Methylene blue nevatakuri vemashoko etsinga: serotonin, dopamine, GABA, neacetylcholine

Chirevo chinowanzotaurwa nezvemethylene blue chinoti inowedzera serotonin, inowedzera dopamine, inodzikamisa GABA, uye inorodza acetylcholine, zvose panguva imwe chete. Chirevo ichocho chinobatanidza zvakawanikwa zvina zvakasiyana murabhoritari sekunge chinhu chimwe chete chinoitika mukati memunhu. Mapepa eongororo ari seri kwacho akayera zvinangwa zvakasiyana, muzvigadziriro zvakasiyana, pazviyero zvine musiyano unenge wakapetwa kane chiuru. Kana wangopatsanura zvinangwa izvi, mufananidzo wacho unova unonakidza zvikuru asiwo unoda kungwarira kupfuura zvinobvumirwa nechirevo ichocho chimwe chete.

Pfungwa inoronga nyaya iyi iri nyore. Morekuru inosunga enzayimu muchubhu yekuedza yaita chinhu chimwe chete: yasunga enzayimu muchubhu yekuedza. Kuti izvi zvinoshandura here huwandu hwemutakuri wemashoko etsinga muuropi hunorarama zvinoenderana nechiyero chinosvika munyama, chimiro chemakemikari chemorekuru painosvika, uye zvimwe zvose zvinoitwa nemorekuru pachiyero chimwe chetecho. Chikamu chimwe nechimwe chiri pasi chinochengeta mibvunzo mitatu iyoyo yakabatanidzwa nezvakawanikwa zvainoreva.

Serotonin: zvinangwa zviviri, zviyero zviviri

Serotonin ine uchapupu hwakasimba kupfuura hwemamwe masisitimu mana aya, uye hunobva pazvinangwa zviviri zvakasiyana zvemamorekuru zvisingafaniri kubatanidzwa.

Chinangwa chekutanga imonoamine oxidase yerudzi A, enzayimu iri mumitochondria inoputsa serotonin. Kushanda kweMAO-A yemunhu yakanatswa kunodzivirirwa nemethylene blue, inosunga zvakasimba, ine Ki iri pedyo ne27 nanomolar, ukuwo MAO-B ichida zviyero zvakakwirira zvikuru isati yakanganiswa, sezvakaratidzwa muongororo yekinetics yakabatanidza dhayi iyi nehuturu hweserotonin. Imwe nhevedzano yeongororo ine hukama yakawana kusarudza kumwe chete uku munyama yepineal gland yemakonzo, umo kuvharwa kweMAO-A kwakawedzera maindole anobva kuserotonin, kwakaderedza 5-HIAA, chigadzirwa chekuputswa kweserotonin, uye kwakashandura kuita kwematatya kwekuzvidzorera panzvimbo yakatwasuka kwakabatana neserotonin, sezvakataurwa muongororo yedhayi dzeredox nemaindole epineal gland. Zvigadziriro zviviri zvakasiyana, nzira imwe chete: kuputswa kushoma, serotonin yakawanda yasara panzvimbo iyo enzayimu ingadai yakaibvisa.

Chinangwa chechipiri mutakuri weserotonin pachawo. Mumasero ane mutakuri wemunhu uyu, methylene blue yakaderedza kutorwa kwechinhu chinotakurwa chinobudisa chiedza chefluorescence uye kweserotonin yakaiswa mucherechedzo, iine IC50 inenge 1.4 micromolar, uye yakadzvinyirira mafambiro emagetsi akakonzerwa neserotonin muzviyero zvepatch-clamp, maererano neongororo yakananga yemethylene blue paSERT. Vanyori vakaongorora dzimwe tsananguro dziri pachena uye vakawana kuti mhedzisiro iyi yaisatsamira pakutumirana mashoko kwecGMP, shanduko dzecalcium, kana huwandu hwevatakuri vari pamusoro pesero.

Cherechedza musiyano pakati penhamba mbiri idzi. Kudzivirirwa kweMAO-A kunoitika pazviyero zvenanomolar. Kudzivirirwa kwemutakuri kunoda dhayi yakawanda inenge yakapetwa kamakumi mashanu. Chiyero chakaderera chinobata enzayimu zvizere chinogona kusatombokanganisa mutakuri zvakanyanya. Munhu anobatanidza izvi muchirevo chimwe chete nezveserotonin ari kuenzanisa mitsara miviri yakasiyana yezviyero kuita mumwe chete.

