Methylene blue a binciken bugun jini da ƙarancin kwararar jini zuwa kwakwalwa: abin da samfuran gwaji uku ke nunawa a zahiri

Jijiyar jini da ta toshe, ƙwayoyin halitta da aka noma aka hana su abinci, da bera mai jijiyoyin wuya da suka ƙuntata suna iya zama kamar nau’o’i uku na gwaji guda. Amma ba haka ba ne. Kowannensu yana neman amsar wata tambaya daban, kuma methylene blue yana ba da amsa daban a kowannensu. Idan aka gauraya su, wallafe-wallafen bincike za su zama kamar suna saɓa wa juna. Idan aka rarrabe su, wani tsari bayyananne zai bayyana, wanda lokacin amfani da shi ne ya fi ƙayyade shi.

Wannan rarrabewa ita ce ainihin manufar wannan bita. Samfuran gwajin ukun su ne bugun jini na gaggawa a wani takamaiman yanki, hana oxygen da glucose tare da sake samar da oxygen a ƙwayoyin halitta da aka noma, da ƙarancin kwararar jini zuwa kwakwalwa mai ɗorewa na tsawon makonni. Hanyar aikin da ake ganin tana haɗa su tana shafar mitochondria, amma sakamakon ya bambanta saboda yanayin tafiyar da sinadarai a ƙwayoyin halitta ya bambanta.

Samfuran gwaji ukun suna amsa tambayoyi daban-daban

Yawanci ana haifar da bugun jini na gaggawa a wani takamaiman yanki a beraye ta hanyar toshe jijiyar jini ta tsakiyar kwakwalwa, wanda ake taƙaitawa da MCAO. Toshewar da take kama da gudan jini tana samar da tsakiyar yankin da ya rasa jini, wanda wani yanki mai suna penumbra yake kewaye da shi. Wannan nama ne da yake cikin haɗari amma ana iya cetonsa idan kwararar jini ta dawo. Tambayar a nan ita ce ko wani matakin magani yana rage saurin faɗaɗar yankin mutuwar nama ko yana kiyaye aikin kwakwalwa a lokacin dawowar kwararar jini.

Hana oxygen da glucose, wanda ake taƙaitawa da OGD, yana aiki a wani mataki dabam ƙwarai. Ana sanya ƙwayoyin kwakwalwa da aka noma a yanayin da oxygen ya kusan zama sifili kuma babu glucose, sannan a mayar da su cikin ruwan nomansu na yau da kullum. Babu gudan jini, babu hanyoyin jini na gefe, babu matsin jini, kuma babu tsarin garkuwar jiki. Tambayar ta shafi ƙwayoyin halitta kaɗai: me ke faruwa da sarrafa oxygen don samar da makamashi, ATP, da rayuwar ƙwayoyin halitta lokacin da sinadaran da suke amfani da su suka ɓace sannan suka dawo?

A ƙarancin kwararar jini zuwa kwakwalwa mai ɗorewa, ana toshe jijiyoyin carotid na ɓangarorin wuya biyu har abada a beraye, wanda ake kira samfurin gwajin 2VO. Kwararar jini zuwa ɓangaren gaba na kwakwalwa tana raguwa kuma ta ci gaba da zama ƙasa na tsawon makonni. Babu mutuwar nama ta kwatsam a wani takamaiman yanki, kuma babu dawo da kwararar jini cikin gaggawa. Tambayar ita ce ko tallafa wa tafiyar da sinadarai na tsawon makonni yana kiyaye jijiyoyin jini, mitochondria, da ƙwaƙwalwar tunawa yayin ƙarancin kwararar jini mai tsawo.

Saboda haka, ingantuwar ƙwaƙwalwar tunawa bayan wata guda na magani a samfurin gwajin 2VO ba ta nuna komai kai tsaye game da ceton kwakwalwar ɗan Adam yayin aikin cire gudan jini na gaggawa ba. Wannan bambanci yana da muhimmanci saboda mafi yawan taƙaitattun bayanan da suke nuna fata mai yawa suna tsallake shi.

