Shuɗin methylene da sinadaran isar da saƙonnin jijiya: serotonin, dopamine, GABA, da acetylcholine

Wata magana da ake yawan yi game da shuɗin methylene ita ce yana ƙara serotonin, yana ƙara dopamine, yana kwantar da GABA, kuma yana ƙarfafa acetylcholine, duk a lokaci guda. Wannan magana tana ɗaukar sakamakon gwaje-gwajen dakin bincike guda huɗu daban-daban a matsayin tasiri guda ɗaya a jikin mutum. Takardun binciken da suka haifar da ita sun auna wuraren aiki daban-daban, a samfuran gwaji daban-daban, kuma a matakan taro da suka bambanta da kusan sau dubu. Idan aka ware wuraren aikin, abin da ake gani yana zama mai ban sha'awa kuma mai buƙatar taka-tsantsan fiye da yadda wannan magana guda ɗaya take nunawa.

Babban ra'ayin da ya tsara wannan bayani mai sauƙi ne. Kwayar sinadari da ta ɗaure da enzyme a bututun gwaji ta yi abu guda ɗaya ne: ta ɗaure da enzyme a bututun gwaji. Ko hakan zai sauya matakin sinadarin isar da saƙonnin jijiya a ƙwaƙwalwa mai rai ya dogara da matakin taron da ya isa naman jiki, da yanayin sinadarin da kwayar take ciki lokacin da ta isa, da duk sauran abubuwan da kwayar take yi a wannan matakin taron. Kowane sashe da ke ƙasa yana haɗa waɗannan tambayoyi guda uku da sakamakon binciken da suka shafa.

Serotonin: wuraren aiki biyu, matakan taro biyu

Serotonin yana da hujjoji mafi ƙarfi daga cikin tsarin guda huɗu, kuma waɗannan hujjojin sun fito ne daga wuraren aikin kwayoyin halitta guda biyu daban-daban waɗanda bai kamata a haɗe su ba.

Wurin aiki na farko shi ne monoamine oxidase nau'in A, enzyme na mitochondria da ke karya serotonin. Shuɗin methylene yana hana aikin MAO-A na ɗan adam da aka tsarkake ta hanyar ɗaurewa sosai, da Ki kusa da 27 nanomolar, yayin da MAO-B yake buƙatar matakan taro mafi yawa kafin a shafe shi, kamar yadda aka nuna a binciken saurin aikin enzyme da ya danganta rinin da gubar serotonin. Wani bincike mai alaƙa ya gano irin wannan zaɓin a naman glandar pineal na bera, inda toshe MAO-A ya ƙara indoles da suka samo asali daga serotonin, ya rage 5-HIAA, samfurin sarrafa serotonin, kuma ya sauya martanin gyara matsayin jiki da ke da alaƙa da serotonin a kwaɗi, kamar yadda aka ruwaito a binciken rinukan redox da indoles na pineal. Samfuran gwaji biyu daban-daban, sakamako mai tafiya a hanya ɗaya: raguwar karyawa, da ƙarin serotonin da ya rage a inda enzyme ɗin zai cire shi.

Wurin aiki na biyu shi ne mai jigilar serotonin kansa. A ƙwayoyin halitta da ke samar da mai jigilar serotonin na ɗan adam, shuɗin methylene ya rage shigar duka sinadarin gwaji mai fitar da haske da serotonin mai alamar bin diddigi, da IC50 kusan 1.4 micromolar. Ya kuma rage magudanar lantarki da serotonin ya haifar a bayanan patch-clamp, bisa ga binciken kai tsaye na aikin shuɗin methylene a SERT. Marubutan sun duba wasu bayanai da za su iya bayyana sakamakon, suka gano cewa tasirin bai dogara da isar da saƙonnin cGMP, sauye-sauyen calcium, ko yawan masu jigilar da ke saman ƙwayar halitta ba.

