Methylxanthines Thiab Cov Kab Mob Neurodegenerative: Ib Qhov Hloov Kho 1

Abstract:

Methylxanthines (MTX) yog purine-derived xanthine derivatives. Thaum ib txwm tshwm sim methylxanthines zoo li caffeine, theophylline, lossis theobromine tau siv dav hauv cov khoom noj, ntau cov khoom siv hluavtaws tab sis kuj tsis yog hluavtaws methylxanthines yog siv los ua tshuaj, tshwj xeeb tshaj yog kho cov hlab ntsws. Dhau li ntawm cov teebmeem bronchoprotective zoo, methylxanthinesare kuj paub tias muaj cov tshuaj tiv thaiv kab mob thiab tiv thaiv oxidative, kho cov kev hloov hauv lipidhomeostasis, thiab muaj cov teebmeem neuroprotective.

Raws li cov neeg laus laus zuj zus, ntau thiab ntau tus neeg pib mob siab rau yuav ua li cas tiv thaiv lawv txoj kev noj qab haus huv. Ntawm lawv, cov tshuaj antioxidants tau raug pov thawj tias yog ib txoj hauv kev zoo los pab tib neeg kom qeeb txoj kev laus thiab txhim kho kev nco.

Antioxidants hais txog cov khoom uas tuaj yeem tiv thaiv dawb radical oxidation hauv lub cev. Cov dawb radicals yog cov tshuaj lom neeg muaj zog heev uas ua los ntawm cov metabolism hauv lub cev lossis lwm yam ib puag ncig. Thaum cov dawb radicals sib sau ua ke rau qee qhov, lawv yuav tawm tsam lub cev hlwb thiab ua rau lub cev tiv thaiv kev puas tsuaj, uas kuj yog ib qho tseem ceeb ntawm tib neeg kev laus. Antioxidants tuaj yeem cuam tshuam thiab tshem tawm cov dawb radicals, yog li ua kom qeeb ntawm cov cell puas.

Qee qhov kev tshawb fawb tau pom tias cov tshuaj antioxidants tuaj yeem txhim kho tib neeg lub cim xeeb. Kev nco yog lub hlwb lub peev xwm los ua thiab khaws cov ntaub ntawv. Nrog lub hnub nyoog thiab kev hloov ntawm lub cev, kev nco yuav maj mam poob. Txawm li cas los xij, ntau yam antioxidants xws li vitamin C, vitamin E, flavonoids, thiab lwm yam tau pom tias tiv thaiv thiab txhim kho lub hlwb ua haujlwm. Cov tshuaj no tuaj yeem txhawb kev loj hlob thiab kev loj hlob ntawm cov hlwb hlwb, txo qis kev puas tsuaj rau lub hlwb hlwb, thiab ntxiv dag zog rau kev sib txuas ntawm hlwb hlwb. Tsis tas li ntawd, antioxidants tuaj yeem pab tswj kev ncaj ncees ntawm cov cell membranes, yog li txhim kho kev xav thiab kev txawj ntse.

Hauv luv luv, antioxidants yog ib txoj hauv kev zoo rau tib neeg kev noj qab haus huv thiab kev nco. Los ntawm kev noj zaub mov kom raug thiab kev ua neej hloov pauv, peb tuaj yeem noj ntau cov tshuaj antioxidants, yog li ntxiv dag zog rau lub cev tiv thaiv thiab tswj lub xeev zoo ntawm kev noj qab haus huv thiab kev nco. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidative thiab inflammatory teb nyob rau hauv lub hlwb, yog li tiv thaiv kev noj qab haus huv. paj hlwb. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm muaj peev xwm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv qhov tshwm sim ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.

Nyem paub txoj hauv kev los txhim kho lub hlwb

Paub cov txheej txheem molecular muaj xws li adenosinereceptor antagonism, phosphodiesterase inhibition, cuam tshuam rau cholinergic system, Wnt signaling, histone deacetylase activation, thiab gene regulation.

Los ntawm kev cuam tshuam rau ntau txoj hauv kev cuam tshuam nrog cov kab mob neurodegenerative ntawm cov txheej txheem pleiotropic sib txawv thiab vim nws cov kev cuam tshuam nruab nrab, kev noj cov tshuaj methylxanthines tau pom tias yog ib qho kev nthuav qhia txog kev cuam tshuam nrog neurodegeneration. Tshwj xeeb tshaj yog nyob rau hauv lub xyoo dhau los, qhov cuam tshuam ntawm methylxanthines nyob rau hauv cov kab mob neurodegenerative tau kawm ntau thiab ntau yam tshiab tau piav qhia.