Bugun jini na gaggawa: kariya lokacin dawowar jini, jinkiri idan bai dawo ba

Sakamakon gaggawa mafi bayyane ya fito ne daga MCAO na ɗan lokaci tare da dawo da kwararar jini. An toshe jijiyar beraye na mintuna 60, sannan aka fara ba su ƙaramin adadin methylene blue ta cikin jijiya a lokacin da kwararar jini ta dawo, tare da ƙarin adadin maganin bayan sa’o’i 3 da kuma a rana ta 2. MRI ya nuna cewa yankin lalacewa a rukunin da aka ba ruwan ɗaukar maganin kaɗai ya faɗaɗa da kusan 19 bisa ɗari zuwa rana ta 2, yayin da yankin lalacewa a rukunin da aka yi wa magani ya ragu da kusan 17 bisa ɗari. Girman yankunan mutuwar nama na ƙarshe ya kasance ƙasa da na rukunin kwatantawa da kusan 30 bisa ɗari, kuma maki na aikin tsarin jijiyoyi sun fi kyau a ranaku 2 da 7. Hotunan binciken sun nuna ingantuwar rayuwar nama a tsakiyar yankin da ya rasa jini da kuma yankin penumbra. Wallafe-wallafen bincike masu faɗi kan kariyar tsarin jijiyoyi suna sanya wannan kariyar da aka daidaita da lokacin dawowar jini tare da sakamakon ƙarancin jini a kwakwalwa gaba ɗaya da rauni.

Yanayin yana canzawa idan jijiyar ta ci gaba da zama a toshe. A wani gwajin MCAO na dindindin, methylene blue da aka bayar yayin da ƙarancin jini yake ci gaba ya rage saurin faɗaɗar yankin lalacewa da hoton diffusion ya nuna. Ya kuma ɗan tsawaita lokacin rashin daidaito tsakanin hotunan perfusion da diffusion, tare da ɗan ingantuwar kwararar jini a wurin, amma girman yankin mutuwar nama na ƙarshe bayan sa’o’i 24 bai bambanta sosai ta fuskar ƙididdiga ba. Ya jinkirta mutuwar naman da yake cikin haɗari, amma bai maye gurbin sake buɗe jijiyar ba.

Wani bincike na uku kan bugun jini na gaggawa ya ƙara bayani game da hanyar aiki da bambance-bambancen adadin magani. Adadin magani guda da aka allura cikin kogon ciki nan da nan bayan toshewar ya nuna mafi girman raguwar yankin mutuwar nama, kusan 50 bisa ɗari, a matsakaicin adadin 5 mg/kg maimakon 1 ko 10 mg/kg, tare da ingantattun maki na ji da motsi. Marubutan sun danganta wannan da kiyaye tsarin mitochondria da ƙaruwar mitophagy, wato kawar da mitochondria da suka lalace ta hanyar zaɓe. Saboda haka, adadin magani, hanyar bayarwa, da jadawalin bayarwa suna da muhimmanci, kuma adadin mg/kg na beraye ba adadin maganin bugun jini na mutane ba ne.

Ƙwayoyin halitta da aka noma: magani ɗaya yana taimakawa ko cutarwa gwargwadon lokacin da ya iso

Gwajin astrocytes shi ne ya fi bayar da darasi kuma shi ne aka fi nakalto ba daidai ba. An sanya astrocytes da aka samu kai tsaye daga bawon kwakwalwar ɓerayen gida a tsananin yanayin hana musu sinadaran da suke buƙata na sa’o’i 6, da oxygen 0.1 bisa ɗari a ruwan noma da babu glucose, pyruvate, ko serum. Bayan haka, an sake samar da oxygen na sa’o’i 24 tare da mayar da sinadaran. Kusan rabin ƙwayoyin halittar sun mutu, wanda ya ba gwajin damar nuna ko tasirin zai kasance mai amfani ko mai cutarwa.

Lokacin da methylene blue yake nan yayin matakin hana sinadaran, rayuwar ƙwayoyin halittar ta ragu, ba ta inganta ba. Amma lokacin da aka ƙara shi a lokacin sake samar da oxygen, ƙananan ƙimomin tattarawa na micromolar sun inganta rayuwar ƙwayoyin halitta kuma sun ƙara amfani da oxygen, shigar glucose, da samar da ATP. A yanayin yau da kullum, waɗannan ƙimomin tattarawa sun ƙara shigar glucose da kusan 89 bisa ɗari a 0.1 micromolar da kuma kusan 200 bisa ɗari a 1 micromolar. An kuma kiyaye glycogen da aikin hexokinase bayan rauni, ba tare da an auna wani ƙaruwa a superoxide ba.