Kuti chimwe chezvinangwa izvi chine basa here mumunhu ari kutora mimwe mishonga inokanganisa serotonin mubvunzo wemishonga, uye unofanira kukurukurwa mugwaro rekudyidzana kwemishonga. Nyaya ino inoratidza zvinangwa; peji iroro ndiro rinopa mazano ekurapa.

Dopamine: uchapupu hwakananga husina kusimba kupfuura humwe

Panyaya yedopamine, kutendeseka kunoda kuzvidzora zvakanyanya. Hapana ongororo yakasimbiswa zvakanaka inoratidza methylene blue ichivhara mutakuri wedopamine kana kusunga zvinogamuchira zvedopamine zvakananga. IC50 yemutakuri ye1.4 micromolar inowanzotaurwa ndeyemutakuri weserotonin, kwete DAT, uye haifaniri kumbopiwa zita idzva.

Zviripo panzvimbo pazvo hazvina kunanga. Sezvo maenzayimu eMAO achiputsawo dopamine, kudzivirirwa kweMAO kunochengetedza dopamine pamwe chete neserotonin nenoradrenaline. Muzvigadziriro zvemitochondria, methylene blue yakavhara kushandurwa kweMPTP, chinhu chine huturu kutsinga, ichiita huturu hunokuvadza hurongwa hwedopamine kuburikidza neMAO-B, iine simba rakaenzana neremushonga weParkinson unonzi deprenyl, sezvinotsanangurwa neongororo yekushandurwa kweMPTP kuita huturu mumuviri pamwe nebasa rine hukama paMAO-B. Ongororo pamhuka dzinowedzera zvimwe zvidimbu zveuchapupu: kuburitswa kwedopamine kwepakutanga kwakakwira kanenge katatu muzvidimbu zvestriatum yemakonzo pa10 micromolar, zvichiongororwa mumamiriro ekutumirana mashoko kwenitric oxide kwete sekuvharwa kwemutakuri, uye mhedzisiro yakasiyana munzvimbo dzakasiyana mushure mekupiwa chiyero chinopararira mumuviri, nedzimwe ongororo dzichiwana serotonin nenoradrenaline zvichikwira asi dopamine isinganyanyi kuchinja.

Saka nyaya yedopamine ndeyechokwadi asi inobva pane zvisina kunanga. Inofamba kuburikidza neenzayimu inobata mamonoamine akati wandei panguva imwe chete, kwete kuburikidza nechinangwa chakanangana nedopamine chete. Chirevo chipi nechipi chekuti methylene blue inowedzera dopamine muvanhu chinodarika nhanho iyo izvi zvingadai zvakaratidzwa.

GABA: kuvhara chinononotsa panzvimbo yekusungira

Zvakawanikwa paGABA zvakanyatsojeka uye zvinopesana nemukurumbira wedhayi iyi. Mumasero ane zvinogamuchira zveGABA-A zvemunhu, methylene blue yakadzivirira mafambiro emagetsi akakonzerwa neGABA kutangira panenge 3 micromolar, iine IC50 iri pedyo ne31 micromolar pakubatanidzwa kunowanzoitika kwealpha1-beta2-gamma2, muongororo yemagetsi emumasero yakaratidza nzvimbo yainoshanda.

Kuratidzwa kwenzvimbo yacho ndicho chikamu chakakosha. Shanduko dzemajini panzvimbo yepicrotoxin hadzina kuchinja kudzivirirwa uku, uye kuenzaniswa kwezvikamu zviduku zvechinogamuchira kwakaratidza kuti nzvimbo dzebenzodiazepine nezinc dzaisava dziri kukonzera izvi. Panzvimbo pezvo, shanduko pamasara maviri emaamino acid anozivikanwa kuti anoumba nzvimbo yekusungira GABA pachayo dzakaderedza kuvharwa zvakanyanya. Izvi zvinoratidza kuti kushanda kwacho kukwikwidzana nechinhu chinosimudzira chinogamuchira panzvimbo yacho, kwete kugadziriswa kwekushanda nekusunga pane imwe nzvimbo. Mhedzisiro iyi yakaramba iripo mumibatanidzwa yezvikamu zviduku inowanikwa pamasinapsi nekunze kwawo, uye yakapera nokukurumidza pakabviswa dhayi nekugezwa.

