Shuɗin methylene don raunin kwakwalwa: fahimtar shaidar binciken kafin gwajin mutane

Bugun kai, toshewar jijiyar jini, da wata cuta mai lalata ƙwayoyin jijiyoyi a hankali duk na iya ƙarewa da matsala ɗaya: kwakwalwa ba ta da isasshen kuzarin yin aikinta. Wannan sakamako na bai ɗaya ne ya sa wani sinadari yake ci gaba da bayyana a wallafe-wallafen bincike na dukkan fannoni ukun. Amma samun sakamako na bai ɗaya ba yana nufin ana gwada ra'ayi ɗaya ba. Magani da aka bayar kafin rauni, magani da aka bayar cikin sa'a ta farko bayan rauni, da magani da aka auna sakamakonsa watanni daga baya suna gwada ra'ayoyi daban-daban, ko da ruwan shuɗi ɗaya ne ke cikin sirinjin.

Wannan maƙala tana bibiyar ɓangaren rauni na waɗannan wallafe-wallafen. Tana duba abin da amfani da shuɗin methylene don raunin kwakwalwa yake nufi a gwaje-gwajen dabbobi, tana bambanta raunin da bugun kai ya haifar da bugun jini da lalacewar ƙwayoyin jijiyoyi ta dogon lokaci, kuma tana nuna dalilin da ya sa lokacin bayar da kashi yake bayyana yawancin bambance-bambancen da ke tsakanin nazari.

Raunuka uku, gazawar samar da kuzari ɗaya

Hanyar da ke haɗa waɗannan samfurori tana cikin mitochondria. A yanayin al'ada, electrons suna wucewa ta sarkar jigilar electrons don samar da ATP, kuma sarkar da ke aiki yadda ya kamata tana takaita sinadaran oxygen masu saurin amsawa. Bayan rauni, wasu sassan sarkar suna gazawa, samar da ATP yana raguwa, kuma samar da radicals masu 'yanci yana ƙaruwa. Bitar Molecular Neurobiology ta 2018 ta bayyana shuɗin methylene a matsayin madadin mai ɗaukar electrons: yana karɓar electrons daga NADH ya miƙa su ga cytochrome c, wanda ke ƙara aikin complex IV kuma ya dawo da samar da ATP ko da farkon sarkar ya samu matsala.

Alkaluman da aka ruwaito a bayyane suke. A shirye-shiryen ƙwayoyin halitta da yankakkun nama, aikin complex IV ya ƙaru daga kashi 30 zuwa 100 yayin da amfani da oxygen ya ƙaru daidai da haka. Wannan yana nuna cewa ƙarin electrons sun yi aiki mai amfani maimakon su tsere a matsayin radicals. A samfurin bugun jini a bera, samar da ATP a yankin da abin ya shafa ya fi na dabbobin da ba a ba magani ba da kusan kashi 30 bayan sa'o'i 24 da bayar da magani. Bitar Biochemistry (Moscow) ta 2022 ta ƙara bayyana sakamakon da ke biyo baya: ƙarancin damuwar oxidation, ƙarancin kumburin jijiyoyi, ƙarancin mutuwar ƙwayoyin halitta bisa tsari, tare da tasiri a kan monoamine oxidase, nitric oxide synthase, samar da sababbin mitochondria, autophagy, da taruwar sunadaran da suka naɗe ba daidai ba.

Saboda haka ra'ayin mai sauƙi ne. Rauni yana toshe hanyar electrons ta al'ada, kuma shuɗin methylene yana samar da wata hanyar kewaye. Duk abin da ke biyo baya ya danganta ne da wane irin rauni ake magana a kai, yaushe aka bayar da sinadarin, da yadda aka auna sakamakon.

