Methylene blue ndi zotumiza mauthenga m’mitsempha: serotonin, dopamine, GABA, ndi acetylcholine

Mawu omwe amanenedwa kawirikawiri ponena za methylene blue ndi akuti imawonjezera serotonin, imawonjezera dopamine, imatontholetsa GABA, ndipo imanola ntchito ya acetylcholine, zonse nthawi imodzi. Mawu amenewa amatenga zomwe zinapezeka m’kafukufuku wa mu labotale pa zinthu zinayi zosiyana ngati kuti ndi zotsatira chimodzi mkati mwa munthu. Maphunziro omwe mawuwa amachokera anayeza zolunjika zosiyanasiyana, m’mitundu yosiyanasiyana ya zitsanzo, pa milingo yomwe imasiyana pafupifupi nthawi chikwi. Mukalekanitsa zolunjikazo, zimene zikuoneka zimakhala zosangalatsa kwambiri komanso zofuna kusamala kwambiri kuposa momwe mawu amodziwo akusonyezera.

Mfundo yokonza nkhaniyi ndi yosavuta. Molekyulu yomwe imamangirira ku enzayimu m’chubu choyesera yachita chinthu chimodzi: yamangirira ku enzayimu m’chubu choyesera. Kaya zimenezi zimasintha mlingo wa chotumiza mauthenga m’mitsempha mu ubongo wamoyo zimadalira mlingo womwe umafika ku minofuyo, mkhalidwe wa mankhwala womwe molekyuluyo imakhala nawo ikafika, ndi zinthu zina zonse zomwe molekyuluyo imachita pa mlingo womwewo. Gawo lililonse pansipa limagwirizanitsa mafunso atatu amenewa ndi zomwe zinapezeka pa kafukufuku wake.

Serotonin: zolunjika ziwiri, milingo iwiri

Pa njira zinayizi, serotonin ili ndi umboni wamphamvu kwambiri, ndipo umboniwo umachokera ku zolunjika ziwiri zosiyana za mamolekyulu zomwe siziyenera kuphatikizidwa.

Cholunjika choyamba ndi monoamine oxidase mtundu A, enzayimu ya m’mitochondria yomwe imaphwanya serotonin. Methylene blue imaletsa MAO-A ya munthu yoyeretsedwa mwa kumangirira mwamphamvu, ndi Ki pafupi ndi 27 nanomolar, pamene MAO-B imafuna milingo yokwera kwambiri isanakhudzidwe, monga momwe zasonyezedwera mu kafukufuku wa liwiro la ntchito ya enzayimu amene anagwirizanitsa utotowu ndi kawopsedwe ka serotonin. Kafukufuku wina wogwirizana nawo anapeza kusankha komweku mu minofu ya chithokomiro cha pineal cha makoswe. Mmenemo, kuletsa MAO-A kunawonjezera ma indole ochokera ku serotonin, kunachepetsa 5-HIAA yomwe imapangidwa serotonin ikaphwanyidwa, komanso kunasintha kachitidwe ka achule kodzibwezeretsa pamalo oyenera komwe kamagwirizana ndi serotonin, monga momwe zafotokozedwera mu kafukufuku wa utoto wa redox ndi ma indole a mu pineal. Zitsanzo ziwiri zosiyana, koma zotsatira zolowera mbali imodzi: kuchepa kwa kuphwanyidwa, ndi serotonin yambiri yotsala pamalo pomwe enzayimuyo ikanachotsa.

Cholunjika chachiwiri ndi chonyamulira serotonin chenichenicho. M’maselo opangidwa kuti akhale ndi chonyamulira cha munthu, methylene blue inachepetsa kutengedwa kwa chinthu chowala cha fluorescent komanso serotonin yoikidwa chizindikiro, ndi IC50 pafupifupi 1.4 micromolar. Inachepetsanso mafunde amagetsi oyambitsidwa ndi serotonin pamiyeso ya patch-clamp, malinga ndi kafukufuku wachindunji wofotokoza methylene blue pa SERT. Olembawo anafufuza zifukwa zina zoonekeratu zomwe zikanatha kufotokoza zimenezi, ndipo anapeza kuti zotsatirazo sizinkadalira kutumiza mauthenga kwa cGMP, kusintha kwa calcium, kapena kuchuluka kwa zonyamulira pamwamba pa maselo.