Hauv qhov kev tshuaj xyuas no peb sau cov kev tshawb pom ntawm methylxanthines txuas rau Alzheimer's kab mob, Parkinson's disease, thiab Ntau Sclerosis txij li xyoo 2017, tsom mus rau kev tshawb fawb txog kev kis kab mob thiab kev kho mob thiab hais txog cov txheej txheem molecular hauv kev sim kab lis kev cai ntawm tes thiab cov tsiaj tshawb fawb no los soj ntsuam cov peev xwm neuroprotective ntawm methyl. kab mob.

Ntsiab lus: methylxanthines; caffeine; theobromine; theophylline; pentoxifylline; propentofylline; istrafylline; Alzheimer tus kab mob; Tus kab mob Parkinson; Ntau Sclerosis.

1. Taw qhia

Qhov kev tshuaj xyuas no qhia txog qhov kev tshawb pom tshiab tshaj plaws ntawm kev sib raug zoo ntawm methylxanthines thiab cov kab mob neurodegenerative, tshwj xeeb tshaj yog Alzheimer's disease (AD), Parkinson'sdisease (PD), thiab Ntau Sclerosis (MS).

Cov kab mob multifactorial no qhia ntau yam kev mob tshwm sim thiab cov txheej txheem xws li neuronal cell poob txuas nrog togliosis, misfolding thiab tsub zuj zuj ntawm cov proteins, oxidative kev nyuaj siab, thiab neuroinflammation.

Nyob rau hauv cov ntaub ntawv ntawm AD, kab mob kev loj hlob yog txuam nrog A peptide generationand aggregation, txuam nrog pathological extracellular thiab intracellular filamentousdeposits, hyperphosphorylated tau proteins, neuroinflammation, thiab synaptic poob.

PDis tus cwj pwm los ntawm dopaminergic neurodegeneration thiab tsub zuj zuj ntawm -synuclein hauv Lewy lub cev. Txog MS, cov txheej txheem neuroinflammatory ua rau demyelination ofneurons yog qhov tseem ceeb ntawm tus kab mob.

Ntau cov kev tshawb fawb tau ua tiav los daws cov lus nug ntawm seb xanthinederivatives zoo li caffeine thiab theobromine muaj txiaj ntsig zoo txog cov yam ntxwv ntawm cov kab mob histopathological uas tshwm sim hauv cov kab mob uas tau hais los saum toj no thiab kev paub tsis meej.

Txawm hais tias qhov tshwm sim ntawm cov kev tshawb fawb soj ntsuam, tshwj xeeb tshaj yog rau AD, washeterogeneous [1], qee cov txheej txheem tau txheeb xyuas, qhia tias yuav ua li cas methylated xanthiderivatives tuaj yeem tiv thaiv kev puas tsuaj neuronal.

Feem ntau, nyob rau hauv physiological concentrations, tiav piv txwv li los ntawm kas fes noj los yog los ntawm kev noj cov methylxanthine-muaj dej haus, methylxanthines ua raws li antagonists ntawm adenosine receptor (AR), histone deacetylase activator, los yog antioxidant.

Kev cuam tshuam rau txoj hauv kev no, xanthine derivatives tuaj yeem hloov kho cov txheej txheem molecular cuam tshuam nrog cov kab mob neurodegenerative xws li tsub zuj zuj ntawm misfolded proteins, oxidativestress, thiab neuroinflammation. Interestingly, tshwj xeeb tshaj yog, lub luag hauj lwm zoo ntawm adenosinereceptor antagonists nyob rau hauv kev kho mob ntawm cov kab mob neurodegenerative tau dhau los ua ntau pom tseeb nyob rau hauv xyoo tas los [2-5].

Nyob rau hauv supraphysiological concentrations, piv txwv li, los ntawm kev noj cov tshuaj methylxanthines, ntxiv mechanisms xws li inhibition ntawm phosphodiesterases thiab high-affinity ATP-dependent cyclic nucleotide transporters raug tshaj tawm, kuj tseem ua rau cov khoom tiv thaiv neuroprotective ntawm methylxanthines [6].