Raunin bugun kai ba bugun jini ba ne

A samfurin raunin kwakwalwa sakamakon bugun kai, ƙarfin bugun yana zuwa ne lokaci guda. Lalacewar farko ta samo asali ne daga ƙarfin bugun: nama yana yagewa, jijiyoyin jini suna fashewa, kuma shingen jini da kwakwalwa yana buɗewa cikin mintuna. Abin da shuɗin methylene zai iya shafa a bisa hankali shi ne zagaye na biyu da ke biyo baya cikin sa'o'i da kwanaki, yayin da mitochondria a cikin naman da ya tsira suke gazawa, kumburi yana yaɗuwa, kuma ruwa yana taruwa. Abubuwan da ake aunawa a waɗannan nazari suna nuna wannan jerin: girman wurin lalacewa, yawan ruwan cikin kwakwalwa, tsirar ƙwayoyin jijiyoyi kusa da wurin bugun, da halayen da suka bayyana daga baya kamar farfaɗowar motsi ko koyon hanyar fita daga hanyar ruɗani.

A samfurin bugun jini ko ƙarancin jini a dukkan kwakwalwa, matsalar tana da wata siga dabam. Gudun jini yana tsayawa, gazawar samar da kuzari tana biyo baya cikin mintuna, kuma dawowar gudun jini yana kawo nasa raunin. A nan, ana daidaita lokacin bayar da kashi da abin da ya faru ga jijiyar jini, sau da yawa cikin mintuna bayan toshewar jijiyar ko dawowar jini. Abubuwan da ake aunawa suna ƙididdige abin da ya faru da nama nan da nan, cikin sa'o'i zuwa kwana ɗaya ko biyu: girman yankin da ya mutu saboda rashin jini, gudun jini, da farfaɗowar aiki da wuri. Wani salo a wallafe-wallafen bugun jini shi ne bayar da magani tun kafin matsalar, wato a ba dabbobi kashi kafin toshe jijiyar jini. Wannan yana gwada rigakafi ta hanyar da babu gwajin raunin kai da zai iya kwaikwaya a mutane cikin bin ƙa'idar ɗabi'a.

Sakamakon bugun jini shi ne mafi ƙarfi a wallafe-wallafen rauni, kuma ya haɗa da sakamakon rashin tasiri mafi bayyana. Berayen da aka ba shuɗin methylene lokacin dawowar jini bayan an toshe jijiyar jini ta tsakiyar kwakwalwa na sa'a ɗaya sun kasance da yankunan mutuwar nama da suka yi ƙasa da kashi 30 a rana ta 2, tare da ceton ƙarin nama a tsakiyar yankin da ke cikin haɗari da yankin da ke kewaye da shi (Shen, 2013). Wani nazarin toshewar dindindin ya gano cewa naman da ke cikin haɗari ya fi jinkirin komawa mataccen nama, amma bai gano raguwar girman yankin mutuwar nama na ƙarshe bayan sa'o'i 24 ba a kowane ɗayan kaso biyun da aka gwada (Rodriguez, 2014). Nazarin toshewa na uku ya rage girman yankin mutuwar nama da kusan rabi a kashi na tsakiya, kuma ya rubuta bayanai kai tsaye game da tsarin mitochondria na ƙanƙanta da mitophagy a cikin kwakwalwar da ta rasa isasshen jini. A lokaci guda, ya ruwaito wani abin da ya saɓa wa tsammani: mutuwar ƙwayoyin halitta bisa tsari da aka auna ta ƙaru yayin da mutuwar ƙwayoyin halitta saboda lalacewa ta ragu (Di, 2015). A samfurin ƙarancin jini a dukkan kwakwalwa kuma, ci gaba da shigar da ƙaramin kashi ya dawo da aikin cytochrome c oxidase, matakan ATP, da ƙarfin lantarki a fatar mitochondria a yankin CA1 na hippocampus mai saurin samun rauni; ya kiyaye waɗannan ƙwayoyin jijiyoyi, kuma ya kare ƙwaƙwalwar wurare (Lu, 2016). Ya dace a ɗan tsaya a kan wannan auna CA1: bayanan ATP da sarkar numfashin ƙwayoyin halitta ne da aka samo kai tsaye daga cikin kwakwalwar da ta samu rauni, alhali wallafe-wallafen TBI galibi suna hasashen waɗannan abubuwa maimakon aunawa.