Onani kusiyana pakati pa manambala awiriwo. Kuletsa MAO-A kumachitika pa milingo ya nanomolar. Kuletsa chonyamulira kumafuna utoto wochuluka pafupifupi nthawi makumi asanu. Mlingo wochepa womwe umakhudza enzayimuyo mokwanira ungakhudze chonyamuliracho pang’ono kwambiri. Aliyense amene akuphatikiza zimenezi kukhala mfundo imodzi yonena za serotonin akuphatikiza magulu awiri osiyana a milingo kukhala amodzi.

Kaya cholunjika chilichonse mwa ziwirizi chimakhudza munthu amene akumwa mankhwala ena ogwira ntchito pa serotonin ndi funso lokhudza mankhwala, ndipo likuyenera kufotokozedwa mu kalozera wa kuyanjana kwa mankhwala. Nkhaniyi imasonyeza zolunjika; tsamba limenelo limapereka malangizo a zachipatala.

Dopamine: umboni wachindunji wofooka kwambiri

Pa dopamine, kunena zoona kumafuna kudziletsa kwambiri. Palibe kafukufuku wokhazikika bwino wosonyeza kuti methylene blue imaletsa chonyamulira dopamine kapena imamangirira mwachindunji ku zolandirira dopamine. IC50 ya chonyamulira ya 1.4 micromolar yomwe imatchulidwa kawirikawiri ndi ya chonyamulira serotonin, osati DAT, ndipo siyenera kutchulidwa ngati kuti ndi ya DAT.

Umboni womwe ulipo ndi wosalunjika. Chifukwa ma enzayimu a MAO amaphwanyanso dopamine, kuletsa MAO kumasunga dopamine limodzi ndi serotonin ndi noradrenaline. M’zitsanzo za mitochondria, methylene blue inaletsa kusinthidwa kwa MPTP, poizoni wa mitsempha, kukhala poizoni wake wa njira za dopamine komwe kumachitidwa ndi MAO-B. Mphamvu yake inali yofanana ndi ya deprenyl, mankhwala a Parkinson, monga momwe kafukufuku wa kusintha MPTP kukhala yogwira ntchito m’thupi ndi kafukufuku wina wokhudza MAO-B akufotokozera. Kafukufuku wa nyama akuwonjezera umboni wapang’onopang’ono: kuwonjezeka pafupifupi katatu kwa kutulutsidwa kwa dopamine pa mkhalidwe wamba m’magawo odulidwa a striatum ya makoswe pa 10 micromolar, komwe kunafufuzidwa pankhani ya kutumiza mauthenga kwa nitric oxide osati ngati kuletsa chonyamulira. Palinso zotsatira zosiyanasiyana m’madera a ubongo pambuyo popereka mankhwala ofalikira m’thupi lonse, ndipo kafukufuku wina anapeza kuti serotonin ndi noradrenaline zinawonjezeka pamene dopamine sinasinthe kwambiri.

Choncho nkhani ya dopamine ili ndi maziko, koma umboni wake si wachindunji. Imadutsa mu enzayimu yomwe imagwira ntchito pa ma monoamine angapo nthawi imodzi, osati pa cholunjika chapadera cha dopamine. Mawu aliwonse akuti methylene blue imawonjezera dopamine mwa anthu amadumpha sitepe yofunika yosonyeza kuti zimenezo zinatsimikizidwadi.

GABA: kuletsa njira yoletsa mauthenga pamalo omangirira

Zomwe zinapezeka pa GABA n’zomveka bwino ndipo zimasiyana ndi mbiri yomwe utotowu uli nayo. M’maselo okhala ndi zolandirira za GABA-A za munthu, methylene blue inaletsa mafunde amagetsi oyambitsidwa ndi GABA kuyambira pafupifupi 3 micromolar. IC50 inali pafupi ndi 31 micromolar pa kapangidwe kofala ka alpha1-beta2-gamma2, malinga ndi kafukufuku wa magetsi a m’maselo amene anazindikira malo omwe imagwirira ntchito.

Kuzindikira malo amene imagwirira ntchito ndi mbali yofunika kwambiri. Kusintha kwa malo a picrotoxin sikunachepetse kuletsako, ndipo kuyerekezera zigawo za zolandirira kunachotsa kuthekera kwakuti imagwira ntchito pa malo a benzodiazepine ndi zinc. M’malo mwake, kusintha pa zigawo ziwiri za ma amino acid zomwe zimadziwika kuti zimapanga malo omangirira a GABA kunachepetsa kwambiri kuletsako. Izi zimasonyeza kuti imagwira ntchito mwa kupikisana ndi choyambitsa ntchito pa malo ake omangirira, osati mwa kusintha ntchito kuchokera pamalo ena a cholandiriracho. Zotsatirazo zinaonekabe pa mitundu yosiyanasiyana ya zigawo za zolandirira za m’masinapsi ndi zakunja kwa masinapsi, ndipo zinatha mwamsanga utotowo utachotsedwa.