Dhau li ntawm cov lus hais saum toj no ntawm xanthine derivatives, cov txheej txheem ntxiv tau pom zoo los yog tsis suav nrog hauv xyoo tas los thiab tau sau cov ntsiab lus hauv qab no nrog rau cov kws kho mob tshiab hais txog cov teeb meem no (tseem saib cov duab thiab cov lus).

2. Mob Alzheimer's

2.1. Epidemiological thiab Clinical Studies

Hauv plaub lub xyoos dhau los, ntau qhov kev tshawb fawb soj ntsuam thiab kev kis mob tshiab tau luam tawm los tshuaj xyuas qhov cuam tshuam ntawm caffeine lossis lwm yam methylxanthines ntawm kev paub txog kev paub txog AD, saib Table 1.

Jee Wook Kim thiab cov npoj yaig tau txheeb xyuas kev sib raug zoo ntawm kev noj haus kas fes thiab AD biomarkers hauv tib neeg lub hlwb siv cov tswv yim neuroimaging xws li positron emission tomography (PET), magnetic resonance imaging scans, thiab soj ntsuam kev soj ntsuam. Cov kev tshawb fawb no suav nrog 411 tus neeg koom nrog cov txheej txheem suav nrog rau cov neeg mob uas twb muaj kev puas siab puas ntsws me (MCI) tab sis tsis muaj kev kuaj mob dementia.

Cov neeg koom nrog txoj kev tshawb fawb tau muab faib ua cov neeg siv khoom siab thiab qis / tsis muaj kas fes: 269 tus neeg koom, haus nocoffee lossis<2 cups/day and 142 participants stated to drink two or more than two cups per day, reflecting higher coffee intake. The authors reported that a higher lifetime coffee intake was significantly associated with a reduced pathological cerebral amyloid deposition and could therefore be linked to a lowered risk for AD or cognitive decline even after controlling for potential cofounders. 

Dhau li ntawm lub koom haum ntawm kev noj haus kas fes nrog txo amyloid deposition, tsis muaj kev sib raug zoo ntawm kas fes kom tsawg thiab AD-sociated qabzib hypometabolism, atrophy los yog cortical thickness, thiab cerebral dawb teeb meem hyperintensities tau kuaj pom [7].Qhov kev tshawb fawb no yog nyob rau hauv txoj kab nrog cov laus cov txiaj ntsig tau los ntawm transgenic. cov qauv nas lossis tsiaj nthuav tawm qhov txo qis A concentration [8,9].

Interestingly, qhov kev tshawb fawb no kuj qhia tau hais tias cov nyhuv tau tshaj tawm hauv cov neeg haus kas fes mus sij hawm ntev qhia tias cov txiaj ntsig zoo ntawm kev haus kas fes ntau dua tiv thaiv kab mob muaj feem cuam tshuam ntau dua uas cuam tshuam nrog kev cuam tshuam rau lub sijhawm ntev es tsis yog lub sijhawm luv luv ntawm caffeine. .Cov txiaj ntsig no tuaj yeem pab piav qhia vim li cas qee qhov kev tshawb fawb yav dhau los suav nrog cov neeg koom nrog luv luv caffeine raug pom tias tsis muaj zog lossis tsis muaj kev sib raug zoo ntawm caffeine nrog kev paub tsis meej lossis amyloid lub nra, hais txog tias tsis yog cov caffeine concentration xwb tab sis kuj yog lub sijhawm ntawm kev kis tau ua lub luag haujlwm tseem ceeb rau cov txiaj ntsig zoo. methylxanthines hauv AD.

Nyob rau hauv cov ntsiab lus no, ib tug tshiab meta-kev soj ntsuam ntawm yim kev soj ntsuam yav tom ntej kev tshawb fawb los ntawm Larsson thiab Orsini yuav tsum tau pom. Tsis muaj kev txheeb cais tseem ceeb ntawm kev haus kas fes thiab kev pheej hmoo ntawm dementia raug kuaj pom los ntawm cov kws sau ntawv. Qhov kev ntseeg siab ntawm 95% ntawm dementia rau ib khob kas fes / hnub yog 0.92, ob khob / hnub 0.90, peb khob / hnub 0.93, plaub khob / hnub 1.01, thiab tsib khob / hnub 1.11.

