Ubururu bwa metilene n'ibinyabutabire bitwara ubutumwa mu myakura: serotonine, dopamini, GABA na asetilikoline

Imvugo ikunze gukoreshwa ku bururu bwa metilene ivuga ko bwongera serotonine, bukongera dopamini, bugatuza GABA, kandi bugakaza imikorere ya asetilikoline, byose icyarimwe. Iyo mvugo ifata ibyavuye mu bushakashatsi bune butandukanye bwo muri laboratwari nk'aho ari ingaruka imwe ibera mu muntu. Inyandiko z'ubushakashatsi iyo mvugo ishingiraho zapimye molekile zitandukanye, mu byitegererezo bitandukanye, ku bwinshi mu mvange butandukana hafi incuro igihumbi. Iyo utandukanyije molekile bwibasira, ibyo ubona birushaho gushishikaza kandi bigasaba ubwitonzi kurusha uko iyo mvugo imwe ibyerekana.

Igitekerezo kigenga iyi ngingo kiroroshye. Molekile ifatana na anzime mu muyoboro w'igerageza iba yakoze ikintu kimwe: kwifatana na anzime mu muyoboro w'igerageza. Kuba ibyo byahindura urwego rw'ikinyabutabire gitwara ubutumwa mu bwonko buzima biterwa n'ubwinshi bugera mu ngirabuzimafatizo, imiterere y'iyo molekile mu rwego rwa shimi igihe ihageze, n'ibindi byose ikora kuri ubwo bwinshi mu mvange. Buri gice gikurikira gikomeza guhuza ibyo bibazo bitatu n'igisubizo cy'ubushakashatsi bireba.

Serotonine: molekile ebyiri zibasirwa, ubwinshi bubiri mu mvange

Mu sisitemu enye, iya serotonine ni yo ifite ibimenyetso bikomeye kurusha izindi, kandi biva kuri molekile ebyiri zitandukanye zitagomba gufatwa nk'imwe.

Molekile ya mbere yibasirwa ni monoamine oxidase yo mu bwoko bwa A, anzime yo muri mitokondiriya isenya serotonine. MAO-A y'umuntu yasukuwe ibuzwa gukora n'ubururu bwa metilene bwifatana na yo cyane, kuri Ki hafi ya 27 nanomolar, mu gihe MAO-B ikenera ubwinshi mu mvange buri hejuru cyane kugira ngo igire icyo ihindukaho, nk'uko byagaragajwe mu bushakashatsi ku muvuduko w'imikorere bwahuje irangi n'uburozi bwa serotonine. Ubundi bushakashatsi bujyanye na bwo bwabonye uko guhitamo MAO-A mu ngirabuzimafatizo z'imvubura pineale z'imbeba. Muri ubwo bushakashatsi, kubuza MAO-A gukora byongereye indole zikomoka kuri serotonine, bigabanya 5-HIAA ikomoka ku ihindurwa rya serotonine, kandi bihindura igisubizo cyikora cyo kongera kwihagarika neza mu bikeri, kijyanye na serotonine, nk'uko byatangajwe mu bushakashatsi ku marangi ya redox na indole zo mu mvubura pineale. Ibyitegererezo bibiri bitandukanye, ariko icyerekezo ni kimwe: isenywa riragabanuka, serotonine ikaguma ahantu anzime yari kuyikura.

Molekile ya kabiri yibasirwa ni poroteyine itwara serotonine ubwayo. Mu turemangingo dukora poroteyine itwara serotonine y'umuntu, ubururu bwa metilene bwagabanyije iyinjizwa ry'ikinyabutabire gitanga urumuri n'irya serotonine yashyizweho ikimenyetso, kuri IC50 hafi ya 1.4 micromolar. Bwanagabanyije imigezi y'amashanyarazi iterwa na serotonine mu bipimo bya patch-clamp, hakurikijwe isuzuma ritaziguye ry'imikorere y'ubururu bwa metilene kuri SERT. Abanditsi basuzumye ibindi bisobanuro byashoboraga gutangwa, basanga iyo ngaruka itari ishingiye ku butumwa bwa cGMP, ku mpinduka za kalisiyumu, cyangwa ku bwinshi bwa poroteyine zitwara serotonine ku buso bw'uturemangingo.