Izi zimabweretsa kusagwirizana kwenikweni komwe kuyenera kunenedwa momveka bwino. Molekyulu yomwe ikufufuzidwa chifukwa chothandiza kukumbukira imachepetsanso kutumiza mauthenga oletsa mwachangu m’chitsanzo cha mu labotale. Kaya kuchepetsako kumachitika mu ubongo wamoyo kumadalira mlingo wa pamalopo, ndipo 31 micromolar ndi wokwera poyerekeza ndi milingo yambiri yofalikira m’thupi lonse, zomwe gawo lomaliza likufotokoza. Kusagwirizanako kokha ndi zomwe kafukufuku wapeza; kuti kuthetsedwe, pangafunike mayesero omwe palibe amene wachitapo.

Acetylcholine: zolunjika ziwiri zogwira mbali zotsutsana

Pa acetylcholine pali zinthu ziwiri zomwe zinapezeka ndipo zimagwira ntchito molowera mbali zotsutsana. Ndicho chifukwa chake ziyenera kufotokozedwa payokha.

Kumbali imodzi, methylene blue imaletsa ma enzayimu omwe amachotsa acetylcholine. Acetylcholinesterase ya maselo ofiira a magazi a ng’ombe inaletsedwa mwa kupikisana pafupifupi pa 0.57 micromolar, enzayimu ya ng’ombe pafupi ndi 0.42 micromolar, ndi ntchito ya esterase ya m’plasma ya munthu pafupi ndi 1.1 micromolar. Butyrylcholinesterase inaletsedwa pa milingo pafupifupi 0.4 mpaka 5.3 micromolar, kutengera mtundu wa nyama ndi momwe chitsanzo chinakonzedwera, monga momwe zafotokozedwera mwachidule mu kuwunika kafukufuku wa ntchito za methylene blue m’njira za mitsempha. Kuchedwetsa kuchotsedwa kumasiya chotumiza mauthenga chochuluka mu sinapsi, mfundo yomwenso mankhwala angapo ovomerezeka a Alzheimer amagwiritsa ntchito.

Koma mmene mankhwalawo alili pali chofunika kuganizira. Mtundu wa buluu womwe uli mu mkhalidwe wa oxidation umaletsa enzayimuyo; mtundu wopanda mtundu womwe uli mu mkhalidwe wa reduction sutero. Kuyika zitsanzo kwa nthawi yaitali komwe kumalola utotowo kulowa mu mkhalidwe wa reduction kumasonyeza kuletsa kochepa chifukwa cha zimenezi zokha. Nambala iliyonse ya mayeso a cholinesterase imakhala ndi chinthu chosadziwika chomwe chingasinthe: kuchuluka kwa utoto womwe unali udakali wabuluu pamene ankayeza.

Kumbali ina, methylene blue imaletsa cholandirira cha nicotinic cha alpha7, chimodzi mwa zolandirira zomwe acetylcholine imagwirira ntchito. Zolandirira za alpha7 za munthu zoikidwa m’maselo a mazira a achule zinaletsedwa ndi IC50 pafupi ndi 3.4 micromolar mwa kuletsa kosapikisana komanso kosadalira voteji, komwe sikunasinthe mphamvu ya choyambitsa ntchito. Ndipo 3 micromolar inathetsa mayankho a masinapsi oyambitsidwa ndi choline m’magawo odulidwa a hippocampus ya makoswe, monga momwe kafukufuku wa cholandirira cha alpha7 akufotokozera. Choncho pa milingo yofanana yotsika ya micromolar, utotowu umasunga chotumiza mauthenga komanso umachepetsa kuyankha kwa chimodzi mwa zolandirira zake. Zotsatira zonse pa kutumiza mauthenga kwa acetylcholine sizingadziwike kuchokera pa chimodzi mwa zomwe zinapezekazo chokha. Kusatsimikizika kumeneku kumagwirizana ndi kafukufuku wochuluka wa Alzheimer, komanso ndi nkhani yokhudzana nayo ya kafukufuku wa kuganiza ndi matenda, koma sikuthetsedwa pano.