Nyob rau hauv txoj kab nrog cov kws sau ntawv, nws yuav tsum tau hais tias tshwj xeeb tshaj yog nyob rau lub sijhawm ntev, kev haus kas fes yuav txawv thiab yog qhov nyuaj rau kwv yees raws nraim. Ntxiv mus, peb txoj kev tshawb fawb qhia txog qhov cuam tshuam ntawm kev haus kas fes ntawm AD kev pheej hmoo tsis suav nrog vim tias lawv siv ntau pawg sib txawv ntawm kev haus kas fes [10–13].

Lwm qhov nthuav dav yog nthuav tawm los ntawm kev tshawb fawb tsis ntev los no los ntawm Iranpour thiab cov npoj yaig txheeb xyuas cov ntaub ntawv los ntawm National Health and NutritionExamination Survey (NHANES) suav nrog 1440 tus neeg koom nrog laus dua 60 xyoo [14].

Los ntawm kev siv cov kev ntsuam xyuas kev txawj ntse sib txawv, cov kws sau ntawv tau tshaj tawm qhov kev sib raug zoo tsis muaj zog ntawm kev noj cov caffeine nrog kev paub txog kev ua haujlwm. Qhov tseem ceeb ntawm kev sib raug zoo ntawm cov txiv neej muaj zog dua li cov poj niam hais txog qhov xav tau ntawm pawg pab pawg-kev tshuaj ntsuam ntxiv nrog rau kev sib koom ua ke hauv kev tshuaj ntsuam meta kom tau txais loj tab sis tej zaum yuav muaj ntau pawg neeg sib txawv.

Insummary, hais txog koob tshuaj dependency, ib tug correlation ntawm kas fes noj thiab AD kev pheej hmoo tseem muaj teeb meem thiab tam sim no tsis tuaj yeem teb yam tsis muaj qhov tsis paub tseeb hauv qhov tsis muaj kev tshawb fawb ntxiv.

2.1.1. Puas yog cov txiaj ntsig zoo vim yog Caffeine lossis lwm cov tshuaj hauv kas fes?

Dhau li ntawm caffeine, kas fes muaj ntau yam khoom siv roj ntsha uas paub tias yog cov khoom siv roj ntsha-xws li phenylindanes lossis molecules uas tsim thaum lub sij hawm ci ntawm kas fes [15,16].

Yog li ntawd, nws yog ib qho nyuaj los teb cov lus nug ntawm seb puas muaj peev xwm pom muaj txiaj ntsig zoo vim yog caffeine lossis lwm yam tshuaj. Hais raws nraim lo lus nug tseem ceeb no, Xue Dong thiab cov npoj yaig tau txheeb xyuas hauv lawv txoj kev kawm txog kev koom tes ntawm kas fes, caffeinated kas fes, decaffeinated kas fes, thiab caffeine kom tsawg los ntawm kas fes nrog kev paub txog kev ua haujlwm.

CERAD (Consortium los Tsim Kev Sau Npe rau Alzheimer's Disease) testand DSST (Digit Symbol Change Test) tau ua nrog ntau dua 2500 tus neeg koom los ntawm NHANES hnub nyoog 60 xyoo lossis laus dua yam tsis muaj kev kuaj mob AD.

Cov koom haum tseem ceeb nrog kev txawj ntse tau tshaj tawm rau kas fes, caffeinated kas fes, thiab caffeinefrom kas fes, tab sis tsis yog rau kas fes decaffeinated [17], underlining lub luag hauj lwm tseem ceeb ntawm methylxanthine caffeine hauv kas fes.

Txawm li cas los xij, raws li cov kev tshawb fawb laus kuj tseem tuaj yeem pom cov txiaj ntsig zoo ntawm lwm cov tshuaj hauv kas fes-ntxiv rau caffeine-qhov txiaj ntsig no yuav tsum tau hais txog qhov cuam tshuam ntawm caffeine tab sis tsis txiav txim siab tias lwm yam tshuaj yuav pab tau, tshwj xeeb tshaj yog ua ke nrog caffeine, kom muaj kev tiv thaiv zoo ib yam [18, 19] ib.

2.1.2. Cov nyhuv ntawm Lwm yam Methylxanthines ntawm Alzheimer's Disease

Dhau li ntawm caffeine, ob peb lwm methylxanthines paub tias muaj peev xwm tiv thaiv kev cuam tshuam txog lawv cov txheej txheem molecular. Txawm li cas los xij, tsawg heev paub txog lawv cov peev xwm tiv thaiv kev ua haujlwm txog AD hauv kev tshawb fawb soj ntsuam lossis cov ntaub ntawv tau los ntawm tib neeg cov qauv.