Zirikana itandukaniro riri hagati y'iyo mibare ibiri. Kubuzwa gukora kwa MAO-A kuba ku rwego rwa nanomolar. Kubuzwa gukora kwa poroteyine itwara serotonine bisaba irangi rikubye hafi incuro mirongo itanu. Ubwinshi buke bugera ku ngirabuzimafatizo bushobora kwifata kuri anzime ku buryo bwuzuye, ariko ntibugire hafi icyo bukora kuri poroteyine itwara serotonine. Uhuza ibi byombi mu mvugo imwe yerekeye serotonine aba afata intera ebyiri zitandukanye z'ingano zikoreshwa akazigira imwe.

Kuba imwe muri izo molekile zibasirwa yagira akamaro mu muntu ufata indi miti igira icyo ikora kuri serotonine ni ikibazo cy'imiti, kandi kigenewe amabwiriza ku mikoranire y'imiti. Iyi ngingo igaragaza molekile zibasirwa; urwo rupapuro ni rwo rutanga inama z'ubuvuzi.

Dopamini: ibimenyetso bitaziguye bidakomeye kurusha ibindi

Kuri dopamini ni ho kuvugisha ukuri bisaba kwirinda kurengera cyane kurusha ahandi. Nta bushakashatsi bwemejwe neza bugaragaza ko ubururu bwa metilene bubuza poroteyine itwara dopamini gukora cyangwa ko bwifatana n'utwakira dopamini mu buryo butaziguye. IC50 ya 1.4 micromolar ya poroteyine itwara ibinyabutabire ikunze kuvugwa ireba poroteyine itwara serotonine, si DAT, kandi ntigomba na rimwe kwitirirwa DAT.

Ibihari ahubwo ni ibimenyetso biziguye. Kubera ko anzime za MAO zihindura na dopamini, kubuza MAO gukora bituma dopamini igumaho, kimwe na serotonine na noradrenaline. Mu byitegererezo bya mitokondiriya, ubururu bwa metilene bwabujije ihindurwa rya MPTP, uburozi bw'imyakura, ikavamo uburozi bwangiza uturemangingo dukoresha dopamini, ihindurwa rikorwa na MAO-B. Imbaraga zo kubibuza zari zigereranywa n'iz'umuti deprenyl ukoreshwa kuri Parkinson, nk'uko ubushakashatsi ku ihindurwa rya MPTP mu mubiri ikaba uburozi n'ubundi bujyanye na MAO-B bubisobanura. Ubushakashatsi ku nyamaswa bwongeraho ibice by'amakuru: irekurwa rya dopamini risanzwe ryiyongereye hafi incuro eshatu mu bice bya striatum y'imbeba kuri 10 micromolar, ariko ibyo byari byizwe mu rwego rw'ubutumwa bwa nitiriki okside aho kuba kubuzwa gukora kwa poroteyine itwara dopamini. Nyuma yo gutanga ikinyabutabire ku buryo kigera mu mubiri wose, ibisubizo byaratandukanye bitewe n'akarere k'ubwonko, aho ubushakashatsi bumwe bwabonye serotonine na noradrenaline byiyongera mu gihe dopamini itahindutse cyane.

Bityo, ibivugwa kuri dopamini bifite ishingiro ariko bishingiye ku nzira iziguye. Binyura kuri anzime ikora kuri monoamine nyinshi icyarimwe, ntibinyura kuri molekile yihariye ya dopamini. Imvugo yose ivuga ko ubururu bwa metilene bwongera dopamini mu bantu iba isimbutse intambwe yo kugaragaza ko ibyo bibaho koko.

GABA: kubuza feri gukora ahantu GABA yifatana

Icyabonetse kuri GABA kirasobanutse kandi kinyuranye n'ibisanzwe bivugwa kuri iri rangi. Mu turemangingo dukora utwakira GABA-A tw'umuntu, ubururu bwa metilene bwagabanyije imigezi y'amashanyarazi iterwa na GABA, bigatangirira hafi ya 3 micromolar. IC50 yari hafi ya 31 micromolar ku miterere isanzwe ya alpha1-beta2-gamma2, nk'uko byagaragajwe mu bushakashatsi ku mikorere y'amashanyarazi bwagaragaje aho igikorwa kibera.

Kugaragaza aho igikorwa kibera ni cyo gice cy'ingenzi. Impinduka ku hantu picrotoxin yifatana ntizahinduye kubuzwa gukora, kandi kugereranya ibice bigize utwakira byerekanye ko bitaberaga ku hantu benzodiazepine na zinc byifatana. Ahubwo, impinduka kuri aside amine ebyiri zizwiho kugira uruhare mu kurema ahantu GABA ubwayo yifatana zagabanyije cyane uko kubuzwa gukora. Ibyo bigaragaza ko ari uguhangana na GABA ahantu ikangura akakira yifatana, aho kuba uguhindura imikorere y'akakira hifashishijwe ahandi hantu. Iyo ngaruka yabonetse mu mpurirane z'ibice bigize utwakira two muri sinapsi no hanze yayo, kandi yahise ishira iyo ikinyabutabire gikuwemo.