Lalacewar ƙwayoyin jijiyoyi ta dogon lokaci ta bambanta da duka biyun. Samfurorin cututtukan Alzheimer, Parkinson, da Huntington suna ba dabbobi kashi na tsawon makonni ko watanni, kuma suna auna taruwar sunadarai, yadda ake sarrafa dopamine, ko raguwar fahimi a hankali. Waɗannan abubuwan aunawa kusan ba su da wani abu na bai ɗaya da wurin lalacewa da aka auna kwanaki bayan bugun kai. Masu karatu da suke ɗaukar sakamako daga fanni ɗaya zuwa wani suna ketarawa da binciken wata iyaka da gwaje-gwajen ba su taɓa ketarewa ba. Jagorarmu ga wallafe-wallafen lalacewar ƙwayoyin jijiyoyi tana sanya waɗannan nazari masu dogon lokaci a nasu mahallin, kuma kwatantawa da shaidar bugun jini kaɗai tana bambanta tsare-tsaren toshe jijiyar jini da tsare-tsaren bugun kai dalla-dalla.

Abin da samfurorin TBI suka yi a zahiri

Ba a wallafa wani gwajin shuɗin methylene a mutane masu raunin kwakwalwa sakamakon bugun kai ba. Duk bayanan TBI sun fito ne daga aikin dabbobi, galibi beraye da ƙananan beraye, kuma sun ta'allaka ne a kan wasu ƙalilan daga cikin gwaje-gwaje da ya dace a ambata, domin bayanansu sun bambanta ta hanyoyin da taƙaitaccen bayani kan ɓoye.

Nazarin farko na bugun bawon kwakwalwa da aka sarrafa ya ba beraye 1 mg/kg ta jijiya sa'a ɗaya bayan ɗan bugun da ba mai tsanani ba, sannan 0.5 mg/kg bayan sa'o'i uku (Watts, 2014). Girman wurin lalacewa da aka auna da MRI ya ci gaba da zama ƙasa a dabbobin da aka ba magani a tsawon makonni biyu na bibiyar sakamako. Kuskuren taka ƙafa a gwajin tafiya ya ragu sosai a ranakun 1, 2, da 7 amma ba a rana ta 14 ba. A duban microscope na rana ta 14, an ƙidaya ƙwayoyin jijiyoyi masu lalacewa a bawon kwakwalwar da ya samu rauni 270 idan aka kwatanta da 368 a kowane filin dubawa, da kuma rini na Nissl da bai bi yanayin al'ada ba 41 idan aka kwatanta da 73. Wato, an sami kariya da wuri, amma fifikon da aka gani a halayya ya ragu zuwa mako na biyu.

Wani tsarin rauni mai yaɗuwa ya yi amfani da bugun matsin ruwa a tsakiyar layin ƙananan beraye da kashi guda na 2 mg/kg ta jijiya cikin rabin sa'a (Fenn, 2015). Dabbobin da aka ba magani sun nuna raguwar aikin kwayoyin gado masu alaƙa da kumburi, ƙarancin ƙwayoyin microglia masu kumburi, ƙarancin taruwar ruwa da ake iya gani, kuma babu hali mai kama da na baƙin ciki a rana ta 7. Sakamakon rashin tasiri ma yana da muhimmanci: raunin kansa ya ƙara ruwan kwakwalwa kaɗan ne kawai, kuma shuɗin methylene bai magance raguwar nauyin jiki ko matsalar daidaita motsi ba. Rage kumburi ba ɗaya yake da cikakkiyar kariya ba.

