I-methylene blue nesifo sikaParkinson: ubufakazi bocwaningo lwangaphambi kolwabantu nolwasemtholampilo

Uma usesha nge-methylene blue nesifo sikaParkinson, uzothola izimangalo ezishiwo ngokuzethemba kodwa ezisekelwe ebufakazini obubuthakathaka. Ucwaningo lwamagundane lapha, ukuhlolwa kwamaseli laphaya, ngakunye kwethulwa sengathi ukwelashwa sekuseduze. Iqiniso lilinganiselwe kakhulu futhi lithakazelisa nakakhulu. Lukhona ucwaningo lwangempela oluqondene nesifo sikaParkinson, lugxile ekuvikeleni ukusebenza kwama-mitochondria, futhi alukasondeli ebufakazini obuqinisekisiwe kubantu. Lesi sihloko sihlela lolo cwaningo ngalunye, ukuze ubone kahle ukuthi yini ekhona nokuthi yini engekho.

Isizathu esenza abacwaningi baqhubeke bebuyela kule nhlanganisela yamakhemikhali sicacile. Amaseli ezinzwa akhiqiza i-dopamine ku-substantia nigra adinga amandla amaningi kakhulu, futhi ukwehluleka kwe-complex I kanye nokucindezeleka okubangelwa yi-oxidation kuyizici ezisemqoka kumamodeli amaningi esifo sikaParkinson. I-methylene blue iwudayi ojikeleza phakathi kwezimo ze-redox, ongathatha ama-electron ku-NADH uwadlulisele ngase-cytochrome c, udlule ngokwengxenye ku-complex I eyonakele futhi unciphise ukucindezeleka okubangelwa yi-oxidation. Indlela yama-mitochondria esekela lokhu kudluliswa iyona exhumanisa konke ukuhlolwa okuphathelene noParkinson okungezansi. Kufanele uqonde ukuthi lokhu kudluliswa kusebenza kanjani ngaphakathi kwamaseli nasezidalweni eziphelele ngaphambi kokwahlulela umphumela owodwa. Abafundi abangakayijwayeli le nhlanganisela kufanele baqale ngokufunda ukuthi i-methylene blue isebenza kanjani ezingeni lamaseli. Gcina lowo mfanekiso engqondweni. Uchaza kokubili ithemba elikhona nezindawo lapho le ndaba ingasasekelwa khona ubufakazi.

Ucwaningo lokuvikela i-striatum

Ukuhlolwa okulawulwe kahle kakhulu okuphathelene noParkinson kwafaka i-rotenone, ubuthi obuthinta i-complex I, ngqo ku-striatum yamagundane, kuhambisana ne-methylene blue efakwe kuleyo ndawo noma kungahambisani nayo. I-rotenone iyodwa yakha izindawo ezinkulu zomonakalo ababhali abazifanisa nokushaywa unhlangothi okubangelwa ukuphazamiseka kwe-metabolism. Udayi owafakwa kanye nayo wanciphisa umthamo wendawo eyonakele cishe ngesigamu, wagcina ukusebenza kwe-cytochrome oxidase, futhi wavimbela ukwanda kokucindezeleka okubangelwa yi-oxidation ezungeze indawo eyonakele. Waphinde wagcina ukusebenza kwe-metabolism ezindaweni ezixhumene ezilawula ukunyakaza, kuhlanganise ne-substantia nigra ne-pedunculopontine nucleus, wagcina ukuxhumana okusebenzayo phakathi kwemijikelezo ye-basal ganglia, futhi wanciphisa ngokwengxenye ukungalingani kokuzwa nokunyakaza phakathi kwezinhlangothi.

Kunemikhawulo emibili ebalulekile. Okokuqala, udayi wanikezwa kanye nobuthi, hhayi ngemva kokuba umonakalo usukhona, ngakho lokhu kuwukuvimbela esimweni esifana nokuhlolwa esitsheni saselabhorethri kunokuba kube ukwelapha isifo. Okwesibili, i-methylene blue ayizange ibuyisele ukusebenza kwe-complex I kuma-mitochondria ahlukanisiwe. Ukuvikelwa kwavela ekusekelweni kokulwa ne-oxidation kanye ne-metabolism ezungeze indawo eyonakele, hhayi ekulungiseni i-complex eyonakele uqobo. Lo mehluko ubonakala kuzo zonke izincwadi zocwaningo.

