Mankhwala osokoneza bongo a Alzheimers (AD mankhwala): J147, CMS121, CAD31

Posted on 07 / 10 / 2022 by aasraw adalembamo J147.

" Matenda a Alzheimer's, omwe amayambitsa matenda a dementia, ndi mtundu wa dementia womwe umayambitsa mavuto a kukumbukira, kuganiza, ndi khalidwe. Zizindikiro nthawi zambiri zimawonekera pang'onopang'ono ndikuwonjezereka pakapita nthawi, ndipo pamapeto pake zimakhala zovuta kwambiri kuti zisokoneze ntchito za tsiku ndi tsiku.Matenda a Alzheimer's amatenga 60% mpaka 80% ya matenda a dementia. Ndipo, pa matenda ambiri, monga matenda a Alzheimer’s (AD) ndi khansa, ukalamba ndiwo chiwopsezo chachikulu kwambiri. "

1.Kodi Alzheimer's and Geroprotectors(GNPs) ndi chiyani?
2.Choyambitsa matenda a Alzheimer
3. Alzheimer's drug(AD mankhwala) ofuna: J147, CMS121, CAD31
4.Conclusion

1.Kodi Alzheimer's and Geroprotectors(GNPs) ndi chiyani?

Alzheimer's ndiye chomwe chimayambitsa matenda a dementia, ndi mtundu wa dementia womwe umayambitsa mavuto ndi kukumbukira, kuganiza ndi machitidwe. Zizindikiro nthawi zambiri zimayamba pang'onopang'ono ndikuwonjezeka pakapita nthawi, zimakhala zovuta mokwanira kusokoneza ntchito za tsiku ndi tsiku.matenda a Alzheimer malipiro a 60 peresenti ku 80 peresenti ya matenda a dementia. Ndipo kukalamba ndilo vuto lalikulu la matenda ambiri, kuphatikizapo matenda a Alzheimer (AD) ndi khansa.

Geroprotectors, ndi senotherapeutic yomwe imakhudza mizu yoyambitsa ukalamba ndi matenda okalamba, ndipo motero imatalikitsa moyo wa nyama. Kafukufuku watsopano wa Salk tsopano watulukira gawo lapaderadera la mankhwalawa, omwe amatchedwa geroneuroprotectors (GNPs), omwe ali AD ofuna mankhwala ndi kuchepetsa ukalamba mu mbewa.

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2.Choyambitsa matenda a Alzheimer

Ochita kafukufuku amakhulupirira kuti palibe chifukwa chimodzi chokha cha matenda a Alzheimer's. Kodi mumadwala matenda a Alzheimer's? Matendawa amayamba chifukwa cha zinthu zingapo, monga chibadwa, moyo ndi chilengedwe. Asayansi apeza zomwe zimawonjezera matenda a Alzheimer's. Ngakhale zina mwaziwopsezo - zaka, mbiri yabanja komanso kubadwa - sizingasinthidwe, umboni womwe ukupezeka ukuwonetsa kuti pangakhale zina zomwe tingakhudze.

-Age

Vuto lodziwika bwino lomwe limayambitsa matenda a Alzheimer's ndikuchulukirachulukira, koma Alzheimer's si gawo lodziwika bwino la ukalamba. Ngakhale zaka zimachulukitsa chiopsezo, sizomwe zimayambitsa matenda a Alzheimer's.

Anthu ambiri omwe ali ndi matendawa ali ndi zaka 65 kapena kupitilira apo. Pambuyo pa zaka 65, chiopsezo cha Alzheimer's chimachulukiranso zaka zisanu zilizonse. Pambuyo pa zaka 85, chiopsezo chimafika pafupifupi gawo limodzi mwa magawo atatu.

-Mbiri yambiri

Chinthu china choopsa choopsa ndicho mbiri ya banja. Amene ali ndi kholo, mchimwene kapena mlongo ndi Alzheimer ndi omwe angathe kukhala ndi matendawa. Vuto limakula ngati oposa mmodzi m'banja ali ndi matendawa.

-Genesis (utsogoleri)

Asayansi amadziwa kuti majeremusi amapezeka mu Alzheimer's. Magulu awiri a majini amachititsa munthu kukhala ndi matenda: majeremusi oopsa komanso majini a deterministic.