A lura da tazarar da ke tsakanin lambobin biyu. Hana aikin MAO-A yana faruwa a matakin nanomolar. Hana aikin mai jigilar yana buƙatar rini kusan sau hamsin fiye da haka. Ƙaramin adadin da ya isa ya yi cikakken tasiri a enzyme na iya kusan rashin tasiri a mai jigilar. Duk wanda ya haɗa waɗannan zuwa da'awa guda ɗaya game da serotonin yana haɗa zangon adadi biyu daban-daban kamar zangon guda ɗaya ne.

Ko ɗaya daga cikin waɗannan wuraren aiki yana da muhimmanci ga mutumin da ke shan wasu magunguna masu shafar serotonin, wannan tambaya ce ta magunguna, kuma wurinta yana cikin jagorar hulɗar magunguna. Wannan labarin yana zayyana wuraren aiki; wancan shafin ne ke ɗauke da shawarar asibiti.

Dopamine: mafi raunin hujja ta kai tsaye

Dopamine shi ne inda gaskiya ta fi buƙatar kamewa. Babu ingantaccen binciken da aka tabbatar sosai wanda ya nuna shuɗin methylene yana toshe mai jigilar dopamine ko yana ɗaurewa kai tsaye da masu karɓar dopamine. IC50 na mai jigilar da ake yawan ambata, wato 1.4 micromolar, na mai jigilar serotonin ne, ba DAT ba, kuma bai kamata a taɓa sauya masa wannan suna ba.

Abin da ake da shi maimakon haka hujja ce ta kaikaice. Saboda enzymes na MAO suna sarrafa dopamine ma, hana aikin MAO yana kiyaye dopamine tare da serotonin da noradrenaline. A samfuran gwajin mitochondria, shuɗin methylene ya toshe sauya sinadarin gubar jijiya MPTP zuwa gubar da ke shafar tsarin dopamine, wanda MAO-B ke yi. Ƙarfin wannan tasirin ya yi kama da na maganin Parkinson deprenyl, kamar yadda binciken kunna MPTP a jiki da wasu bincike masu alaƙa da MAO-B suka bayyana. Binciken dabbobi ya ƙara wasu ƙananan bayanai: an sami ƙaruwa kusan sau uku a sakin dopamine na asali daga yankakkun naman striatum na bera a 10 micromolar, a binciken isar da saƙonnin nitric oxide maimakon binciken toshe mai jigilar. Bayan ba da sinadarin ta hanyar da ya shiga dukkan jiki, sakamakon ya bambanta daga yanki zuwa yanki; wasu bincike sun gano serotonin da noradrenaline suna ƙaruwa yayin da dopamine kusan bai sauya ba.

Saboda haka, bayanin dopamine yana da tushe, amma ta kaikaice. Yana bi ne ta enzyme da ke sarrafa monoamines da dama a lokaci guda, ba ta wani wurin aiki da ya keɓanta ga dopamine ba. Duk wata da'awa cewa shuɗin methylene yana ƙara dopamine a mutane tana tsallake matakin da ya kamata a nuna hakan a zahiri.

GABA: toshe birki a aljihun ɗaurewa

Sakamakon binciken GABA takamaimai ne, kuma ya saɓa wa sunan da rinin ya yi. A ƙwayoyin halitta da ke samar da masu karɓar GABA-A na ɗan adam, shuɗin methylene ya hana magudanar lantarki da GABA ya haifar, tun daga kusan 3 micromolar, da IC50 kusa da 31 micromolar ga tsarin alpha1-beta2-gamma2 da aka fi samu, a binciken ilimin lantarkin ƙwayoyin halitta da ya gano wurin aikin.

Gano wurin aikin shi ne ɓangaren da ya fi muhimmanci. Sauye-sauyen tsarin halitta a wurin picrotoxin ba su sauya hana aikin ba, kuma an kawar da yiwuwar wuraren benzodiazepine da zinc ta hanyar kwatanta ƙananan sassan mai karɓar. Maimakon haka, sauye-sauye a wuraren amino acid biyu da aka san suna samar da aljihun ɗaurewar GABA kansa sun rage toshewar sosai. Wannan ya nuna cewa aikin hamayya ne na gasa a wurin sinadarin da ke kunna mai karɓar, maimakon sauya aikin ta ɗaurewa a wani wuri dabam. Tasirin ya ci gaba a haɗin ƙananan sassa na cikin synapse da wajen synapse, kuma ya gushe da sauri bayan an wanke rinin.

