Methylene blue nechirwere cheParkinson: humbowo hwekutsvakurudza kusati kwaitwa muvanhu uye kwemakiriniki

Tsvaga nezvemethylene blue nechirwere cheParkinson uye uchawana zvirevo zvinotaurwa nechivimbo asi zvakavakirwa pahumbowo hushoma. Chidzidzo chemakonzo apa, muyedzo wemasero apo, chimwe nechimwe chichiratidzwa sokunge nzira yekurapa yava pedyo. Chokwadi chacho chine muganhu wakakura uye chinonyanya kufadza. Pane tsvakurudzo chaiyo yakanangana neParkinson, yakanyanya kutarisisa kuchengetedzwa kwemitochondria, asi ichiri kure zvikuru nekupa humbowo muvanhu. Chinyorwa chino chinoronga tsvakurudzo iyoyo chidzidzo nechidzidzo, kuti uone chaizvo zviripo nezvisipo.

Chikonzero nei vatsvakurudzi vachiramba vachidzokera kumushonga uyu chiri nyore kunzwisisa. Masero etsinga anobudisa dopamine ari musubstantia nigra anoshandisa simba rakawanda zvikuru, uye kukundikana kwecomplex I pamwe nekushushikana kunokonzerwa neoxidation zviri pakati pezvinhu zvinokosha mumamodheru mazhinji eParkinson. Methylene blue idhayi rinotenderera pakati pekugamuchira nekupa maerekitironi, richikwanisa kutora maerekitironi kubva kuNADH roaendesa kucytochrome c, richinzvenga chikamu checomplex I yakakuvadzwa uye richideredza kushushikana kunokonzerwa neoxidation. Mashandiro emitochondria ari seri kwekutakurwa uku ndiwo anobatanidza miedzo yese yeParkinson iri pasi apa. Zvakakosha kunzwisisa kuti kutakurwa uku kunoitika sei mukati memasero nemuzvipenyu zvakazara usati watonga mhedzisiro imwe chete. Vaverengi vasati vajaira mushonga uyu vanofanira kutanga nekuverenga mashandiro emethylene blue mumasero. Ramba uchifunga nezvemashandiro iwayo. Anotsanangura zvose zvinopa tariro nenzvimbo dzinoperera humbowo.

Chidzidzo chekuchengetedzwa kwestriatum

Muyedzo wakajeka zvikuru une chekuita neParkinson wakapinza rotenone, muchetura unokanganisa complex I, zvakananga mustriatum yemakonzo, paine kana pasina methylene blue munzvimbo iyoyo. Rotenone yoga yakakonzera nzvimbo huru dzakakuvadzwa dzakafananidzwa nevanyori nesitiroko dzinobva mukukanganisika kwekushandiswa kwesimba. Dhayi rakapinzwawo panguva imwe chete rakaderedza vhoriyamu yenzvimbo yakakuvadzwa nehafu, rakachengetedza kushanda kwecytochrome oxidase, uye rakadzivirira kuwedzera kwekushushikana kunokonzerwa neoxidation munzvimbo dzakatenderedza pakakuvadzwa. Rakachengetedzawo kushandiswa kwesimba munzvimbo dzakabatana dzinodzora kufamba, kusanganisira substantia nigra nepedunculopontine nucleus, rakachengetedza kubatana kwekushanda pakati penzira dzebasal ganglia, uye rakaderedza zvishoma kusafanana kwekunzwa nekufamba pakati pemativi emuviri.

Pane zvinhu zviviri zvinokosha zvinoganhurira kududzirwa kwemhedzisiro iyi. Chekutanga, dhayi rakapiwa pamwe chete nemuchetura, kwete mushure mekunge kukuvara kwatoitika, saka uku kudzivirira munzvimbo yakafanana nemuyedzo wemurabhoritari pane kuva kurapa chirwere. Chechipiri, methylene blue haina kudzorera kushanda kwecomplex I mumitochondria yakaparadzaniswa. Kudzivirirwa kwakabva mukuderedzwa kweoxidation uye kutsigirwa kwekushandiswa kwesimba munzvimbo yakatenderedza pakakuvadzwa, kwete mukugadziriswa kwecomplex yacho yakakuvadzwa. Musiyano iwoyo unooneka muzvinyorwa zvese zvetsvakurudzo.