Hanyar aikin ta fi sauƙin fahimta idan aka kwatanta ta da janareta na madadin wutar lantarki. Methylene blue yana aiki a matsayin wani madadin mai ɗaukar electron wanda yake karɓar sinadaran da ke bayar da electron sannan ya miƙa su zuwa cytochrome c da complex IV. Wannan yana tallafa wa kwararar electron da samar da ATP, yayin da yake rage zubar electron daga matakan farko. A lokacin tsananin ƙarancin sinadaran, wannan ƙarfafa aikin yana zama illa, domin yana ƙara buƙatar makamashi a lokacin da oxygen da glucose suka kusan ɓacewa, wanda zai iya sa ajiyar ƙarshe ta ƙare da sauri. Bayan sinadaran sun dawo, wannan halayya tana zama fa’ida, domin tana taimaka wa mitochondria da suka lalace su yi amfani da oxygen da glucose da aka dawo da su yadda ya kamata. Wannan ne kuma dalilin da ya sa bayanan da suke bayyana jigilar electron a mitochondria suke buƙatar a haɗa su da yanayin ƙarancin sinadaran.

Abin lura guda: wannan ƙa’idar lokaci ta shafi wannan tsarin shirya astrocytes ne. Wani binciken ƙwayoyin halitta da aka yi tare da shi, wanda ya yi amfani da wani nau’in ƙwayoyin halitta, ƙarancin sinadaran da bai kai tsanani ba, da ƙaramin tattarawar magani, ya sami kariya ko da lokacin da aka yi amfani da maganin yayin ƙarancin sinadaran. Nau’in ƙwayoyin halitta, oxygen da ya rage, ƙimar tattarawa, da tsarin gwajin su ne suke ƙayyade ko tasirin zai zama mai amfani ko mai cutarwa.

Ƙarancin kwararar jini mai ɗorewa: ƙwaƙwalwar tunawa, cytochrome oxidase, da jijiyoyin jini na tsawon makonni

Gwaje-gwajen yanayi mai ɗorewa sun yi amfani da ƙaramin adadin magani kowace rana na tsawon makonni, ba babban adadi guda na gaggawa ba. A binciken farko, beraye da aka toshe jijiyoyin carotid ɗinsu har abada sun karɓi 4 mg/kg kowace rana na wata guda. An bayar da maganin bayan kowane zaman horo na yau da kullum domin a nufi ƙarfafa abin da aka koya a ƙwaƙwalwa maimakon ƙwarewar yin aikin a lokacin. Dabbobin da aka toshe musu jijiyoyi sun koyi bambance abubuwan gani a hankali fiye da sauran, kuma sun fi rauni a wani gwajin ƙwaƙwalwar tunawa mai wuya. Amma iya iyo, motsi, da gane wari ba su canza ba. Maganin yau da kullum ya rage matsalolin koyo da ƙwaƙwalwar tunawa ba tare da canza halayen motsi gaba ɗaya ba.

Wani bincike na biyo baya ya auna aikin cytochrome oxidase, wato complex IV na mitochondria, a yankunan kwakwalwa 44 bayan wannan tsarin magani na wata guda. Toshewar ta rage aikin enzyme a bawon kwakwalwa na gani, na gaban goshin kwakwalwa, da na perirhinal, har ma da hippocampus da amygdala. Ta kuma raunana daidaituwar aiki tsakanin bawon kwakwalwa na gani da hippocampus. Maganin ya kiyaye aikin enzyme a yankunan kuma ya ƙarfafa waɗannan alaƙoƙin tafiyar da sinadarai tsakanin yankuna, kuma aikin da aka kiyaye ya yi alaƙa da kyakkyawan sakamako wajen yin aikin gwaji. Waɗannan alaƙoƙi suna bayyana daidaituwar aikin enzymes na tafiyar da sinadarai, ba ma’aunan kai tsaye na haɗin aiki tsakanin sassan kwakwalwar ɗan Adam ba. Bitocin tafiyar da makamashi a kwakwalwa suna taimakawa wajen bayyana wannan bambanci.

Wani bincike daban na mako guda ya yi amfani da 2 mg/kg kowace rana kuma ya ƙara wani sinadarin hana hanyar sigina domin gwada hanyar aikin. Da maganin, kwararar jini zuwa kwakwalwa ta tashi daga kusan 60 zuwa kusan 100 mL ga kowane 100 g a minti ɗaya, kuma yawan jijiyoyin jini a hippocampus ya tashi daga kusan 15.1 zuwa 23 bisa ɗari. Duk waɗannan ingantattun sakamakon biyu sun ragu a wani ɓangare lokacin da aka toshe hanyar siginar rayuwar ƙwayoyin halitta ta PI3K/Akt, kuma Akt da aka haɗa wa phosphate ya ƙaru da maganin. Sakamakon kwararar jini, yawan jijiyoyin jini, shingen kariya, da ƙwayoyin jijiyoyi yana nuna kariyar jijiyoyin kwakwalwa da jijiyoyin jini da ke da alaƙa da siginar PI3K/Akt, maimakon tasirin tafiyar da sinadarai kaɗai.