Kuvulala kwakukulu

Pali kulumikizana pakati pa kuvulala kwamutu ndi chiopsezo chamtsogolo cha matenda amisala. Tetezani ubongo wanu pomanga lamba wanu wapampando, kuvala chisoti chanu mukamachita nawo masewera, komanso "kugwetsa" nyumba yanu.

-Kugwirizanitsa mutu wamutu

Umboni wina wamphamvu kwambiri umakhudza thanzi la ubongo ndi thanzi labwino. Kulumikizana kumeneku kumakhala kosavuta, chifukwa ubongo umadyetsedwa ndi mitsempha yamatumbo yambiri ya thupi, ndipo mtima uli ndi udindo wopopera magazi kudzera mu mitsempha iyi ku ubongo.

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3. Alzheimer's drug(AD mankhwala) ofuna: J147, CMS121, CAD31

Masiku ano, Alzheimer's ili patsogolo pa kafukufuku wamankhwala. Ofufuzawo akuyesetsa kuti adziwe zambiri zamatenda a Alzheimer's ndi matenda ena amisala momwe angathere. Zina mwazinthu zopita patsogolo kwambiri zawunikira momwe Alzheimer's imakhudzira ubongo. Chiyembekezo ndikumvetsetsa bwino kumeneku kudzatsogolera kuchipatala chatsopano. Njira zambiri zomwe zikuchitika pakadali pano zikufufuzidwa padziko lonse lapansi.

Kuchepetsa kutaya mankhwala 2,4-Dinitrophenol (DNP) zopindulitsa mukumanga thupi

Salk's Cellular Neurobiology Laboratory inayamba ndi mankhwala awiri omwe amasonyeza mankhwala: fisetin, mankhwala opangidwa kuchokera ku zipatso ndi ndiwo zamasamba, ndi curcumin, kuchokera ku zonunkhira zam'madzi. Kuyambira izi, gululi linapanga atatu AD mankhwala Ovomerezeka chifukwa cha kuthekera kwawo kuteteza mphutsi ku zoopsa zambiri zomwe zimakhudzana ndi ubongo wokalamba. Labu inasonyeza kuti awa atatu opangidwa (omwe amatchedwa CMS121, CAD31 ndi J147), komanso fisetin ndi curcumin, zinachepetsanso zizindikiro za ukalamba, komanso matenda a maganizo, ndipo zimawonjezera moyo wamkati wa mbewa kapena ntchentche.

Chofunika kwambiri, gululo linawonetsa kuti njira za maselo zomwe zimagwiridwa ndi odwala AD izi ndi zofanana ndi mankhwala ena ofufuza bwino omwe amadziwika kuti athe kupatsa moyo wa zinyama zambiri. Pachifukwachi, ndipo pogwiritsa ntchito zotsatira za maphunziro awo akale, timuyi imanena kuti fisetin, curcumin ndi odwala atatu omwe ali ndi mankhwala osokoneza bongo AD ali ndi tanthauzo la kukhala geroneuroprotectors.

Maphunziro ena mu labu akudziwitsani ngati mankhwalawa ali ndi zotsatira pa ziwalo kunja kwa ubongo. "Ngati mankhwalawa ali ndi phindu kwa machitidwe ena a thupi, monga kusunga impso ndi matenda onse a minofu, akhoza kugwiritsidwa ntchito m'njira zina zothandizira kapena kuteteza matenda a ukalamba," anatero Schubert.

