I-methylene blue nama-neurotransmitter: i-serotonin, i-dopamine, i-GABA, ne-acetylcholine

Umusho ovame ukushiwo nge-methylene blue uthi inyusa i-serotonin, inyusa i-dopamine, ithulisa i-GABA, futhi ilola i-acetylcholine, konke ngesikhathi esisodwa. Lowo musho uthatha imiphumela emine ehlukene yaselabhorethri njengomphumela owodwa ngaphakathi komuntu. Amaphepha ocwaningo okusekelwe kuwo alinganisa izindawo ezihlukene ezihlosiwe, kumasampula alungiselelwe ngezindlela ezihlukene, emazingeni okujiya ahluka cishe ngokuphindwe ngenkulungwane. Uma usuhlukanisa izindawo ezihlosiwe, isithombe siba mnandi ngokwengeziwe futhi sidinga ukuqapha okwengeziwe kunalokho okuvunyelwa yilowo musho owodwa.

Umqondo ohlela konke ulula. I-molecule ebophezela ku-enzyme eshubhini lokuhlola yenze into eyodwa: ibophelele ku-enzyme eshubhini lokuhlola. Ukuthi lokho kuyashintsha yini izinga le-neurotransmitter ebuchosheni obuphilayo kuncike ezingeni lokujiya elifinyelela esicutshini, esimweni samakhemikhali i-molecule ekuso lapho ifika, nakukho konke okunye i-molecule ekwenzayo kulelo zinga lokujiya. Isigaba ngasinye ngezansi sigcina leyo mibuzo emithathu ixhumene nomphumela ehambisana nawo.

I-serotonin: izindawo ezimbili ezihlosiwe, amazinga amabili okujiya

I-serotonin inobufakazi obuqine kakhulu kulezi zinhlelo ezine, futhi buvela ezindaweni ezimbili ezihlukene zamangqamuzana ezihlosiwe okungafanele zihlanganiswe.

Indawo yokuqala ehlosiwe yi-monoamine oxidase yohlobo A, i-enzyme yama-mitochondria ediliza i-serotonin. I-MAO-A yomuntu ehlanziwe ivinjelwa yi-methylene blue njengento evimbelayo ebophezela ngokuqinile, ene-Ki esondele ku-27 nanomolar, kuyilapho i-MAO-B idinga amazinga okujiya aphakeme kakhulu ngaphambi kokuba ithinteke, njengoba kuboniswe ocwaningweni lwe-kinetics olwaxhumanisa udayi nobuthi be-serotonin. Ucwaningo oluhambisana nalolu lwathola ukukhetha okufanayo esicutshini sendlala ye-pineal yamagundane, lapho ukuvinjelwa kwe-MAO-A kwandisa ama-indole avela ku-serotonin, kwehlisa umkhiqizo wokugaywa kwe-serotonin i-5-HIAA, futhi kwashintsha ukusabela kwamasele kokuzibuyisela endaweni eqondile okuhlobene ne-serotonin, njengoba kwabikwa ocwaningweni lwamadayi e-redox nama-indole e-pineal. Amasampula amabili alungiselelwe ngezindlela ezihlukene, umphumela oya ohlangothini olufanayo: ukudilizwa okuncane, ne-serotonin eningi egcinwe lapho i-enzyme ibingayisusa khona.

Indawo yesibili ehlosiwe yisithuthi se-serotonin uqobo. Kumaseli akhiqiza isithuthi somuntu, i-methylene blue yehlisa ukumuncwa kokubili kwento esetshenziswayo ekhanya nge-fluorescence ne-serotonin efakwe uphawu, nge-IC50 ecishe ibe ngu-1.4 micromolar, futhi yacindezela imisinga kagesi evuswa yi-serotonin ekuqoshweni kwe-patch-clamp, ngokusho kokuhlolwa okuqondile kokusebenza kwe-methylene blue ku-SERT. Ababhali bahlola ezinye izincazelo ezisobala futhi bathola ukuthi umphumela wawuzimele ekudlulisweni kwezimpawu nge-cGMP, ezinguqukweni ze-calcium, nasebuningini bezithuthi ebusweni beseli.