Ucwaningo lokuvikela i-dopamine

Imodeli yamagundane lapho ubuthi busabalala khona emzimbeni wonke yasondela kakhulu ekushintsheni kwezicubu okubonakala esifweni sangempela sikaParkinson. I-rotenone eyanikezwa ngephampu encane yanciphisa i-dopamine ku-striatum futhi yabulala amaseli ezinzwa akhiqiza i-dopamine ku-substantia nigra, kuyilapho ukunikezwa kanyekanye kwe-methylene blue ngomthamo ophansi kwabuyisela amazinga e-dopamine cishe ngokuphelele futhi kwanciphisa kakhulu ukulahleka kwamaseli ezinzwa, ukuvinjelwa kwe-complex I-III, izinhlobo ze-oksijini ezisabela kalula, kanye nokungasebenzi kahle ekuhlolweni kwe-rotarod, indlela yokuhamba, ne-catalepsy (PMID 21454572). Ucwaningo lwesibili lwamagundane olusebenzisa i-rotenone nokunikezwa ngaphansi kwesikhumba lwathola ukuncipha kwe-lipid peroxidation, i-gliosis, i-TNF-alpha, ne-caspase-3 okuhambisana nomthamo, futhi umthamo ophakeme kakhulu wagcina kangcono ukubonakala kwe-tyrosine hydroxylase ngokudaywa kwezicubu. Ezingeni lama-mitochondria, i-methylene blue esezingeni le-nanomolar yakhuphula i-hydrogen peroxide njengesignali ye-hormesis ngaphandle kokulimaza i-DNA yama-mitochondria, futhi ukunikezwa kwayo kusengaphambili kwavikela ama-mitochondria engxenye engezansi ye-midbrain emonakalweni we-mtDNA obangelwa yi-rotenone.

Ucwaningo lwe-MPTP kumagundane amancane lukhomba ohlangothini olufanayo, kodwa lunombandela oqaphelekayo nakakhulu. Ukunikezwa kusengaphambili kwe-20 mg/kg/day kwagcina amaseli ezinzwa e-nigrostriatal kanye ne-dopamine ku-striatum, futhi kwatholakala ukuthi ukudluliswa kwezimpawu nge-BDNF kwakuhilelekile (PMID 29882218). Okukholisa kakhulu, ucwaningo lwe-MPTP/probenecid lwesikhathi eside lwaqala ukunikeza i-methylene blue ngomlomo kuphela ngemva kokuvela kokuphazamiseka kokuzwa iphunga, kodwa noma kunjalo lwathuthukisa ukuzwa iphunga, ukuxhumanisa ukunyakaza, nokuphila kwamaseli ezinzwa akhiqiza i-dopamine (PMID 29684508). Okubaluleke kakhulu, lelo thimba lenza ukuhlolwa kokulawula okufunwa abagxeki futhi labonisa ukuthi umthamo ophansi awuzange wehlise i-MPP+ ku-striatum, okuwumkhiqizo we-metabolism onobuthi, ngaleyo ndlela likhipha incazelo elula kakhulu yomphumela odukisayo wokuhlola. Ucwaningo lwamaseli ezinzwa akhiqiza i-dopamine aphathwe nge-MPP lwengeza imininingwane yendlela yokusebenza: ukubuyiselwa kokusebenza kwe-complex I ne-ATP kanye nokudluliswa kwezimpawu zokulwa ne-oxidation nge-AKT-Nrf2 (PMID 34352280), kanye nokuloba kofuzo lwe-parkin okuqhutshwa yi-NRF2 nokubuyiselwa kokwakheka kwama-mitochondria amasha kumodeli yokucindezeleka kwesikhathi eside.

Imodeli yegundane ye-6-OHDA, imodeli yakudala yokulimala ohlangothini olulodwa, inikeza umphumela olinganiselwe kakhulu. I-methylene blue enikezwa ngomlomo nsuku zonke, eyaqalwa ngemva kokuhlinzwa, yagcina kancane amaseli ezinzwa akhiqiza i-dopamine ku-substantia nigra futhi yathuthukisa ezinye izici zokunaka, kodwa ayizange ibuyisele ukusebenza kokunyakaza noma kwezidladla zangaphambili (PMID 28694175). Umphumela olinganiselwe nawo uyafundisa. Inhlanganisela evikela yonke into kuyo yonke imodeli ngokuvamile isuke ingavikeli lutho. Lapha iphethini yezinzuzo iyahluka ngendlela eyenzeka ngayo ebhayolojini yangempela.