De Leeuw tau tshawb xyuas lub koom haum ntawm cov khoom noj khoom haus sib txawv nrog rau kev kho mob hauv cov neeg mob uas muaj kev paub tsis meej. Theobromine tau tshaj tawm tias tau nce ntxiv hauv pawg neeg mob uas qis dua A 42 tab sis kuj tseem muaj ntau dua thiab phosphorylated tau qib. Tsis tas li ntawd, cov qib theobromine siab tau pom tias muaj kev sib raug zoo nrog kev paub tsis meej hauv cov neeg mob me me kev paub tsis meej (MCI) [20].

Thaum xub thawj siab ib muag, cov txiaj ntsig no yuav taw tes rau qhov cuam tshuam tsis zoo ntawm methylxanthines hauv kev kis kab mob. Txawm li cas los xij, nws yuav tsum tau muab coj los xav, tias caffeine yog metabolized hauv lub siab rau theobromine.

Kev hloov pauv sai lossis hloov pauv metabolization ntawm caffeine tuaj yeem nce theobromine tab sis txo qis caffeine. Theobromine piv rau caffeine tau pom tias muaj qis dua los tiv thaiv amyloidogenic peev xwm [21].

Yog li ntawd, kev koom tes ntawm kev nce theobromine nrog kev paub tsis meej yuav cuam tshuam los ntawm kev txo qis ntawm caffeine sai dua uas ua rau qis qis dua caffeine.

Txawm li cas los xij, raws li caffeineis tsis tau kawm nyob rau hauv daim ntawv no qhov kev piav qhia muaj peev xwm yog kwv yees. Txawm li cas los xij, nyob rau hauv cov lus sib cav no, ib tsab xov xwm tsis ntev los no los ntawm Mullins thiab cov npoj yaig tau tham txog seb cov ntaub ntawv genome-wide nucleotide polymorphism (SNP) tuaj yeem pab kwv yees tus neeg teb rau kev noj zaub mov.

CYP1A2 noob encoding cytochrome P450 1A2 yog lub luag haujlwm rau kwv yees li 95% ntawm caffeine metabolization, thiab kaum peb SNPs cuam tshuam nrog cov noob no. Ib qho ntawm cov SNPs no (rs762551) cuam tshuam rau qhov rhiab heev forcaffeine thiab sai npaum li cas nws tau metabolized [22].

Hmoov tsis zoo, nws tsis paub meej tias qhov SNP no cuam tshuam nrog AD, tab sis qhov tsis ntseeg-qhov SNP hauv CYP1A2 noob muaj kev cuam tshuam ntawm kev noj caffeine yuav piav qhia txog cov txiaj ntsig ntawm kev tshawb fawb soj ntsuam thiab yuav tsum tau muab coj los xav rau kev sim tshuaj ntxiv, txij li SNP cov ntaub ntawv tam sim no tau nrawm thiab. pheej yig tau.

Yog li, hauv kev tshawb fawb soj ntsuam, CYP1A2 variants yuav tsum tau suav tias yog ib qho tseem ceeb ntxiv uas cuam tshuam rau cov tshuaj pharmacokinetics ntawm methylxanthines.

Qhov tseem ceeb, cov tshuaj pharmacokinetics ntawm methylxanthines tuaj yeem cuam tshuam ntxiv los ntawm kev ua neej nyob lossis kev noj haus. Piv txwv li, kev haus caffeine ua ke nrog kev haus luam yeeb tau raug tshaj tawm tias muaj feem cuam tshuam nrog ntau dua ob zaug nce caffeine plasma qib uas tuaj yeem ua rau muaj cov tsos mob muaj tshuaj lom caffeine [23].

Hauv cov ntsiab lus, qhov tsis muaj kev paub txog qib methylxanthine plasma lossis cov kev ua neej nyob uas cuam tshuam nrog cov tshuaj pharmacokinetics ntawm methylxanthines, thiab kev tshuaj xyuas ntxiv ntawm CYP1A2 variants, ua rau nws nyuaj rau kwv yees lub zog ntawm methylxanthines intreating lossis tiv thaiv cov kab mob neurodegenerative thiab yuav tsum raug suav hais tias yog ib qho kev sib txawv ntawm methylxanthine. caveat ininterpreting cov kev tshawb fawb yav dhau los.