Qaphela igebe phakathi kwalezi zinombolo ezimbili. Ukuvinjelwa kwe-MAO-A kwenzeka emazingeni e-nanomolar. Ukuvinjelwa kwesithuthi kudinga udayi omningi cishe ngokuphindwe ngamashumi amahlanu. Izinga eliphansi lokuchayeka elisebenza ngokugcwele ku-enzyme lingase lisithinte kancane kakhulu isithuthi. Noma ubani ohlanganisa lokhu kube isimangalo esisodwa nge-serotonin uhlanganisa izigaba ezimbili ezihlukene zamanani omuthi kube sisodwa.

Ukuthi noma iyiphi yalezi zindawo ezihlosiwe ibalulekile yini kumuntu othatha eminye imithi ethinta i-serotonin kuwumbuzo wemithi, futhi indawo yawo isemhlahlandleleni wokusebenzisana kwemithi. Lesi sihloko senza ibalazwe lezindawo ezihlosiwe; lelo khasi linikeza izeluleko zokwelashwa.

I-dopamine: ubufakazi obuqondile obubuthakathaka kakhulu

Ku-dopamine, ukwethembeka kudinga ukuzithiba okukhulu kakhulu. Alukho ucwaningo oluqinisekiswe kahle olubonisa i-methylene blue ivimba isithuthi se-dopamine noma ibophezela ngokuqondile kuma-receptor e-dopamine. I-IC50 yesithuthi engu-1.4 micromolar evame ukucashunwa ingeyesithuthi se-serotonin, hhayi i-DAT, futhi akufanele neze ibhalwe kabusha njengengeye-DAT.

Okukhona kunalokho akusebenza ngokuqondile. Ngenxa yokuthi ama-enzyme e-MAO agaya ne-dopamine, ukuvinjelwa kwe-MAO kugcina i-dopamine kanye ne-serotonin ne-noradrenaline. Kumasampula ama-mitochondria alungiselelwe ukuhlolwa, i-methylene blue yavimba ukuguqulwa kwesithako esinobuthi ezinzwaneni i-MPTP, okwenziwa yi-MAO-B, kube yisithako esinobuthi ohlelweni lwe-dopamine, ngamandla aqhathaniswa nomuthi we-Parkinson i-deprenyl, njengoba kuchazwa ocwaningweni lokuvuselelwa kwe-MPTP ibe nobuthi emzimbeni nasocwaningweni oluhlobene lwe-MAO-B. Ucwaningo lwezilwane lwengeza izingcezu zobufakazi: ukukhuphuka cishe ngokuphindwe kathathu kokukhishwa kwe-dopamine okuyisisekelo ezincezwini ze-striatum yamagundane ku-10 micromolar, okwacwaningwa esimweni sokudluliswa kwezimpawu nge-nitric oxide kunokuba kube ukuvinjelwa kwesithuthi, kanye nemiphumela engafani ezifundeni ezihlukene ngemva kokunikezwa komuthi othinta umzimba wonke, olunye ucwaningo luthola i-serotonin ne-noradrenaline zikhuphuka kuyilapho i-dopamine ingashintshi cishe nhlobo.

Ngakho indaba ye-dopamine iyiqiniso kodwa ayiqondile. Idlula ku-enzyme ephatha ama-monoamine amaningana ngesikhathi esisodwa, hhayi endaweni yokusebenza eqondene ne-dopamine kuphela. Noma yisiphi isimangalo sokuthi i-methylene blue inyusa i-dopamine kubantu seqe isinyathelo lapho lokho bekufanele kuboniswe khona ngempela.

I-GABA: ukuvimba ibhuleki ephaketheni lokubophezela

Umphumela we-GABA ucacile futhi uphikisana nedumela likadayi. Kumaseli akhiqiza ama-receptor e-GABA-A omuntu, i-methylene blue yavimbela imisinga kagesi evuswa yi-GABA kusukela cishe ku-3 micromolar, nge-IC50 esondele ku-31 micromolar ekuhlelweni okuvamile kwe-alpha1-beta2-gamma2, ocwaningweni lwe-electrophysiology olwaveza indawo yokusebenza.

Ukuhlonzwa kwendawo yokusebenza yikho okuyigugu. Ukuguqulwa kofuzo endaweni ye-picrotoxin akuzange kushintshe ukuvinjelwa, futhi izindawo ze-benzodiazepine ne-zinc zakhishwa njengamathuba ngokuqhathanisa izingxenye ezincane zama-receptor. Esikhundleni salokho, ukuguqulwa kwezinsalela ezimbili ezaziwayo ukuthi zakha iphakethe lokubophezela le-GABA uqobo kwehlisa kakhulu ukuvinjelwa, okukhomba ukuthi ukusebenza kuwukuphikisana ngokuncintisana endaweni ye-agonist kunokuba kube ukuguqulwa kwe-allosteric kwenye indawo. Umphumela waqhubeka ezinhlelweni ezihlukene zezingxenye ezincane ezisemasynapse nangaphandle kwama-synapse, futhi waphela ngokushesha lapho udayi ukhishwa ngokugeza.