Igatsha le-alpha-synuclein

Ngokuhlukile emsebenzini wobuthi, uhlelo lwe-methylthioninium esesimweni se-reduction lwahlola ukuthi le nhlanganisela iyakuphazamisa yini ukuhlangana kwe-alpha-synuclein ngokwayo. Kumaseli aveza i-alpha-synuclein yabantu, isimo se-reduction sasusa ukunqwabelana kwasekuqaleni nokunemicu, nge-EC50 eseduze no-1 micromolar, futhi ukunikezwa ngomlomo amasonto ayisithupha kwanciphisa ukushintsha kwezicubu okuhlobene nesifo ezindaweni eziningana zobuchopho, ngenkathi kulungisa izici zokunyakaza okungajwayelekile kumagundane amancane aguqulwe ngofuzo (PMID 29375308). Ucwaningo olulandelayo ohlotsheni lwesibili lwamagundane aguqulwe ngofuzo lwathola ukuthi i-alpha-synuclein kuma-synapse yabuyela emazingeni ohlobo olungaguquliwe ngofuzo, kwabuye kwalungiswa ukungajwayeleki kwama-receptor e-glutamate, kodwa ngaphandle kwemiphumela ekholisayo ekuziphatheni (PMID 35709886).

Qaphela ukushintshwa kwenhlanganisela. Lezi zifundo zasebenzisa i-LMTM/HMTM, usawoti osesimweni se-reduction ozinzisiwe owenzelwe uhlelo lwe-Alzheimer, hhayi i-chloride esesimweni se-oxidation ethengiswa njengodayi. Ukusebenza kahle kwesinye isimo akudluliseleki ngokuzenzakalelayo kwesinye, umehluko umlando wokuhlolwa kwe-Alzheimer owuchaza kabanzi.

Izizathu ezintathu zokufunda wonke umphumela kabili

Okokuqala, cishe yonke imithamo inikezwa ngesikhathi esifanayo nobuthi noma ngaphambi kwabo. Udayi usuke ukhona ngaphambi kobuthi noma kanye nabo. Lokho kuhlola ukuthi ukusekela ama-mitochondria kungakuvimbela yini ukulimala, okuyisayensi efanele, kodwa akufanekiseli isiguli esiqala isithasiselo ngemva kweminyaka yokulahleka kwamaseli ezinzwa osekuvele kwenzeka.

Okwesibili, i-methylene blue ivimbela yona kanye i-enzyme eyenza i-MPTP isebenze. I-MPTP, eyisandulela sobuthi, ayinabungozi kuze kube yilapho i-MAO-B iyiguqula ibe yi-MPP+. I-methylene blue icindezela lokho kuguqulwa emazingeni e-nanomolar, ngakho umphumela wokuvikela ocwaningweni lwe-MPTP ungasho ukuthi ubuthi abuzange benziwe busebenze, kunokuba usho ukuthi amaseli ezinzwa avikelwa. Ucwaningo lwesikhathi eside olungenhla luyamelana nalokhu kugxekwa ngenxa yokuhlolwa kwalo kokulawula i-MPP+. Izifundo ezingenakho lokho kuhlolwa kokulawula azikwazi.

Okwesithathu, umonakalo obangelwa ubuthi awusona isifo sikaParkinson. I-rotenone, i-MPTP, ne-6-OHDA zifanekisela ngokunembile ukulahleka kwe-dopamine nokucindezeleka okubangelwa yi-oxidation, kodwa hhayi ukuqhubeka kwesifo phakathi kwamashumi eminyaka, ukusabalala kokushintsha kwezicubu okuhlobene ne-synuclein, noma ukwakheka kabusha kwemijikelezo yezinzwa okwenzeka esifweni sabantu. Ukuvikelwa ezilwaneni kuyisizathu sokwenza ukuhlolwa kwabantu, hhayi ukuboniswa kusengaphambili kwemiphumela yakho.