Me ya sa babu ɗaya daga cikin waɗannan da ya yi daidai da kulawar bugun jini ta gaggawa

Ikon sarrafa yanayin gwaji a dakin bincike shi ne dalilin da ya sa ba za a ɗauki waɗannan sakamakon a yi amfani da su kai tsaye ba. Ƙwayoyin halitta da aka noma ba su da gudan jini ko tsarin shigar magani, rarrabuwarsa, sarrafa shi, da fitar da shi daga jiki. Samfurin gwajin 2VO ƙarancin kwararar jini ne mai tsawo a kwakwalwa gaba ɗaya, ba wani abu da ya toshe jijiya kwatsam a wani takamaiman yanki tare da penumbra da bai wuce mintuna kaɗan da samuwa ba. Ko MCAO na beraye yana amfani da dabbobi matasa masu lafiya, maganin sa barci, toshewar da take iri ɗaya, da bayar da magani a daidaitattun lokuta. Wannan ya bambanta da tsofaffin marasa lafiya masu gudan jini iri-iri, taruwar kitse a bangon jijiyoyi, hawan jini, ciwon sukari, da lokutan fara alamomi da ba a sani ba.

Babu wani gwajin ɗan Adam da aka wallafa, wanda aka raba mahalarta zuwa rukuni bisa bazuwar zaɓe, da ya tabbatar da methylene blue a matsayin maganin gaggawa ga bugun jini da ƙarancin jini yake haifarwa. Wani binciken hoton kwakwalwar ɗan Adam da ake ambata wani lokaci ya ɗauki manya 26 masu lafiya, ba masu bugun jini ba. Adadin magani guda da aka sha ta baki ya canza siginar kwakwalwa da ke da alaƙa da aikin gwaji, tare da ɗan ingantuwar tuna abin da aka koya. Wannan yana nuna aiki a tsarin jijiyoyi na tsakiya, ba ingancin maganin bugun jini ba. Jagororin gaggawa na yanzu sun fi mayar da hankali kan dawo da kwararar jini da sauri ta narkar da gudan jini da maganin cikin jijiya ga marasa lafiya da suka cancanta, da cire gudan jini ga toshewar manyan jijiyoyi da suka dace. Hanyoyin kula da bugun jini na gaggawa da aka amince da su ne kaɗai aka tabbatar da su. Kada a taɓa jinkirta kulawa idan ana zargin bugun jini domin a bayar da methylene blue, kuma iyakokin amfani da adadin maganin gwaje-gwajen kafin na ɗan Adam suna bayyana dalilin da ya sa ba za a ɗauki jadawalin beraye a matsayin tsarin maganin marasa lafiya ba.

Batun aminci yana ƙara jaddada wannan iyaka. Methylene blue da ake bayarwa ta cikin jijiya yana ɗauke da gargaɗi a cikin akwatin lakabi game da matsananciyar cutar serotonin syndrome ko wadda za ta iya jawo mutuwa idan aka haɗa shi da magungunan da suke tasiri kan serotonin, ciki har da SSRIs, SNRIs, da magungunan hana MAO, waɗanda mutane da yawa a shekarun da bugun jini ya fi faruwa suke sha. Ba a yarda a yi amfani da shi ga masu ƙarancin G6PD ba saboda haɗarin fashewar jajayen ƙwayoyin jini. Yana kuma hana siginar nitric oxide, wanda yake ƙara juriyar jijiyoyin jini da matsin jini a wasu yanayi, don haka bai kamata a bayyana shi kawai a matsayin maganin da yake ƙara kwararar jini zuwa kwakwalwa ba. Tsarin 1 mg/kg ta cikin jijiya da aka amince da shi don methemoglobinemia da aka samu daga baya ba tsarin maganin bugun jini ba ne.

Taƙaitaccen bayani na gaskiya yana da iyaka, amma yana da tushe. A kusa da lokacin dawowar kwararar jini bayan ƙarancin jini na ɗan lokaci a wani takamaiman yanki, ƙaramin adadin methylene blue ya rage ci gaban lalacewa a beraye. A toshewar dindindin, ya jinkirta mutuwar nama amma bai hana ta ba. A astrocytes, ya cutar lokacin tsananin ƙarancin sinadaran kuma ya taimaka lokacin sake samar da oxygen. Yayin ƙarancin kwararar jini mai ɗorewa, ya kiyaye cytochrome oxidase, jijiyoyin jini, da ƙwaƙwalwar tunawa na tsawon makonni. Mai jigilar electron guda, yanayi uku, amsoshi uku.