Ibi bituma habaho ibintu bibiri bisa n'ibivuguruzanya bikwiye kuvugwa mu buryo bweruye. Molekile iri gukorerwaho ubushakashatsi ku gufasha kwibuka inagabanya ihererekanywa ryihuse ry'ubutumwa bugabanya ibikorwa by'imyakura mu gikoresho cya laboratwari. Kuba uko kugabanya bibera mu bwonko buzima biterwa n'ubwinshi bwayo aho igikorwa kibera, kandi 31 micromolar iri hejuru ugereranyije n'ubwinshi bwinshi bushobora kugera mu mubiri wose, nk'uko igice cya nyuma kibigarukaho. Ibyo bintu bisa n'ibivuguruzanya ni byo byabonetse; kubisobanura burundu byasaba amagerageza atarakorwa n'umuntu n'umwe.

Asetilikoline: inzira ebyiri zinyuranye

Kuri asetilikoline hari ibyabonetse bibiri biganisha mu byerekezo binyuranye, ari na yo mpamvu bigomba gutangazwa ukwabyo.

Ku ruhande rumwe, ubururu bwa metilene bubuza gukora anzime zikuraho asetilikoline. Acetylcholinesterase yo mu turemangingo dutukura tw'amaraso y'inka yabujijwe gukora mu buryo bwo guhatanira aho yifatana hafi ya 0.57 micromolar, anzime y'inka hafi ya 0.42 micromolar, n'imikorere ya esterase yo muri plasma y'umuntu hafi ya 1.1 micromolar. Butyrylcholinesterase yabujijwe gukora ku bwinshi buri hagati ya 0.4 na 5.3 micromolar, bitewe n'ubwoko bw'ikinyabuzima n'uko icyitegererezo cyateguwe, nk'uko byakusanyijwe mu isuzuma ry'imikorere y'ubururu bwa metilene muri sisitemu y'imyakura. Gutinza ikurwaho bituma ikinyabutabire gitwara ubutumwa gisigara ari kinshi muri sinapsi, ari na yo ngingo ishingirwaho n'imiti myinshi yemewe ya Alzheimer.

Ariko iyo mikorere ya shimi ifite ikintu ishingiraho. Imiterere y'ubururu yabayeho okisidasiyo ibuza anzime gukora; imiterere itagira ibara yabayeho igabanurwa ntibikora. Kuyireka igihe kirekire mu igerageza, bigatuma irangi rigabanurwa, bituma haboneka kubuzwa gukora kudakomeye kubera iyo mpamvu yonyine. Buri mubare w'igerageza kuri cholinesterase uba ufite ikintu kitagaragara gishobora kuwuhindura: ingano y'irangi ryari rikiri ubururu igihe ryapimwaga.

Ku rundi ruhande, ubururu bwa metilene bubuza gukora akakira nikotinike ka alpha7, kamwe mu twakira asetilikoline ikoreraho. Utwakira alpha7 tw'umuntu twakorewe mu ntanga ngore z'ibikeri twabujijwe gukora kuri IC50 hafi ya 3.4 micromolar, binyuze mu kubuza gukora kutari uko guhatanira aho kwifatana kandi kudashingiye kuri volitaje, kutahinduye imbaraga z'ikinyabutabire gikangura akakira. Kuri 3 micromolar, ubururu bwa metilene bwakuyeho ibisubizo bya sinapsi byaterwaga na koline mu bice bya hipokampe y'imbeba, nk'uko ubushakashatsi ku kakira alpha7 bubitangaza. Bityo, ku bwinshi bwo hasi busa buri ku rwego rwa micromolar, irangi rituma ikinyabutabire gitwara ubutumwa kigumaho ariko rikanagabanya imikorere ya kamwe mu twakira twacyo. Ingaruka rusange ku butumwa bwa asetilikoline ntishobora kumenyekana hashingiwe kuri kimwe gusa muri ibyo byabonetse. Uko kudasobanuka gufitanye isano n'inyandiko z'ubushakashatsi zagutse kuri Alzheimer, n'ibiganiro bifitanye isano na zo ku bushakashatsi ku bushobozi bwo gutekereza no ku ndwara, ariko ntigukemukira hano.