Nazari biyu a ƙananan beraye sun yi amfani da jadawali iri ɗaya, 1 mg/kg bayan sa'a ɗaya, 0.5 mg/kg bayan sa'o'i shida, sannan bayar da kashi kullum na kwanaki uku, kuma suka ƙara binciken hanyar aikin sinadarin. A samfurin bugun bawon kwakwalwa, maganin ya rage girman wurin lalacewa bayan sa'o'i 24, sa'o'i 72, da rana ta 14, tare da kiyaye ƙwayoyin jijiyoyi da ƙara alamomin autophagy (Zhao, 2016). A samfurin bugun matsin ruwa, ya rage mutuwar ƙwayoyin jijiyoyi bisa tsari, ya ƙarfafa shingen jini da kwakwalwa mai zubarwa, kuma ya inganta maki na aikin jijiyoyi a tsawon makonni biyu (Shen, 2019). Sai dai yawan ruwan kwakwalwa bai nuna wani bambanci zuwa sa'o'i 72 ba a nazarin Zhao, kuma aikin gwajin rotarod bai nuna bambanci a ranakun 1 da 3 ba a nazarin Shen. An sami canji a wuraren lalacewa da tsirar ƙwayoyin halitta; kumburi da motsi a farkon lokaci ba koyaushe suka bi wannan canjin ba.

Gwajin da ya fi fice wajen lokaci shi ne wanda aka jinkirta bayar da kashi (Watts, 2016). Da samfurin bugun kai iri ɗaya, ba a bayar da kashi na farko ba sai bayan sa'o'i 24 da rauni. Zuwa rana ta 2, rukunin da aka jinkirta wa magani ya nuna raguwar wurin lalacewa kwatankwacin dabbobin da aka yi wa magani a sa'o'in farko, kuma raguwar ta ci gaba a ranakun 7 da 14. Alamar tasiri a halayya ta fi rauni: ingantar kuskuren taka ƙafa a rukunin da aka jinkirta wa magani ta kasance yanayi ne da bai kai muhimmancin ƙididdiga ba. Dakin gwaje-gwaje ɗaya, samfurin ɗaya, damar bayarwa ta sa'o'i 24 ɗaya. Wannan shaida ce ta gaske cewa damar bayar da magani tana wuce sa'o'in farko, kuma ita ce dukkan shaidar wannan ra'ayin. A lura da tarkon kalmar jinkirtawa a wasu wurare: wasu nazari na Rasha da takensu ya shafi kariyar ƙwayoyin jijiyoyi da aka jinkirta sun bayar da kashi bayan mintuna 30, kuma sun yi amfani da jinkirtawa don nufin sakamako mai ɗorewa, ba fara magani a makare ba.

Wani ƙaramin nazari na rauni a takamaiman wuri a beraye ya cika bayanin lokaci daga wata fuskar: bayar da kashi nan da nan kafin raunin da bayar da shi mintuna 30 bayan raunin duk sun rage matsalar aikin gaɓoɓi (Stelmashook, 2019). Bayar da magani kafin rauni yana aiki a dakin gwaje-gwaje ne musamman saboda dakin gwaje-gwajen ne yake tsara lokacin raunin.

Tsananin kula da kashi yana da muhimmanci a nan. Bitocin sun bayyana ƙananan kaso a matsayin masu ƙarfafa numfashin mitochondria, manyan kaso kuma a matsayin masu hana shi; wannan shi ne yanayin matakai biyu da ake gani a ilimin aikin shuɗin methylene. Shi ya sa ba za a karanta sakamakon da ma'anar cewa ƙarin shuɗi yana nufin ƙarin farfaɗowa ba. Kowane nazari yana gwada wuri guda ne a kan lankwasasshen zane. Bayanin dangantakar kashi da martani yana bibiyar wannan zane a samfurori daban-daban, kuma bayanin aminci da illolin gefe yana bayyana abin da manyan kaso suke yi maimakon haka.

A karanta wannan tebur daga gefe zuwa gefe: sinadari ɗaya, lokuta daban-daban uku. Rigakafi yana cikin layin tsakiya, magani nan da nan yana cikin layuka biyu na farko, sakamako na baya kuma yana cikin layin farko da na uku.

Rigakafi, magani nan da nan, sakamako na baya

Rigakafi shi ne da'awar da aka fi saurin fahimta ba daidai ba. A samfurorin ƙarancin jini, dabbobin da aka ba kashi kafin toshewar jijiyar jini sun fi samun sakamako mai kyau. Wani lokaci ana kawo wannan sakamakon kamar shuɗin methylene yana kare kowace kwakwalwa daga kowace matsala ta gaba. Ba haka yake nunawa ba. Yana nuna cewa mitochondria da aka shirya da wata madadin hanyar electrons suna fi jure wa dakatar da gudun jini da aka tsara. Babu wanda yake tsara lokacin samun raunin kai.