Wannan yana haifar da saɓani na gaske da ya kamata a faɗa a fili. Kwayar sinadarin da ake bincika don tallafa wa ƙwaƙwalwar tunawa tana kuma rage saurin isar da saƙonnin hanawa a kwanon gwaji. Ko wannan raguwar tana faruwa a ƙwaƙwalwa mai rai ya dogara da matakin taro a wurin, kuma 31 micromolar yana da yawa idan aka kwatanta da yawancin matakan da ake samu a dukkan jiki, abin da sashe na ƙarshe zai tattauna. Saɓanin kansa shi ne sakamakon binciken; warware shi zai buƙaci gwaje-gwajen da ba a gudanar ba tukuna.

Acetylcholine: hanyoyin aiki biyu masu saɓawa

Acetylcholine yana da sakamakon bincike biyu da ke jan akala zuwa ɓangarori masu saɓawa, kuma wannan ne ainihin dalilin da ya sa dole a bayyana su dabam.

A gefe ɗaya, shuɗin methylene yana hana aikin enzymes da ke kawar da acetylcholine. An hana aikin acetylcholinesterase na jajayen ƙwayoyin jinin saniya ta hanyar gasa a kusan 0.57 micromolar, enzyme na saniya a kusa da 0.42 micromolar, da aikin esterase na plasma na ɗan adam a kusa da 1.1 micromolar. An kuma hana aikin butyrylcholinesterase a tsakanin kusan 0.4 zuwa 5.3 micromolar, bisa nau'in dabba da samfurin gwaji, kamar yadda aka taƙaita a bitar ayyukan shuɗin methylene a tsarin jijiyoyi. Rage saurin kawarwa yana barin ƙarin sinadarin isar da saƙo a synapse, irin dalilin da ke bayan wasu magungunan Alzheimer da aka amince da su.

Amma aikin sinadarin yana da wani sharaɗi. Nau'insa mai shuɗi da aka oksidanta yana hana aikin enzyme; nau'insa marar launi da aka rage ta hanyar redox ba ya yi. Gwaje-gwajen da aka bar haɗin sinadaran na dogon lokaci, har suka ba rinin damar sauyawa zuwa nau'in da aka rage, suna nuna raunin hana aikin saboda wannan dalili kaɗai. Kowace lambar gwajin cholinesterase tana zuwa da wani abu mai sauyawa da ba a gani: nawa daga cikin rinin har yanzu yake shuɗi lokacin da aka auna shi.

A gefe ɗaya kuma, shuɗin methylene yana toshe mai karɓar nicotinic alpha7, ɗaya daga cikin masu karɓar da acetylcholine ke aiki a kansu. An hana aikin masu karɓar alpha7 na ɗan adam da aka samar a ƙwayoyin ƙwai na kwaɗi da IC50 kusa da 3.4 micromolar. Wannan ya faru ta hanyar hamayya marar gasa kuma marar dogaro da ƙarfin lantarki, wadda ba ta sauya ƙarfin sinadarin da ke kunna mai karɓar ba. Kuma 3 micromolar ya kawar da martanin synapse da choline ke haifarwa a yankakkun naman hippocampus na bera, kamar yadda binciken mai karɓar alpha7 ya ruwaito. Saboda haka, a matakan taro masu kama da juna a ƙananan zangon micromolar, rinin yana kiyaye sinadarin isar da saƙo kuma yana rage aikin ɗaya daga cikin masu karɓarsa. Ba za a iya gano jimillar tasirin da yake yi a isar da saƙonnin acetylcholine daga ɗaya daga cikin waɗannan sakamakon kaɗai ba. Wannan rashin tabbas yana da alaƙa da sauran binciken Alzheimer, da tattaunawar da ke da alaƙa game da binciken fahimi da cututtuka, amma ba a warware shi a nan ba.