Ntxiv mus, hluavtaws methylxanthines yog cov khoom siv nthuav dav uas yuav tsim nyog los kho lossis tiv thaiv AD, vim tias lawv muaj peev xwm ua raws li phosphodiesteraseinhibitors.

Kev tshuaj xyuas tsis ntev los no ntawm kev sim tshuaj, kab mob kis, thiab meta-analysesreported propentofylline raws li tsuas yog phosphodiesterase inhibitor tau ua tiav kev sim tshuaj ntsuam xyuas kev sim uas qhia txog kev txhim kho kev paub thiab kev dementia hnyav hauv cov neeg mob me-rau-mob AD.

Propentofylline tau pom tias yog qhov zoo tshaj plaws inhibitorout ntawm phosphodiesterase-inhibiting xanthine derivatives los ntawm inhibiting ntau phosphodiesterase isoforms, tshwj xeeb tshaj yog phosphodiesterase 2 thiab 4.

Cov kws sau ntawv thiaj li hais qhia kev sib koom ua ke ntawm propentofylline nrog phosphodiesterase 5 inhibitor sildenafil rau kev tiv thaiv lossis kev kho mob ntawm AD [6]. Raws li cov ntaub ntawv no txuas ntxiv kev sim tshuaj ntsuam xyuas cov txiaj ntsig ntawm cov khoom siv hluavtaws methylated xanthine ntawm AD cov tsos mob thiab qhov hnyav yuav tsum tau ua.

Nws yuav tsum tau txiav txim siab tias cov kev tshawb fawb soj ntsuam tuaj yeem muaj kev txwv xws li cov neeg tsis muaj neeg sawv cev, qhov cuam tshuam ntawm kev tsis meej pem, lossis kev mob siab rau tus kheej ntawm cov neeg koom rau kev tshaj tawm lawv tus kheej haus kas fes. Lwm cov ntsiab lus nthuav dav yog tus neeg muaj caffeine rhiab heev thiab cov tshuaj pharmacokinetic saum toj no ntawm methylxanthines.

2.2. Tsiaj Studies/Molecular Pathways

Hais txog kev noj caffeine, kev tshawb fawb tsiaj los ntawm Liang Jin thiab cov npoj yaig qhia tias txoj hnyuv permeability thiab qhov ncauj nqus ntawm caffeine tsis cuam tshuam rau hauv cov qauv kev lom zem ntawm tsev neeg AD. Lawv tau tshaj tawm tias plasma caffeine concentration thiab tag nrho lub hlwb raug tsis sib txawv ntawm cov tsiaj qus thiab APP / PS1 nas tom qab tswj qhov ncauj.

APP/PS1 nas muaj tib neeg transgenes rau ob qho tib si APP coj tus Swedishmutation thiab PSEN1 uas muaj L166P kev hloov pauv, yog li sawv cev rau tus qauv transgenicmouse uas overproduces A thiab feem ntau yog siv los kawm txog cov neuropathologicmechanisms ntawm AD nrog rau kev kho cov tshuaj ntawm AD [ 26] ib.

Nyob rau hauv txoj kab nrog rau qhov no, cov kws sau ntawv tau pom nyob rau hauv ib txoj kev tshawb fawb yav dhau los, tias qhov ntau ntawm plab hnyuv thiab hepatic Cyp1a2 tsis txawv hauv APP/PS1 nas piv rau cov nas qus [27].Cov ntaub ntawv no qhia tias caffeine yog ib qho kev kho mob rau AD txij thaum nws uptake yog tsis muaj kev puas tsuaj rau cov neeg mob uas raug kev txom nyem los ntawm tus kab mob neurodegenerative no.

Lwm txoj kev tshawb nrhiav tsiaj, ua los ntawm Zappettini thiab cov npoj yaig, tau siv tus qauv nas ntawm AD-zoo li Tau pathology (THY-Tau22transgenic nas) rau kev tshawb nrhiav txog qhov tshwm sim ntev ntawm lub neej thaum ntxov raug rau caffeine thaum cev xeeb tub.

Lawv qhov kev tshawb pom qhia tias Tau kab mob ntsig txog kab mob tshwm sim ua ntej hauv cov xeeb leej xeeb ntxwv ntawm cov nas uas muaj caffeine thiab yog li qhia tias caffeine exposure thaum cev xeeb tub yog qhov muaj feem cuam tshuam rau kev pib ntxov AD-zoo li pathology [28].