Izvi zvinogadzira kupesana kwechokwadi kwakakodzera kutaurwa pachena. Morekuru iri kuongororwa kuti inogona kutsigira ndangariro inodzvinyirirawo kutumirwa kunokurumidza kwemashoko anoderedza kushanda kwetsinga mundiro yekuedza. Kuti kudzvinyirirwa ikoko kunoitika muuropi hunorarama zvinoenderana nechiyero chiripo panzvimbo yacho, uye 31 micromolar yakakwirira kana ichienzaniswa nezviyero zvizhinji zvinosvika mumuviri wose, izvo zvinokurukurwa muchikamu chekupedzisira. Kupesana kwacho pachako ndiko kwakawanikwa; kukugadzirisa kungada ongororo dzisina munhu ati aita.

Acetylcholine: nzira mbiri dzinopesana

Paacetylcholine pane zvakawanikwa zviviri zvinonanga kumativi anopesana, ndicho chikonzero chaicho nei zvichifanira kutaurwa zvakasiyana.

Kune rimwe divi, methylene blue inodzivirira kushanda kwemaenzayimu anobvisa acetylcholine. Acetylcholinesterase iri mumasero matsvuku eropa remombe yakadzivirirwa nenzira yekukwikwidzana panenge 0.57 micromolar, enzayimu yemombe pedyo ne0.42 micromolar, uye kushanda kweesterase muplasma yemunhu pedyo ne1.1 micromolar. Butyrylcholinesterase yakadzivirirwa pazviyero zvinotangira panenge 0.4 kusvika 5.3 micromolar zvichienderana nerudzi rwemhuka nezvigadziriro, sezvakapfupikiswa muongororo yemashandiro emethylene blue muhurongwa hwetsinga. Kunonotsa kubviswa kunosiya mutakuri wemashoko wakawanda musinapsi, pfungwa imwe chete iri seri kwemishonga yakati wandei yakatenderwa yeAlzheimer.

Asi mashandiro emakemikari aya ane chinodiwa chakabatana nawo. Chimiro chebhuruu chiri muoxidized state chinodzivirira enzayimu; chimiro chisina ruvara chiri mureduced state hachidaro. Uye nguva refu dzekusiya musanganiswa wakagadzirirwa kuedzwa, dzinobvumira dhayi kupinda mureduced state, dzinoratidza kudzivirirwa kushoma nokuda kwechikonzero ichocho chete. Nhamba ipi neipi yemuedzo wecholinesterase ine chinhu chinoshanduka chisingaonekwi: kuti dhayi yakawanda sei yakanga ichiri yebhuruu payakayerwa.

Kune rimwe divi, methylene blue inovhara chinogamuchira chenicotinic chealpha7, chimwe chezvinogamuchira zvinoshandirwa neacetylcholine. Zvinogamuchira zvealpha7 zvemunhu zvakaiswa mumasero emazai asati akura ematatya zvakadzivirirwa neIC50 iri pedyo ne3.4 micromolar kuburikidza nekudzivirira kusingakwikwidzani uye kusingatsamiri pamagetsi ari pamembrane, kusingachinji simba rechinhu chinosimudzira chinogamuchira. Uye 3 micromolar yakabvisa mhinduro dzemasinapsi dzakakonzerwa necholine muzvidimbu zvehippocampus yemakonzo, sezvinotaurwa neongororo yechinogamuchira chealpha7. Saka pazviyero zvakafanana zvakaderera zvemicromolar, dhayi inochengetedza mutakuri wemashoko uku ichideredza kushanda kwechimwe chezvinogamuchira zvawo. Mhedzisiro yose pakutumirana mashoko kweacetylcholine haigoni kutorwa kubva pane chimwe chete chezvakawanikwa izvi. Kusajeka uku kwakabatana nezvinyorwa zvakakura zveongororo dzeAlzheimer, uye nehurukuro ine hukama yeongororo dzekufunga nezvirwere, asi hakugadziriswi pano.