- Otsatira a Alzheimer's (AD drug) ofuna: J147

Curcumin, chofunika kwambiri cha Indian curry spice turmeric, ndi mzere wambirimbiri womwe umachepetsa kutupa, kupanga ROS, poizoni wa poizoni, ndi excitotoxicity, ndipo imakhala yogwira mtima kwambiri m'mafano a AD. Komabe, curcumin imakhala ndi zochepetsetsa kwambiri, zosafunika, komanso ubongo wovuta. Kupititsa patsogolo ntchito yokhudzana ndi ubongo komanso kuchepetsa kagayidwe kake, tinagwiritsira ntchito SAR kuyendetsa njira zowonjezeretsa mavitamini kuti izi zitheke kuwonjezera pa mphamvu zake komanso zochitika zake. Poyamba, labile diketo ya curcumin inasinthidwa ku pyrazole kupanga CNB-001, ndi kukhazikika bwino ndi ntchito zopanda ubongo pa curcumin. Kufufuza kwa magulu ozungulira pa mapuloteni atatu a phenyl a CNB-001 akuwulula kuti magulu a hydroxyl si oyenerera kuti achite ntchito zisanu ndi ziwiri zoyesera. Kuwonjezera kwa magulu awiri a methyl ku pyrazole pachokha puloteni ya phenyl inatsogolera CNB-023 ndi mphamvu yabwino ya CNB-001. Komabe, CNB-023 ndi lipophili (cLogP = 7.66), ndipo imagwirizanitsa ndi chikhalidwe chamaphunziro ali ndi zolemba zambiri. Pofuna kuchepetsa lipophilicity ndikuzindikira zochepa zomwe zimafunika kuchita, magulu awiri a cinnamyl adachotsedweratu ndikupangitsanso kukhathamiritsa kambiri kumayambitsa kamolekyu kakang'ono kwambiri J147. J147 ndi nthawi 5-10 yochuluka kwambiri muzoyesa zonse monga CNB-001, pamene curcumin ili ndi zochepa kapena zosachita muyeso iliyonse. J147 sikuti imakhala yamphamvu koma imakhalanso ndi zinthu zabwino (MW = 350, cLogP = 4.5, tPSA = 42). J147 (1146963-51-0) adaphunziridwa mochulukira muzochitika zakale za zakale komanso za AD zomwe zakhala zothandiza kwambiri.

Wodandaula wina yemwe amachita J147 atha kutsitsidwa kuti akhale amine / ma hydrazines onunkhira omwe atha kukhala amtundu wa khansa. Pofufuza kuthekera uku, kukhazikika kwamadzimadzi kwa J147 kunaphunziridwa mu microsomes, mu mbewa plasma, ndi vivo. Zinawonetsedwa kuti J147 (1146963-51-0) sizonyansa kwa amines kapena hydrazines, kuti scaffold ndi yolimba, ndipo kuti amasinthidwa kuti awiri kapena atatu metabolites okosijeni mwa anthu, mbewa, makoswe, monkey, ndi mbatata microsomes. Kupenda chitetezo cha metabolites, tapanga maselo onse atatu a chiwindi a m'magazi ndipo timayesa kuti tizilombo toyambitsa matenda tizilombo toyambitsa matenda tizilombo toyambitsa matenda. Palibe imodzi ya metabolitesyi ndi poizoni, ndipo ambiri a metabolites ali ndi zinthu zofanana ndi za J147.

- Otsatira a Alzheimer's (AD drug) ofuna kutsatira: CMS121

CMS121 ndizochokera ku fisetin. Kwa zaka zingapo zapitazi, tawonetsa kuti flavonoid fisetin ndimagwiridwe apakamwa, oletsa kutsekemera, komanso opititsa patsogolo kuzindikira m'mitundu ingapo yamavuto a CNS. Fisetin imagwira ntchito molimbana ndi antioxidant ndipo imatha kupangitsa kuti ma GSH azikhala ovuta. Kuphatikiza apo, fisetin imakhala ndi ma neurotrophic komanso anti-inflammatory. Zochita zingapozi zikuwonetsa kuti fisetin imatha kuchepetsa kuchepa kwa ntchito yamitsempha yokhudzana ndi zovuta zingapo. Komabe, EC50 yake yokwera kwambiri pamayeso oyeserera (2-5 μM), low lipophilicity (cLogP 1.24), high tPSA (107), komanso kupezeka kwa bioavailability kuli ndi fisetin yocheperako yopitilira patsogolo ngati ofuna mankhwala.

Chovuta chake chinali kupititsa patsogolo mphamvu ya fisetin munjira zingapo zama neuroprotective pomwe nthawi yomweyo amasintha mawonekedwe ake am'magazi kuti azigwirizana kwambiri ndi mankhwala osokoneza bongo a CNS (molekyulu cular 400, cLogP-5, tPSA-90, HBD-3, Njira ziwiri zosiyanasiyana zinagwiritsidwa ntchito kukonza fisetin. Poyamba, magulu osiyanasiyana a hydroxyl adasinthidwa mwatsatanetsatane kuti athetse ma metabolites a sulfate / glucuronidate. Pogwiritsa ntchito njira yachiwiri, flavone scaffold idasinthidwa kukhala quinoline, pomwe nthawi yomweyo imakhala ndi fisetin. vitro ischemia kuyesa. Zochita zitatu zowonjezera za fisetin zidasungidwa muzotumphukira, kuphatikiza kukonza kwa GSH, kuletsa kwa bakiteriya lipopolysaccharide (LPS) komwe kumapangitsa kuti microglial activation, komanso kusiyanasiyana kwama cell a PC7, njira inayake ya neurotrophic. Chotsatira cha Flavone CMS-12 ndi quinolone chochokera CMS-140 ndichoposa 121 ndi 600 champhamvu kwambiri, motsatana, kuposa fisetin muyeso la ischemia (Chithunzi . Chifukwa chake, ndizotheka kukhalabe ndi mawonekedwe amitundu yambiri ya polyphenol pomwe mukuwongolera zonse za thupi ndi zamankhwala m'deralo.