Lokhu kudala ukuphikisana kwangempela okufanele kushiwo ngokusobala. I-molecule ecwaningelwa ukusekela inkumbulo iphinde icindezele ukudluliswa okusheshayo kwezimpawu ezivimbelayo esitsheni sokuhlola. Ukuthi lokho kucindezelwa kwenzeka yini ebuchosheni obuphilayo kuncike ezingeni lokujiya lendawo, futhi u-31 micromolar uphakeme uma kuqhathaniswa namazinga amaningi okuchayeka komzimba wonke, okuxoxwa ngawo esigabeni sokugcina. Lokho kuphikisana ngokwakho kungumphumela otholakele; ukukuxazulula kungadinga ukuhlolwa okungakaze kwenziwe muntu.

I-acetylcholine: izindawo ezimbili zokusebenza eziphikisanayo

I-acetylcholine inemiphumela emibili edonsela ezinhlangothini eziphikisanayo, okuyikho kanye okwenza kufanele ibikwe ngokwehlukana.

Ngakolunye uhlangothi, i-methylene blue ivimbela ama-enzyme asusa i-acetylcholine. I-acetylcholinesterase yamaseli abomvu egazi lenkomo yavinjelwa ngokuncintisana cishe ku-0.57 micromolar, i-enzyme yezinkomo eduze kuka-0.42 micromolar, nomsebenzi we-esterase ku-plasma yomuntu eduze kuka-1.1 micromolar, kuyilapho i-butyrylcholinesterase yavinjelwa ebangeni elicishe libe ngu-0.4 kuya ku-5.3 micromolar kuye ngohlobo lwesilwane nendlela yokulungiselela isampula, njengoba kufingqwe ekubuyekezweni kokusebenza kwe-methylene blue ohlelweni lwezinzwa. Ukubambezela ukususwa kushiya isidlulisi esiningi ku-synapse, okuwumqondo ofanayo osekelwe kuwo imithi eminingana egunyaziwe ye-Alzheimer.

Kodwa lokhu kusebenza kwamakhemikhali kunombandela. Isimo esiluhlaza okwesibhakabhaka esifakwe i-oxidation sivimbela i-enzyme; isimo esingenambala esenziwe i-reduction asiyivimbeli, futhi ukuhlolwa okushiya udayi isikhathi eside ezimweni eziwuvumela ukuba wenziwe i-reduction kubika ukuvinjelwa okubuthakathaka ngenxa yaleso sizathu kuphela. Noma iyiphi inombolo yokuhlolwa kwe-cholinesterase iza nesici esishintshashintshayo esingabonakali: ukuthi ungakanani udayi owawusaluhlaza okwesibhakabhaka lapho kukalwa.

Ngakolunye uhlangothi, i-methylene blue ivimba i-receptor ye-nicotinic ye-alpha7, enye yezamukeli i-acetylcholine esebenza kuzo. Ama-receptor e-alpha7 omuntu akhiqizwa kumaseli amaqanda amasele avinjelwa nge-IC50 esondele ku-3.4 micromolar ngokuphikisana okungancintisani futhi okungancikile ku-voltage, okungashintshanga amandla e-agonist, futhi u-3 micromolar waqeda ukusabela kwama-synapse okuqhutshwa yi-choline ezincezwini ze-hippocampus yamagundane, njengoba kubikwa ocwaningweni lwe-receptor ye-alpha7. Ngakho emazingeni afanayo aphansi e-micromolar, udayi ugcina isidlulisi futhi unciphisa ukusebenza kwenye yama-receptor aso. Umphumela ophelele ekudlulisweni kwezimpawu ze-cholinergic awukwazi ukutholwa ngokubheka omunye wale miphumela kuphela. Lokho kungacaci kuxhumene nezincwadi zocwaningo lwe-Alzheimer ezibanzi, kanye nengxoxo ehlobene yocwaningo lwamakhono okucabanga nezifo, ngaphandle kokuxazululeka lapha.