Kwatancen, a wuri guda

Ninkin goma sau uku ne ke raba wurin aikin da ya fi saurin amsawa da wanda ya fi jinkirin amsawa. Wannan tazara ita ce labarin a cikin tebur guda ɗaya.

Shin waɗannan matakan taro suna isa ƙwaƙwalwa?

Lambar bututun gwaji ba ta da ma'ana sai an haɗa ta da lambar matakin da jiki ya samu. Bayan allura cikin jijiya da aka yi a lokaci guda, kusa da 1.4 mg ga kowane kg, an ruwaito matsakaicin matakin plasma na ɗan adam kusan 5 micromolar. A bincike masu alaƙa kuma, adadin 100 mg da aka sha ta baki ya haifar da matakin kusan 0.08 micromolar a jini gaba ɗaya. Binciken rarrabuwar sinadarin a jikin bera ya gano matakan ƙwaƙwalwa kusan sau goma zuwa ashirin na matakan da ke yawo a jini. Sai dai wannan jimillar rini ce a naman jiki da aka niƙa, ba rini da aka oksidanta wanda yake a sake a synapse ba. Kuma ɗaurewa da furotin na plasma kusa da kashi 94 cikin ɗari, tare da rarrabuwar rinin zuwa ƙwayoyin jini, suna ƙara rage ɓangaren da yake a sake.

Idan aka kwatanta da teburin, tsarin yana nuna matakai ne, ba kawai amsar eh ko a'a ba. Matakin hana aikin MAO-A yana ƙasa sosai da matakan da aka saba samu bayan ba da sinadarin cikin jijiya, don haka wannan tasirin yana da yiwuwar faruwa bisa ilimin aikin magunguna duk lokacin da aka ba da rinin ta wannan hanya. Tasirin cholinesterase da alpha7 yana cikin ƙananan zangon micromolar, wanda matakan koli bayan ba da sinadarin cikin jijiya suke kaiwa, amma adadin da aka saba sha ta baki na iya kasa kaiwa. IC50 na GABA-A, wato 31 micromolar, yana sama da yawancin matakan da za a iya tsammanin samu a dukkan jiki. Wannan ya sa wannan takamaiman toshewar ta fi wahalar jinginawa ga abin da ke faruwa a jikin mutum gaba ɗaya. Kowane layi na wannan kwatancen yana buƙatar gargaɗi iri ɗaya: matakin taron da ya dace shi ne na rini da yake a sake, wanda aka oksidanta, kuma yake wajen ƙwayoyin halitta a wurin aikin. Babu ɗaukar samfurin jini da ke auna wannan adadin kai tsaye.

Abin da bai kamata a kammala ba

Babu wani layi a teburin da ya tabbatar cewa shuɗin methylene yana ƙara ko rage kowane sinadarin isar da saƙonnin jijiya a mutum ta hanyar da za a iya hasashe tabbatacce. Hana aikin enzyme a samfurin da aka tsarkake, toshe mai jigilar a rukunin ƙwayoyin halitta da aka reno, da hamayya da mai karɓar a yankakken nama duk kowannensu mataki ɗaya ne na gwaji mai sarrafawa, wanda bai kai ga ainihin abin da ke faruwa a synapse ba. Kuma sashen acetylcholine ya nuna sakamako biyu na gaskiya masu saɓawa da suka bar rashin tabbas. Amfani da wannan shafi cikin lura shi ne ɗaukarsa a matsayin taswirar wuraren da aka nuna kwayar sinadarin tana ɗaurewa, tare da bayyana ƙarfin ɗaurewar, domin tattaunawar hanyoyin aiki ta kasance a kan abin da aka auna a zahiri. Game da yadda waɗannan wuraren aiki suke hulɗa da magungunan da likita ya rubuta, jagorar hulɗar magunguna ita ce shafin da ke ɗaukar wannan nauyi, tare da ƙarin bayanai a tushen ilimin aikin magunguna da bayanin hanyoyin aiki da ke tare da shi.