- Otsatira a Alzheimer's (AD drug) ofuna: CAD31

Zotsatira zambiri za thupi za CAD31 zinali zabwino poletsa zochitika zina zoopsa zokhudzana ndi matenda ozunguza bongo.

CAD31 ndi omwe amatenga mankhwala osokoneza bongo a Alzheimer's (AD) omwe adasankhidwa chifukwa chokhoza kuyambitsa kubwereza kwa maselo am'mimba am'mimba omwe amachokera m'mimba mwa mbewa komanso mu mbewa za APPswe / PS1ΔE9 AD. Pofuna kusunthira CAD-31 kupita kuchipatala, zoyeserera zidachitika kuti adziwe momwe angatetezere mankhwala ndi mankhwala, komanso kuyesa momwe angathandizire pochita mbewa ya AD.

CAD31 imakhala ndi mphamvu zogwiritsira ntchito matendawa m'magazi asanu ndi limodzi omwe amatsutsana ndi zoopsa zomwe zimachitika mu ubongo wakale. Maphunziro azachipatala ndi oyambirira akuwonetsa kuti CAD31 ndi ubongo wa ubongo ndipo mwachiwonekere ndi otetezeka. Pamene udyetsedwa kale, zizindikiro za APPswe / PS1ΔE9 AD makoswe kuyambira m'miyezi ya 10 kwa miyezi yambiri ya 3 mu njira yothandizira ya matenda, kuchepetsa kukumbukira kukumbukira ndi kutupa kwa ubongo, komanso kuwonjezeka kwa mawu mapuloteni a synaptic. Deta yamadzimadzi ya deta ya ubongo ndi plasma inasonyeza kuti zotsatira za CAD-31 zimayambira pa mafuta amchere amadzimadzi ndi kutupa. Kusanthula mwachindunji za chiwerengero cha ma geneti kunasonyeza kuti CAD-31 inali ndi zotsatira zazikulu zowonongeka bwino ndi AD mphamvu zamagetsi.

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4.Conclusion

Gulu lofufuzira tsopano likuyang'ana kupeza ma GNP awiri m'mayesero a anthu. Chombo cha fisetin, CMS121, panopa ndi maphunziro a toxicology omwe amafunikira kuti FDA ivomereze kuyambitsa mayesero. Kupangidwa kwa curcumin, J147, ndi pansi pa FDA ndondomeko ya chiwongoladzanja kuti ayambe kuyesedwa kwa AD m'ma oyambirira chaka chino. Gululi likukonzekera kuphatikiza zizindikiro za sayansi ya ukalamba ku ukalamba m'mayesero a zachipatala kuti ayese zotsatira zowonongeka kowopsa. Ofufuzawo amanena kuti kupezeka kwa ogwiritsa ntchito mankhwalawa kwa AD kumatsimikizira njira yomwe anagwiritsira ntchito mankhwala omwe ayamba kukhala njira yodziŵira zina GNP mankhwala zomwe zidzakuthandizira kulimbikitsa ukalamba wathanzi. Izi zikhoza kufulumizitsa kwambiri mapaipi a mankhwala kuti athetse matenda a ukalamba omwe pakalipano palibe mankhwala.

AASraw ndi katswiri wopanga J147, CMS121, CAD31 ufa womwe uli ndi labu yodziyimira pawokha ndi fakitale yayikulu monga chithandizo, zonse zopanga zizichitika motsogozedwa ndi CGMP ndikuwongolera kachitidwe kabwino. Dongosolo loperekera ndi lokhazikika, malonda onse ogulitsa ndi ogulitsa ndi ovomerezeka.Mwalandiridwa kuti mudziwe zambiri za AASraw!

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