Kuenzanisa, panzvimbo imwe chete

Pane musiyano wezviyero zvine simba regumi rakapetwa katatu pakati pechinangwa chinonyanya kunzwa nechinonzwa zvishoma kupfuura zvimwe. Kupararira ikoko ndiko kuri kupfupikiswa nenyaya iyi mutafura imwe chete.

Zviyero izvi zvinosvika muuropi here?

Nhamba yemuchubhu yekuedza haina chainoreva kana pasina nhamba yechiyero chinosvika mumuviri padivi payo. Mushure mekupinzwa kamwe chete mutsinga kwechiyero chiri pedyo ne1.4 mg per kg, avhareji yezviyero muplasma yevanhu inenge 5 micromolar yakataurwa, ukuwo chiyero che100 mg chakatorwa nemuromo chakabudisa zviyero muropa rose zviri pedyo ne0.08 micromolar munhevedzano imwe chete yezvinyorwa zveongororo. Ongororo yekupararira mumuviri wemakonzo inowana zviyero muuropi zvakapetwa kanenge kagumi kusvika kamakumi maviri pane zviri muropa riri kutenderera. Zvisinei, izvi zvinoreva dhayi yose munyama yakapwanywa ikasanganiswa, kwete dhayi yakasununguka iri muoxidized state pasinapsi. Kusungwa nemapuroteni eplasma kunenge 94 percent pamwe nekuparadzana kwayo pakati pemasero eropa nedzimwe nzvimbo kunoderedza chikamu chakasununguka.

Kana zvichienzaniswa netafura, mufananidzo wacho une nhanho dzakasiyana pane kungova hongu kana kwete. Kudzivirirwa kweMAO-A kunoitika pazviyero zviri pasi zvikuru pezvinowanzosvika mushure mekupiwa mutsinga, uye kunonzwisisika maererano nekushanda kwemishonga pose panopiwa dhayi nenzira iyoyo. Mhedzisiro pacholinesterase nealpha7 iri mumutsara wezviyero zvakaderera zvemicromolar unopindirana nezviyero zvepamusoro zvinosvikwa mushure mekupiwa mutsinga, asi zviyero zvakajairika zvinotorwa nemuromo zvingasasvika pairi. IC50 yeGABA-A ye31 micromolar iri pamusoro pezviyero zvizhinji zvinofungidzirwa kuti zvinogona kusvika mumuviri wose, zvichiita kuti kuvharwa uku kuve kwakaoma zvikuru kunzi kunoitika mumunhu wose. Mutsara mumwe nomumwe wekuenzanisa uku unoda yambiro imwe chete: chiyero chinokosha ndechedhayi yakasununguka, iri muoxidized state, iri kunze kwemasero panzvimbo yechinangwa, huwandu husingayerwi zvakananga nekutorwa kweropa kupi nokupi.

Zvisingafaniri kugumiswa

Hapana mutsara mutafura unosimbisa kuti methylene blue inowedzera kana kuderedza chero mutakuri wemashoko etsinga mumunhu nenzira inogona kufanotaurwa. Kudzivirirwa kweenzayimu muchigadziriro chakanatswa, kuvharwa kwemutakuri mumutsara wemasero akarerwa murabhoritari, uye kudzivirirwa kwechinogamuchira muchidimbu chenyama, chimwe nechimwe inhano imwe inodzorwa iri kure nezvinoitika chaizvo pamasinapsi. Chikamu cheacetylcholine chinoratidza zvakawanikwa zviviri zvechokwadi zvichipesana zvichisiya kusava nechokwadi. Kushandisa peji rino zvine mutoro kuriita mepu yezvinangwa zvakaratidzwa kuti morekuru inosunga, simba rekusunga richinyorwa, kuitira kuti hurukuro yemaitiro ekushanda irambe yakasungirirwa kune zvakayerwa chaizvo. Kuti zvinangwa izvi zvinodyidzana sei nemishonga yakanyorerwa nemupi wehutano, gwaro rekudyidzana kwemishonga ndiro peji rinotakura mutoro iwoyo, pamwe nerumwe ruzivo mune zvinokosha zvekushanda kwemishonga nemutsananguri ane hukama wemaitiro ekushanda.