayo akufanele nanini kulibaziswe ngenjongo yokunika imethylene blue, yaye imida yokudlulisela iidosi zophando lwangaphambi kovavanyo lwezonyango ebantwini ichaza ukuba kutheni iishedyuli zeempuku zingafanele zifundwe njengeenkqubo zonyango lwabantu.

Umxholo wokhuseleko uyawuqinisa lo mda. Imethylene blue efakwa emthanjeni inesilumkiso esikwibhokisi malunga neserotonin syndrome eyingozi kakhulu okanye ebulalayo xa idityaniswa namayeza achaphazela iserotonin, kuquka iiSSRI, iiSNRI, nezithinteli zeMAO, ezithathwa zizigulana ezininzi ezikwiminyaka apho istroke sixhaphake khona. Ayivumelekanga kubantu abaswele iG6PD ngenxa yomngcipheko wokuqhekeka kweeseli ezibomvu zegazi. Ikwathintela ukuthunyelwa kwemiqondiso yenitric oxide, nto leyo eyandisa ukuxhathisa kwemithambo nokunyusa uxinzelelo kwezinye iimeko, ngoko ayifanele ichazwe nje njengechiza elandisa ukuhamba kwegazi engqondweni. Inkqubo evunyiweyo ye1 mg/kg efakwa emthanjeni yemethemoglobinemia efunyenweyo ayiyonkqubo yonyango lwestroke.

Isishwankathelo esinyanisekileyo sinomda kodwa sisekelwe kwiziphumo zokwenene. Ngexesha lokubuyiselwa kokuhamba kwegazi kwi-ischemia yethutyana egxile kwindawo enye, idosi ephantsi yemethylene blue yanciphisa ukukhula komonakalo kwiimpuku. Xa ukuvaleka kwakusisigxina, yalibazisa ukufa kwezicubu kodwa ayizange ikuthintele. Kwii-astrocyte yenzakalisa ngexesha lokuvinjwa kakhulu yaza yanceda xa kubuyiselwa ioksijini. Ngexesha lokuhamba kwegazi okuphantsi ixesha elide, yagcina icytochrome oxidase, imithambo, nenkumbulo kwiiveki ezininzi. Isithuthi esinye, iimeko ezintathu, iimpendulo ezintathu.