Kuyerekezera konse pamalo amodzi

Kusiyana kwa milingo ya mphamvu zitatu za khumi kumalekanitsa cholunjika chomwe chimakhudzidwa mosavuta kwambiri ndi chomwe chimakhudzidwa movuta kwambiri. Kusiyanasiyana kumeneko ndi nkhani yonse m’tebulo limodzi.

Kodi milingo imeneyi imafika ku ubongo?

Nambala ya m’chubu choyesera ilibe tanthauzo popanda nambala ya mlingo womwe umafika m’thupi pambali pake. Pambuyo popereka kamodzi kudzera mumtsempha pafupifupi 1.4 mg pa kg, pakhala malipoti a milingo ya mu plasma ya anthu ya pafupifupi 5 micromolar pa avareji. Mlingo wa 100 mg womwedwa unatulutsa milingo ya m’magazi athunthu pafupi ndi 0.08 micromolar m’kafukufuku wa mtundu womwewo. Kafukufuku wa kufalikira m’thupi mwa makoswe amapeza milingo ya mu ubongo pafupifupi nthawi khumi mpaka makumi awiri kuposa ya m’magazi oyenda. Komabe, imeneyo ndi utoto wonse mu minofu yopukutidwa ndi kusakanizidwa, osati utoto womasuka wa mu mkhalidwe wa oxidation pa sinapsi. Ndipo kumangirira ku mapuloteni a mu plasma pafupi ndi 94 peresenti, limodzi ndi kugawikira kwa utoto m’maselo a magazi, kumachepetsa gawo lomwe limakhala lomasuka.

Poyerekezera ndi tebulo, zimene zikuoneka zimakhala ndi magawo osiyanasiyana, osati kungoti zimachitika kapena sizichitika. Kuletsa MAO-A kumachitika pa milingo yotsika kwambiri kuposa yomwe imapezeka kawirikawiri popereka utotowu kudzera mumtsempha, ndipo n’kotheka malinga ndi mmene mankhwala amagwirira ntchito nthawi iliyonse yomwe utotowo waperekedwa mwanjira imeneyo. Zotsatira pa cholinesterase ndi alpha7 zili m’gulu la milingo yotsika ya micromolar yomwe ingafikiridwe ndi milingo yapamwamba pambuyo popereka kudzera mumtsempha, koma yomwe milingo yamba yomwedwa ingalephere kufikira. IC50 ya GABA-A ya 31 micromolar ili pamwamba pa milingo yambiri yomwe ingayembekezeredwe kufalikira m’thupi lonse, zomwe zimapangitsa kuletsa kumeneku kukhala kovuta kwambiri kunena kuti kukuchitika mwa munthu wathunthu. Mzere uliwonse wa kuyerekezera kumeneku umafuna chenjezo lomwelo: mlingo wofunika ndi wa utoto womasuka, wa mu mkhalidwe wa oxidation, womwe uli kunja kwa maselo pa cholunjikacho, kuchuluka komwe kutenga magazi sikumayeza mwachindunji.

Zomwe siziyenera kutsimikiziridwa

Palibe mzere wa m’tebulo womwe umatsimikizira kuti methylene blue imawonjezera kapena kuchepetsa chotumiza mauthenga chilichonse mwa munthu m’njira yodziwikiratu. Kuletsa enzayimu m’chitsanzo choyeretsedwa, kuletsa chonyamulira m’maselo okulitsidwa mu labotale, ndi kuletsa cholandirira m’gawo lodulidwa, chilichonse chili sitepe imodzi yoyesedwa mosamalitsa kutali ndi zomwe zimachitikadi m’masinapsi. Ndipo gawo la acetylcholine limasonyeza zinthu ziwiri zoona zomwe zimagwira mbali zotsutsana n’kusiya kusatsimikizika. Njira yoyenera yogwiritsira ntchito tsambali ndi kuliona ngati mapu a zolunjika zomwe molekyuluyi yasonyezedwa kuti imagwira, ndi mphamvu yake pa chilichonse yolembedwa, kuti kukambirana za njira zogwirira ntchito kuzidalira zomwe zinayezedwadi. Ponena za momwe zolunjikazi zimayanjanirana ndi mankhwala olembedwa ndi dokotala, kalozera wa kuyanjana kwa mankhwala ndi tsamba lomwe limafotokoza zimenezo, limodzi ndi mfundo zina zochokera ku maziko a mmene mankhwala amagwirira ntchito komanso nkhani yothandizana nayo yofotokoza njira zogwirira ntchito.