Zvidzidzo zvekuchengetedzwa kwedopamine

Modheru yemakonzo yaishandisa muchetura waipararira mumuviri wose yakaswedera pedyo nezvinoitika muchirwere cheParkinson chaicho. Rotenone yaipinzwa nepombi diki yakaderedza dopamine mustriatum uye ikauraya masero etsinga anobudisa dopamine musubstantia nigra, uku methylene blue yaipiwa pamwero mudiki panguva imwe chete yakapotsa yadzorera dopamine yose uye yakaderedza zvikuru kurasika kwemasero etsinga, kuvharirwa kwecomplex I-III, marudzi eoxygen anokurumidza kuita makemikari, uye kutadza mumiedzo yekugara patsvimbo inotenderera, mafambiro, nekugara kwemuviri wakaomarara usingafambi (PMID 21454572). Chidzidzo chechipiri chemakonzo aishandisa rotenone, nemishonga yaipiwa pasi peganda, chakawana kuderera kwelipid peroxidation, gliosis, TNF-alpha, necaspase-3 kwaienderana nemwero waipiwa, uye mwero mukuru ndiwo wakanyanya kuchengetedza kupendwa kwetyrosine hydroxylase. Mumitochondria, methylene blue pamwero wenanomolar yakawedzera hydrogen peroxide sechiratidzo chehormesis, kureva kupindura kunobatsira pakushushikana kudiki, isina kukuvadza DNA yemitochondria; uye kuipiwa muchetura usati washandiswa kwakadzivirira mitochondria yechikamu chezasi cheuropi hwepakati kubva pakukuvadzwa kwemtDNA kunokonzerwa nerotenone.

Tsvakurudzo yeMPTP mumbeva inoratidza nzira imwe chete, asi ine ganhuriro yakanyanya kukosha. Kupiwa methylene blue pamwero we20 mg/kg/day muchetura usati washandiswa kwakachengetedza masero etsinga enzira yenigrostriatal nedopamine yemustriatum, paine zviratidzo zvekuti kutumirana mashoko kweBDNF kwaibatanidzwa (PMID 29882218). Chidzidzo cheMPTP/probenecid chaiitwa kwenguva refu chakapa humbowo hunonyengetedza kupfuura ipapo: chakatanga kupa methylene blue nemuromo mushure mekunge kutadza kunzwa hwema kwaoneka, asi zvakadaro chakavandudza kunzwa hwema, kurongeka kwekufamba, nekupona kwemasero etsinga anobudisa dopamine (PMID 29684508). Chinokosha zvikuru ndechekuti boka iroro rakaita muyedzo wekuenzanisa unokumbirwa nevanopokana, uye rakaratidza kuti mwero mudiki hauna kuderedza MPP+, chinhu chine muchetura chinobva mukushandurwa kweMPTP, mustriatum. Izvi zvinobvisa tsananguro iri nyore zvikuru yekuti mhedzisiro yakangobva pamaitirwo emuyedzo. Basa remumasero etsinga anobudisa dopamine akapiwa MPP rinowedzera tsananguro yemashandiro: kudzorerwa kwekushanda kwecomplex I neATP pamwe nekutumirana mashoko kweAKT-Nrf2 kunorwisa oxidation (PMID 34352280), pamwe nekunyorwa kwejini reparkin kunotungamirirwa neNRF2 uye kudzorerwa kwekuumbwa kwemitochondria mitsva mumodheru yekushushikana kwenguva refu.

Modheru yemakonzo ye6-OHDA, inozivikanwa nekukonzera kukuvara kudivi rimwe chete, inopa mhedzisiro ine pundutso diki zvikuru. Methylene blue yaipiwa nemuromo zuva nezuva, ichitangwa mushure mekuvhiyiwa, yakachengetedza zvishoma masero etsinga anobudisa dopamine musubstantia nigra uye yakavandudza zvimwe zvinhu zvekukwanisa kutarisisa, asi haina kudzorera kufamba kana kushanda kwemakumbo epamberi (PMID 28694175). Pundutso diki iyi inodzidzisa. Mushonga unonzi unogadzirisa zvese mumodheru yese unowanzova usingagadzirisi chinhu. Pano, pundutso inosiyana sezvinowanzoita mashandiro chaiwo ezvipenyu.