Ntxiv rau caffeine, cov teebmeem neuroprotective ntawm nws cov metabolite theobromine kuj tau txheeb xyuas hauv kev tshawb fawb tsiaj. Yoneda thiab cov npoj yaig tau tshaj tawm tias qhov ncauj tau tswj hwm qhov ncauj theobromine (0.05% rau 30 hnub) tuaj yeem kuaj pom hauv cov ntshav thiab cerebral cortex hauv cov tsiaj qus-typemice. (Cov nas uas siv ntawm no yog C57BL / 6NCr nas, lub npe ntawm cov nomenclature tsuas yog los ntawm lawv lub hauv paus, txij li tom qab tsim cov substrain C57BL / 6 ntawm TheJackson Laboratory cov sublines C57BL / 6N thiab C57BL / 6J tau sib cais thiab Cr stands rau tus dej. vim tias lub tuam txhab no tau txais lawv cov qoob loo hauv xyoo 1974 [29]).

Nws tuaj yeem ua tus phosphodiesterase inhibitor hauv lub hlwb thiab txhim kho cAMP / CREB / BDNF pathwaysin ib txoj hauv kev uas txhawb nqa cell ciaj sia thiab kev ua haujlwm ntawm lub paj hlwb. Ntxiv mus, theobromine-fedmice tau pom qhov ua tau zoo dua ntawm kev kawm peb-qib lub cev muaj zog [30]. Cov kev tshawb pom no ua rau muaj txiaj ntsig zoo ntawm cov khoom lag luam cacao ntawm kev kawm thiab kev nco.

Nyob rau hauv rooj plaub ntawm adenosine A2 receptor (A2AR) antagonist istradefylline, ib qho tshuaj uas tau pom zoo rau PD hauv Nyij Pooj (kom paub meej cov ntaub ntawv saib tom qab), cov tsiaj tu tsiaj ua los ntawm Orr thiab cov npoj yaig tau tshawb xyuas lub peev xwm ntawm cov tshuaj no los txhim kho kev paub txog kev ua haujlwm hauv cov nas laus. nrog AD-zoo li amyloid plaque pathology.

Cov kws sau ntawv tau tshaj tawm txog kev nco txog kev nco thiab kev nyob hauv APP transgenic nas kho nrog cov tshuaj istradefylline tsawg dua (tsawg dua lossis sib npaug li 10 mg / kg / hnub) thiab qhia txog qhov tseem ceeb ntawm kev tshawb nrhiav ntxiv ntawm adenosine receptor antagonist raws li qhov muaj peev xwm kho tau rau AD lossis lwm yam kab mob neurodegenerative. lwm PD [31].

Nyob rau hauv cov ntsiab lus no, ib tug tsis ntev los no nyob rau hauv vitrostudy los ntawm Franco thiab cov npoj yaig qhia tias antagonists ntawm A2AR cuam tshuam rau kev ua haujlwm ntawm N-methyl D-aspartate ionotropic glutamate receptors (NMDAR) txij thaum A2AR activation coj mus rau siab dua NMDAR functionality hauv neurons [32].

Nyob rau xyoo tas los no, ntau qhov kev tshawb fawb tau ua tiav los qhia txog cov txheej txheem molecular uas ua rau pom cov txiaj ntsig zoo ntawm methylxanthines zoo li caffeine hauv AD.

Gastaldo thiab cov npoj yaig tau tshuaj xyuas hauv lawv txoj kev kawm yog tias cov khoom xyaw zaub mov (nrog rau cov caffeine) tuaj yeem cuam tshuam rau Peptide aggregation hauv AD los ntawm txoj hauv kev tsis ncaj, membrane-mediated pathway vim cov membranes paub tias ua lub luag haujlwm tseem ceeb hauv cov theem pib ntawm peptide aggregation.

Cov kws sau ntawv siv cov khoom siv hauv lub hlwb los txheeb xyuas qhov cuam tshuam ntawm caffeine ntawm qhov loj thiab ntim feem ntawm cov sib sau ua ke uas muaj cov ntawv hla ntawm daim nyias nyias active fragment A 25-35.