Igereranya, ahantu hamwe

Ubwinshi bukenewe kuri molekile yibasirwa yoroshye kugira icyo ihindukaho kurusha izindi butandukanye n'ubukenewe ku itoroshye kurusha izindi ku ntera y'inshuro icumi yazamuwe ku mpamyabumenyi ya gatatu. Iryo tandukaniro ni iyi ngingo yose mu mbonerahamwe imwe.

Ubu bwinshi mu mvange bugera mu bwonko?

Umubare wo mu muyoboro w'igerageza nta cyo usobanura utari kumwe n'umubare w'ubwinshi bugera ku ngirabuzimafatizo. Nyuma yo gutera mu mutsi ingano imwe yihuse hafi ya 1.4 mg kuri kg, hatangajwe impuzandengo y'ubwinshi muri plasma y'umuntu hafi ya 5 micromolar, mu gihe ingano ya 100 mg yafashwe mu kanwa yatanze ubwinshi mu maraso yose hafi ya 0.08 micromolar mu nyandiko zo muri urwo rwego rw'ubushakashatsi. Ubushakashatsi ku ikwirakwira mu mbeba bwerekana ko ubwinshi mu bwonko bukubye hafi incuro icumi kugeza kuri makumyabiri uburi mu maraso atembera. Icyakora, ubwo ni ubwinshi bw'irangi ryose mu ngirabuzimafatizo zasyawe zikavangwa, si irangi ryigenga ryabayeho okisidasiyo riri kuri sinapsi. Kwifatana na poroteyine zo muri plasma hafi ya 94 ku ijana, hamwe no gukwirakwira kw'irangi mu turemangingo tw'amaraso, bigabanya kurushaho igice cyaryo cyigenga.

Iyo ugereranyije n'imbonerahamwe, ubona ko hari inzego zitandukanye aho kuba igisubizo cya yego cyangwa oya gusa. Kubuzwa gukora kwa MAO-A bibera ku bwinshi buri hasi cyane y'ubukunze kuboneka iyo irangi ritewe mu mutsi, bityo bikaba bishoboka mu rwego rw'imikorere y'imiti igihe cyose ritanzwe muri ubwo buryo. Ingaruka kuri cholinesterase na alpha7 zibera mu ntera yo hasi ya micromolar, ishobora kugerwaho n'ubwinshi bwo hejuru nyuma yo gutera mu mutsi, ariko ingano zisanzwe zifashwe mu kanwa zishobora kutayigeraho. IC50 ya GABA-A ya 31 micromolar iri hejuru y'ubwinshi bwinshi bushoboka kugera mu mubiri wose, bityo uko kubuzwa gukora kukaba ari ko kugoye cyane gushingiraho mu muntu muzima. Buri murongo w'iri gereranya ukeneye kwitonderwa kimwe: ubwinshi bufite akamaro ni ubw'irangi ryigenga, ryabayeho okisidasiyo, riri hanze y'uturemangingo aho molekile yibasirwa iri, kandi nta gupima amaraso kubupima mu buryo butaziguye.

Ibyo udakwiye gufata nk'umwanzuro

Nta murongo n'umwe wo mu mbonerahamwe wemeza ko ubururu bwa metilene bwongera cyangwa bugabanya ikinyabutabire icyo ari cyo cyose gitwara ubutumwa mu myakura mu muntu ku buryo bushobora guteganywa. Kubuzwa gukora kwa anzime mu cyitegererezo cyasukuwe, kubuzwa gukora kwa poroteyine itwara ikinyabutabire mu turemangingo tworowe, no kubuzwa gukora kw'akakira mu gice cy'ingirabuzimafatizo, buri kimwe ni intambwe imwe yagenzuwe itandukanye n'ibibera muri sinapsi. Igice cya asetilikoline na cyo cyerekana ibyabonetse bibiri by'ukuri bifite ibyerekezo binyuranye, bigasiga ingaruka rusange zitazwi neza. Gukoresha uru rupapuro mu buryo bushyize mu gaciro ni ukurufata nk'ikarita ya molekile ubururu bwa metilene bwagaragajweho ko bwifatana na zo, hamwe n'imbaraga zo kwifatana zigaragajwe, kugira ngo ibiganiro ku mikorere bikomeze gushingira ku byapimwe koko. Ku buryo izo nzira zikorana n'imiti yanditswe na muganga, amabwiriza ku mikoranire ni rwo rupapuro rutanga ibyo bisobanuro, hamwe n'andi makuru mu ngingo z'ibanze ku mikorere y'imiti no mu nyandiko iyiherekeza isobanura uburyo bw'imikorere.