Magani nan da nan shi ne inda shaidar TBI ta fi taruwa. Bayar da kashi a sa'o'in bayan bugun kai yana nufin jerin matakan rauni na biyu yayin da yake ci gaba: gazawar samar da kuzari, damuwar oxidation, kumburi, da taruwar ruwa. Ingantar wuraren lalacewa da taruwar ruwa a nan sakamakon magani ne na gaske, amma magani ne ga wani tsari da ke gudana, ba mayar da naman da ya yage yadda yake ba.

Sakamako na baya shi ne ra'ayi na uku. Halayya da aka auna makonni bayan rauni, ko sarrafa sunadarai da aka auna watanni bayan fara samfurin lalacewar ƙwayoyin jijiyoyi, yana amsa ko kariyar farko ta ɗore ko kuma ko matakai masu tafiya a hankali sun sauya alkibla. Ƙaramin wurin lalacewa bayan sa'o'i 24, wani yanayin ingantar halayya da bai kai muhimmancin ƙididdiga ba bayan kashi da aka jinkirta na sa'o'i 24, da ingantar gwajin hanyar ruɗani watanni bayan fara bayar da kashi na dogon lokaci, da'awoyi uku ne daban-daban masu buƙatar shaida daban-daban. A yanzu, ta farko ce kaɗai ta cika ma'aunin shaidarta fiye da sau ɗaya.

Abin da wannan shaida ba za ta iya nunawa ba

Kowane sakamako da ke sama yana da iyaka iri ɗaya. Mitochondria na dabbobin dangin bera suna amsawa ga shuɗin methylene ta hanyoyin da mitochondria na mutane wataƙila za su iya yi, amma bera da aka ba kashi ta jijiya mintuna bayan bugun da aka daidaita ƙarfinsa ba mutum ba ne da ya isa sashen gaggawa sa'o'i bayan faɗuwa. Maganin sa barci, sarrafa tsananin rauni, dabbobi matasa masu lafiya, da ɗan gajeren lokacin bibiyar sakamako duk suna takaita abin da za a iya amfani da shi a wani yanayi. Babu wani nazarin shuɗin methylene a raunin fashewa ko kaɗan, don haka irin raunin da ya fi shafar masu karatu na soja shi ne mafi ƙarancin shaida.

Haka kuma, babu wata hanyar sauya kashin dabbobi zuwa na mutane da ake bayarwa a nan. Wallafe-wallafen dabbobi suna amfani da hanyoyin jijiya da cikin ramin ciki, da kaso da aka zaɓa domin sarrafa gwaji, ba ɗigon sha da ake sayarwa a shaguna ba. Babu wani abu a waɗannan nazari da ya kafa tsarin amfani ga mutane, kuma babu wani abu a nan da ya gwada shuɗin methylene tare da kulawar raunin kai ta yau da kullum.

Saboda haka taƙaitaccen bayani na gaskiya zai shiga sakin layi ɗaya. A dabbobin dangin bera, shuɗin methylene da aka bayar kusa da lokacin raunin kwakwalwa sakamakon bugun kai ko ƙarancin jini yana kiyaye samar da kuzarin mitochondria, kuma wannan kiyayewar tana biye da ƙananan wuraren lalacewa da maki na farfaɗowa mafi kyau. Wani nazarin bugun kai ya riƙe wani ɓangare na tasirin rage wurin lalacewa duk da jinkirta kashi na farko da sa'o'i 24. Ba a gwada ko wani daga cikin waɗannan abubuwa yana faruwa a kwakwalwar mutane da suka samu rauni ba, kuma wallafe-wallafen TBI da na bugun jini suna gwada lokuta daban-daban da abubuwan aunawa daban-daban. Duk wanda yake sayar da tabbaci bisa wannan shaida yana ƙara wani abu da gwaje-gwajen ba su taɓa ƙunsar sa ba.