Bazi realpha-synuclein

Zvakasiyana nebasa remuchetura, chirongwa chemethylthioninium iri muchimiro chakagamuchira maerekitironi chakaedza kuona kana mushonga wacho uchikanganisa kuungana kwealpha-synuclein pachako. Mumasero aibudisa alpha-synuclein yemunhu, chimiro ichi chakabvisa miunganidzwa yepakutanga neiya yakaita setambo, paEC50 iri pedyo ne1 micromolar; uye kuipiwa nemuromo kwemavhiki matanhatu kwakaderedza kukuvara kunoenderana nechirwere munzvimbo dzakasiyana dzeuropi, kuchigadzirisawo mafambiro asina kujairika mumbeva dzakashandurwa majini (PMID 29375308). Chidzidzo chakatevera mune rimwe boka rembeva dzakashandurwa majini chakawana alpha-synuclein iri panosangana masero etsinga yadzokera pamwero wembeva dzisina kuchinjwa majini, uye kusagadzikana kwema receptor eglutamate kwagadziriswa, kunyange hazvo pakanga pasina mhedzisiro inonyengetedza pamaitiro adzo (PMID 35709886).

Cherechedza kuchinjwa kwechinhu chakashandiswa. Zvidzidzo izvi zvakashandisa LMTM/HMTM, munyu wakagadzikiswa uri muchimiro chakagamuchira maerekitironi wakagadzirirwa chirongwa cheAlzheimer, kwete chloride iri muchimiro chakabvisa maerekitironi inotengeswa sedhayi. Kushanda kwechimwe chimiro hakungorevi kuti chimwe chinoshandawo, musiyano unotsanangurwa zvakadzama nehumbowo hwemiedzo yeAlzheimer.

Zvikonzero zvitatu zvekuverenga mhedzisiro yega yega kaviri

Chekutanga, pamiedzo inenge yese, mushonga unopiwa pamwe chete nemuchetura kana kuti muchetura usati wapiwa. Dhayi rinenge riripo muchetura usati wavapo kana panguva imwe chete nawo. Izvi zvinoedza kuona kana kutsigira mitochondria kuchigona kudzivirira kukuvara, uye iyi itsvakurudzo yesainzi yakakodzera, asi hazvimiririri murwere anotanga mushonga wekuwedzera mushure memakore achirasikirwa nemasero etsinga.

Chechipiri, methylene blue inovharira enzayimu yacho inoita kuti MPTP ive nemuchetura. MPTP haisati yakuvadza kusvikira MAO-B yaishandura kuva MPP+. Methylene blue inoderedza kushandurwa ikoko pamwero wenanomolar, saka kudzivirirwa kunooneka muchidzidzo cheMPTP kungareva kuti muchetura hauna kumbobvira waitwa kuti ukwanise kukuvadza, pane kuti masero etsinga akachengetedzwa. Chidzidzo chenguva refu chiri pamusoro chinoramba chine humbowo kunyangwe paine kupokana uku, nekuti chakaita muyedzo wekuenzanisa weMPP+. Zvidzidzo zvisina muyedzo iwoyo hazvigoni kubvisa kupokana uku.

Chechitatu, kukuvara kunokonzerwa nemuchetura hakusi chirwere cheParkinson. Rotenone, MPTP, ne6-OHDA zvinonyatsotevedzera kurasika kwedopamine nekushushikana kunokonzerwa neoxidation, asi hazvitevedzeri kufambira mberi kwemakumi emakore, kupararira kwekukanganisika kwesynuclein, kana kuchinjwa kwenzira dzetsinga kunoitika muchirwere chemunhu. Kuchengetedzwa kwemhuka chikonzero chekuita miedzo, kwete kufanozivisa mhedzisiro yayo.