Ukuqhathanisa, endaweni eyodwa

Izindawo ezihlosiwe ezizwela kakhulu nezizwela kancane kakhulu zihlukaniswa umehluko wamazinga amathathu wokuphindaphinda ngeshumi. Lelo banga yilesi sihloko etafuleni elilodwa.

Ingabe la mazinga okujiya afinyelela ebuchosheni?

Inombolo yaseshubhini lokuhlola ayisho lutho ngaphandle kwenombolo yokuchayeka eceleni kwayo. Ngemva kokufakwa emthanjeni ngesikhathi esisodwa komthamo osondele ku-1.4 mg nge-kg, kuye kwabikwa amazinga amaphakathi ku-plasma yomuntu acishe abe ngu-5 micromolar, kuyilapho umthamo ophuzwayo ongu-100 mg wakhiqiza amazinga egazini eliphelele asondele ku-0.08 micromolar ezincwadini zocwaningo ezihlobene. Ucwaningo lokusatshalaliswa emzimbeni wamagundane luthola amazinga asebuchosheni aphakeme cishe ngokuphindwe kashumi kuya kwamashumi amabili kunamazinga ajikelezayo egazini, nakuba lokho kungudayi ophelele esicutshini esigaywe saba ingxube efanayo, hhayi udayi okhululekile ofakwe i-oxidation ku-synapse, futhi ukubophezela emaprotheni e-plasma okusondele kumaphesenti angu-94 kanye nokuhlukaniseka phakathi kwe-plasma namaseli egazi kwehlisa ingxenye ekhululekile.

Uma kuqhathaniswa netafula, iphethini inamazinga kunokuba ihlukaniseke nje ngo-yebo noma cha. Ukuvinjelwa kwe-MAO-A kwenzeka emazingeni aphansi kakhulu kunokuchayeka okuvamile ngokufakwa emthanjeni, futhi kuyenzeka ngokwemigomo yokusebenza kwemithi noma nini lapho udayi unikezwa ngaleyo ndlela. Imiphumela ye-cholinesterase ne-alpha7 isebangeni eliphansi le-micromolar elifinyelelwa ngamazinga aphezulu okuchayeka ngokufakwa emthanjeni, kodwa imithamo evamile ephuzwayo ingase ingafinyeleli kulo. I-IC50 ye-GABA-A engu-31 micromolar ingaphezulu kwamazinga amaningi okuchayeka komzimba wonke angenzeka ngokunengqondo, okwenza lokho kuvinjelwa kube nzima kakhulu ukukubhekisela kumuntu ophelele. Umugqa ngamunye walokhu kuqhathanisa udinga isexwayiso esifanayo: izinga lokujiya elibalulekile yilodayi okhululekile, ofakwe i-oxidation, ongaphandle kwamaseli endaweni ehlosiwe, okuyinani okungekho kuthathwa kwegazi okulilinganisa ngokuqondile.

Iziphetho okungafanele uzifinyelele

Awukho umugqa etafuleni oqinisekisa ukuthi i-methylene blue inyusa noma yehlisa noma iyiphi i-neurotransmitter kumuntu ngendlela ebikezelwayo. Ukuvinjelwa kwe-enzyme kusampula ehlanziwe, ukuvinjelwa kwesithuthi ohlwini lwamaseli akhulisiwe, nokuphikiswa kwe-receptor ocezwini lwesicubu ngakunye kukude ngesinyathelo esisodwa esilawulwayo nokwenzeka ngempela kuma-synapse, futhi isigaba se-cholinergic sibonisa imiphumela emibili eyiqiniso ephikisanayo ishiye ukungaqiniseki. Ukusetshenziswa kwaleli khasi ngokucophelela kuwukulithatha njengebalazwe lezindawo i-molecule ekhonjiswe ukuthi ibambelela kuzo, amandla okubambelela ebhaliwe, ukuze ingxoxo yezindlela zokusebenza ihlale isekelwe kulokho okwalinganiswa ngempela. Mayelana nokuthi lezi zindawo zokusebenza zisebenzisana kanjani nemithi enikezwe ngencwadi kadokotela, umhlahlandlela wokusebenzisana kwemithi uyikhasi elithwala lowo msebenzi, kanye nomongo owengeziwe ezintweni eziyisisekelo zesayensi yemithi nasencazelweni ehambisanayo yezindlela zokusebenza.