Ubufakazi kubantu: abukho okwamanje

Kusukela ngo-2026, akukho ukuhlolwa okushicilelwe okwabiwa ngokungahleliwe futhi akukho ukuhlolwa kokungenelela okubhalisiwe okuqhubekayo kwe-methylene blue, i-LMTM, noma i-HMTM kwesifo sikaParkinson. Ukubuyekezwa kwakamuva kwezindlela zokwelapha kwabala ukuhlolwa kukaParkinson okushicilelwe okunguziro nokuqhubekayo okunguziro. Izinhlelo ze-LMTM/HMTM ezibhalisiwe ziphathelene nesifo se-Alzheimer kanye nohlobo lokuwohloka komqondo kwe-frontotemporal oluthinta ukuziphatha, futhi imiphumela yazo ayidluliseleki kuParkinson. Noma ubani othengisa i-methylene blue yezimpawu zikaParkinson namuhla usuke enweba iziphetho ezitholwe kumagundane namaseli. Lokho kwenwetshwa kweziphetho kwehlulekile ezintweni eziningi ezazicatshangelwa ukuvikela izinzwa futhi ezazibukeka zithembisa kakhulu kunale.

Amaphuzu okuphepha aqondene neziguli zikaParkinson

Lesi sigaba asisona isexwayiso esivamile. Siphathelene nokusebenzisana nemithi iziguli zikaParkinson eziyisebenzisa ngempela. I-methylene blue ngokwayo iyisivimbeli esinamandla se-MAO-A esisebenza ngokubuyiseleka emuva, futhi ivimbela i-MAO-B emazingeni aphezulu. I-rasagiline, i-selegiline, ne-safinamide ziyizivimbeli ze-MAO-B ezinemiyalelo evimbela noma exwayisa ngokuzihlanganisa nezinye izivimbeli ze-MAO, ngoba ukuvinjelwa okweqelanayo kungadala ubuthi be-serotonin nokusabela okunyusa umfutho wegazi. Ukwengeza i-methylene blue ohlelweni olunjalo lwemithi kuwukusebenzisana okubalulekile ngokomtholampilo, futhi akukho datha kaParkinson eqinisekisa ukuthi izinhlobo ze-LMTM/HMTM ezisesimweni se-reduction ziyakugwema.

Ukusebenzisana nemithi yokucindezeleka esebenza ku-serotonin kubhalwe phansi kubantu. Ekubuyekezweni okuhlelekile kwezehlakalo zokudideka ngemva kokufakwa kwe-methylene blue ngomthambo, izehlakalo ezingama-25 kwezingu-26 zenzeka ezigulini ezazisebenzisa umuthi wokucindezeleka osebenza ku-serotonin, futhi imikhiqizo ye-methylene blue ephuzwa ngomlomo nayo iye yabikwa ukuthi ibangele i-serotonin syndrome. Ukucindezeleka kwengqondo kuvamile esifweni sikaParkinson futhi kuvame ukwelashwa ngama-SSRI noma ama-SNRI, ngakho lokhu kusebenzisana kuyenzeka kalula kuleli qembu kunasemiphakathini eminingi. Imininingwane egcwele yokuphepha nokusebenzisana kanye nesithombe esibanzi socwaningo lwasemtholampilo kusiza ukuqonda lezi zingozi esimweni sazo. Noma ubani ocabangela ukusebenzisa i-methylene blue kanye nemithi kaParkinson noma yokucindezeleka kwengqondo udinga ukuqondiswa nguchwepheshe wezokwelapha ngaphambi kokuzama noma yini, hhayi ngemva kokuvela kwezimpawu.

Isiphetho singafingqwa ohlwini olulodwa. Amamodeli obuthi nawe-synuclein abonisa ukuvikelwa okungaguquguquki kwama-mitochondria ne-dopamine, okunemiphumela ehambisana nomthamo ngempela; izici ezintathu ezishiwo ezingadukisa imiphumela yokuhlola zibeka imingcele kuyo yonke imiphumela ye-MPTP neyokunikezwa ngesikhathi esifanayo nobuthi; kanti ubufakazi bokusebenza kahle kubantu busesekuhlolweni okunguziro. Lolu uhlelo locwaningo okufanele lulandelwe, hhayi ukwelashwa okufanele kuthengwe.