Humbowo muvanhu: hahusati hwavapo

Kusvika muna 2026, hapana muyedzo wakabudiswa wakagovera vanhu mumapoka zvisina kurongwa, uye hapana muyedzo uri kuenderera mberi wakanyoreswa wekuedza methylene blue, LMTM, kana HMTM pakurapa chirwere cheParkinson. Ongororo ichangobva kuitwa yenzira dzekurapa yakanyora kuti paive nemiedzo yeParkinson yakabudiswa inosvika zero uye iri kuenderera mberi inosvika zero. Zvirongwa zvakanyoreswa zveLMTM/HMTM zviri pachirwere cheAlzheimer nefrontotemporal dementia yerudzi runonyanya kukanganisa maitiro, uye mhedzisiro yazvo haigoni kungoshandiswa kuParkinson. Ani naani ari kutengesa methylene blue yezviratidzo zveParkinson nhasi ari kufungidzira kubva pamakonzo nemasero. Kufungidzira kwakadaro kwakakundikana pazvinhu zvizhinji zvaifungidzirwa kuti zvinodzivirira masero etsinga, zvainge zvatoratidza tariro yakakura kupfuura ichi.

Nyaya dzekuchengeteka dzakanangana nevarwere veParkinson

Chikamu chino hachisi kungoyambira pamusoro penjodzi dzakajairika. Chinotaura nezvekudyidzana nemishonga inotorwa chaizvo nevarwere veParkinson. Methylene blue pachayo inovharira MAO-A zvine simba asi nenzira inogona kudzokera kumashure, uye inovharirawo MAO-B pamwero yakakwirira. Rasagiline, selegiline, nesafinamide mishonga inovharira MAO-B ine mirayiridzo inorambidza kana kuyambira pamusoro pekuisanganisa nemimwe mishonga inovharira MAO, nekuti kuvharirwa kunopindirana kunowedzera njodzi yekukuvadza kunokonzerwa neserotonin uye kukwira kwakanyanya kweBP. Kuwedzera methylene blue pachirongwa chakadaro kunokonzera kudyidzana kwemishonga kunokosha pakurapa, uye hapana humbowo hweParkinson hunoratidza kuti zvimiro zveLMTM/HMTM zvakagamuchira maerekitironi zvinodzivisa kudyidzana uku.

Kudyidzana nemishonga yekuora mwoyo inoshanda paserotonin kwakanyorwa muvanhu. Muongororo yakarongeka yezviitiko zvekuvhiringidzika kwepfungwa mushure mekupinzwa kwemethylene blue mumuviri, 25 pazviitiko 26 zvakaitika muvarwere vaitora mushonga wekuora mwoyo unoshanda paserotonin, uye zvigadzirwa zvemethylene blue zvinotorwa nemuromo zvakakonzerawo zviitiko zvakashumwa zveserotonin syndrome. Kuora mwoyo kunowanikwa kazhinji muchirwere cheParkinson uye kunowanzorapwa nemaSSRI kana maSNRI, saka kudyidzana uku kungangoitika zvakanyanya pano kupfuura mumapoka mazhinji evanhu. Tsananguro yakazara yekuchengeteka nekudyidzana kwemishonga pamwe nekuongorora tsvakurudzo yakafara yemakiriniki zvinobatsira kunzwisisa njodzi idzi. Ani naani ari kufunga nezvemethylene blue pamwe nemishonga yeParkinson kana yekuora mwoyo anoda kutarisirwa nenyanzvi yezvekurapa asati aedza chero chinhu, kwete mushure mekunge zviratidzo zvaoneka.

Mhedziso inogona kupfupikiswa murondedzero imwe. Mamodheru emuchetura nesynuclein anoratidza kudzivirirwa kwemitochondria nedopamine kunoramba kuchionekwa, nemhedzisiro inoshanduka zvechokwadi zvichienderana nemwero waipiwa; zvinhu zvitatu zvadomwa zvinogona kukanganisa dudziro zvinoganhurira mhedzisiro yese yeMPTP neyekupiwa mushonga pamwe nemuchetura; uye humbowo hwekushanda muvanhu hunomira pamiedzo zero. Icho chirongwa chetsvakurudzo chakakodzera kuteverwa, kwete nzira yekurapa yakakodzera kutengwa.