Caffeine tau tshaj tawm tias nws tau muab faib rau hauv daim nyias nyias hauv thawj 150 ns ntawm cov molecular dynamics simulation thiab tau pom tias feem ntau yog nyob rau hauv lub taub hau-tail interface ntawm daim nyias nyias - thiab qee qhov ib ntus hauv cov tub ntxhais hydrophobic. Cov A 25-35 peptides tau pom los ntawm microscopyto daim ntawv tshaj tawm amyloid fibrils, nyob rau sab saum toj ntawm daim nyias nyias ntawm cov caffeine.

Ntxiv mus, siv X-ray diffraction lawv pom tias caffeine ua rau membranethickening thiab ib tug txo nyob rau hauv daim nyias nyias fluidity, thiab lub xub ntiag ntawm lub A 25-35 peptidesan nce nyob rau hauv lub zos daim nyias nyias curvature, uas yog induced los ntawm theformation ntawm extracellular A aggregates thiab fibrils. Tsis tas li ntawd, lawv pom nyob rau hauv lawv cov kev tshawb fawb UV-pom spectroscopy siv thioflavin T, ib qho kev nce ntxiv hauv cov fluorescentsignal ntawm -sheets ntawm 420 nm tom qab ntxiv cov caffeine [33].

Cov txiaj ntsig zoo sib xws hais txog kev cuam tshuam ntawm caffeine ntawm daim nyias nyias tau txais nyob rau hauv ib qho ntawm cov kws sau ntawv cov kev tshawb fawb ua ntej [34].Hais txog caffeine thiab A peptides, Gupta thiab cov npoj yaig tau tshaj tawm los ntawm lawv cov molecular dynamics simulations ib qho kev tsis sib haum xeeb ntawm cov qauv ntoo khaub lig ntawm A {{2. }} fibrilsin muaj caffeine. Cov nyhuv destabilization no tuaj yeem cuam tshuam ntxiv rau kev tsim cov aggregates [35].

Hais txog A homeostasis, Janitschke, thiab cov npoj yaig tau tshuaj xyuas cov teebmeem ntawm methylxanthines caffeine, theobromine, theophylline, pentoxifylline, thiab propentofylline hauv tib neeg neuroblastoma hlwb.

Lawv tau txiav txim siab tias cov tshuaj xanthinederivatives txo cov qib A ntawm pleiotropic mechanisms los ntawm kev hloov cov txheej txheem ntawm amyloid precursor protein los ntawm amyloidogenic mus rau cov uas tsis yog-amyloidogenic pathwayvia cuam tshuam cov protein stabilities thiab noob kab lus raws li zoo raws li muaj feem xyuam rau cov koom nrog secretases ncaj qha.

Ntxiv mus, cov methylxanthines no txo ​​oxidative kev nyuaj siab, theem ntawm cov roj cholesterol, thiab aggregation ntawm A 1-42 nyob rau hauv SH-SY5Y neuroblastoma hlwb [21].Lwm txoj kev, uas caffeine tuaj yeem kho nws cov tshuaj pharmacological, yog cholinergic system.

Nyob rau hauv cov ntsiab lus no, Fabiani thiab cov npoj yaig tau siv ib leeg-channel kaw thiab ntsuas fluorescent los tshuaj xyuas qhov cuam tshuam ntawm caffeine ntawm nicotinicacetylcholine receptor (AChR).

Lawv cov txiaj ntsig tau pom tias caffeine ua ib feem agonist andan ion channel blocker ntawm neuronal 7 thiab cov leeg nqaij nicotinic receptors (AChR) ntawm qhov sib txawv thiab qhia cov methylxanthine no ua cov tshuaj ntau hom tshuaj rau kev kho mob ntawm AD [36].

Interestingly, Kumar thiab cov npoj yaig tau soj ntsuam ntau dua 600 molecules ntawm lub hauv paus chiv keeb rau lawv lub peev xwm los hloov cov acetylcholine metabolism. Lawv pom tias caffeine muaj qhov sib piv AChE inhibitory muaj peev xwm ua tau los ntawm donepezil, ib qho tshuaj siv los kho mob me me mus rau nruab nrab dementia.

Tsis tas li ntawd, caffeine qhia tias tsis muaj kev cuam tshuam rau neurotoxicity hauv thawj (E18) hippocampal neurons tab sis ua rau muaj txiaj ntsig zoo rau kev muaj sia nyob thiab tiv thaiv los ntawm neurodegeneration [37].

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