Neuroprotective Activities Ntawm Curcumin hauv Parkinson's Disease: Kev Ntsuam Xyuas Ntawm Cov Ntawv Sau

Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791

Department of Pharmacology, Dubai Medical College, Dubai 20170, United Arab Emirates; dr.eslam@dmcg.edu; Tel.: plus 971-4212-0556

Abstract: Parkinson tus kab mobkab mob (PD) yog ib qho kev mob qeeb qeeb uas cuam tshuam rau dopaminergic neurons ntawm substantia nigra pars compacta (SNpc), uas yog tus cwj pwm los ntawm kev txo qis ntawm dopamine (DA) hauv lawv cov terminals striatal. Kev kho mob ntawm PD nrog levodopa lossis DA receptor agonists hloov qhov kev ua haujlwm ntawm depleted DA hauv striatum. Kev kho mob ntev nrog cov neeg ua haujlwm no feem ntau muaj cov teebmeem kev kho mob sib txawv thiab ua rau muaj kev loj hlob ntawm dyskinesia uas tsis xav tau. Yog li ntawd, ib qho tseem ceeb unmeted xav tau nyob rau hauv kev tswj ntawmParkinson tus kab mobkab mob yog qhov kev tshawb pom ntawm txoj hauv kev tshiab uas tuaj yeem ua rau qeeb, nres, lossis thim rov qab cov txheej txheem ntawm neurodegeneration. Novel tej zaum kev kho mob uas muaj tej yam ntuj tso nrogneuroprotectivecov kev ua ub no raug tsim. Curcumin yog polyphenolic compound cais los ntawm rhizomes ntawm Curcuma longa (turmeric). Nws tau raug pom tias muaj zog tiv thaiv kab mob, antioxidant, dawb radical scavenging, mitochondrial tiv thaiv, thiab hlau-chelating teebmeem, thiab yog suav hais tias yog ib tug cog lus kho mob thiab nutraceutical tus neeg saib xyuas rau kev kho mob ntawm PD. Txawm li cas los xij, molecular thiab cellular mechanisms uas kho cov tshuaj pharmacological ntawm curcumin tseem tsis paub ntau. Kev txhawb nqa ntawm nicotinic receptors thiab, ntau qhov tseeb, xaiv 7 nicotinic acetylcholine receptors ( 7-nAChR), tau pom los ua si Citation: Nebrisi, EENeuroprotectiveCov haujlwm ntawm Curcumin hauvParkinson tus kab mobKab Mob: Kev Tshawb Fawb Cov Ntawv Sau. Int. J. Mol. Sci. 2021, 22, 11248. https://doi.org/ 10.3390/ijms222011248

Academic Editor: Botond Penke lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob los ntawm "cholinergic anti-inflammatory txoj kev". Tsis ntev los no, 7-nAChR tau raug npaj los ua txoj hauv kev kho mob hauv PD. Hauv qhov kev tshuaj xyuas no, cov ncauj lus kom ntxaws mechanisms ntawm lubneuroprotectivekev ua ub no ntawm curcumin ua tus neeg sawv cev kho mob tuaj yeem pabParkinson tus kab mobcov neeg mob tab tom tham thiab piav qhia meej.

Ntsiab lus: curcumin; Tus kab mob Parkinson; neuroprotection; anti-inflammatory; antioxidant; 7-nAChR

Cistanche herba muaj cov nyhuv neuroprotective zoo heev

1. Taw qhia

Parkinson tus kab mobKab mob (PD) yog tus kab mob neurodegenerative thib ob tshaj plaws tom qabAlzheimer tus kab mobkab mob (AD), uas tau piav qhia thawj zaug los ntawm tus kws kho mob Askiv thiab kws phais mob, JamesParkinson, leej twg sau nws Essay ntawm Shaking Palsy hauv 1817, thiab tom qab ntawd tau muaj npeParkinson tus kab mobkab mob los ntawm Jean-Marie Charcot [1]. PD yog ib qho kev ua haujlwm qeeb qeeb ntau dua li tsis yog ib qho kab mob xwb, cuam tshuam nrog cov neuropathological degeneration loj hauv dopaminergic neurons ntawm SNpc thiab lawv cov terminals hauv striatum.

Pathologically, tus kab mob no txawv los ntawm phosphorylation ntawm alpha-synuclein protein thiab tsim ntawm proteinaceous inclusions, Lewy lub cev (LB) nyob rau hauv neurons thiab Lewy neurites (LN) nyob rau hauv axons thiab dendrites, raws li zoo raws li dopaminergic nigrostriatal neuronal degeneration [2]. Mechanistically, ntau yam tau cuam tshuam rau hauv dopaminergic neuronal degeneration: (1) Kev hloov caj ces ua rau muaj protein ntau misfolding thiab oxidative kev nyuaj siab. (2) Kev cuam tshuam rau co toxins ua rau mitochondrial tsis ua haujlwm thiab nce hauv cov pa oxygen reactive (ROS). (3) Neuroinflammation thiab mob ntev microglial activation, ob qho tib si ua rau cov neuronal degeneration los ntawm kev tso cov pro-inflammatory mediators thiab hloov lwm yam molecular thiab cellular functions [3–5].

PD yog ib qho teeb meem ntsig txog hnub nyoog, qhov uas muaj tus kab mob ntau ntxiv nrog rau cov hnub nyoog nce qib. Hauv cov teb chaws uas muaj kev lag luam, qhov kev nthuav dav yog nyob ib ncig ntawm 1 feem pua ​​​​rau cov neeg muaj hnub nyoog tshaj 6 xyoo 0 thiab 0.3 feem pua ​​​​rau cov neeg ntawm txhua lub hnub nyoog [6]. Txawm hais tias feem coob ntawm cov neeg mob tsis sib xws, kwv yees li 10-15 feem pua ​​​​ntawm cov neeg mob muaj keeb kwm zoo ntawm PD. Ib puag ncig kev thuam, ntawm lwm yam, ua rau muaj kev hloov pauv hauv PD, suav nrog mitochondrial dysfunction, oxidative kev nyuaj siab, kev hloov pauv hauv cov protein tuav, kev tiv thaiv kab mob tiv thaiv kab mob, thiab kev hloov pauv rau lwm yam molecular thiab cellular functions [3,7].

Txog niaj hnub no, tsis muaj tshuaj kho lossis txwv tsis pub muaj PD. Feem ntau ua haujlwm tsis zoo hauv dopaminergic system hauv lub hlwb, Levodopa lossis L-dopa (L-3,4-dihydroxyphenylalanine) tau qhia nyob rau xyoo 1960 raws li ib qho tshuaj ntawm dopamine (DA) uas txhim kho intracerebral DA concentration. Txij li thaum nws pom zoo los ntawm FDA xyoo 1970, L-dopa tau ua tus qauv kub kho rau PD. Txawm li cas los xij, tom qab ob peb lub hlis mus rau ntau xyoo ntawm kev kho mob nrog L-dopa, cov neeg mob tsim muaj kev phiv xws li dyskinesia [8,9], uas yog hu ua L-dopa-induced dyskinesia (LIDs). Nrog rau kev txwv ntawm kev siv L-dopa, lwm cov tswv yim tau siv los txhim kho dopamine tso tawm, xws li DA agonist, monoamine oxidase type B inhibitors (MAO-B), catechol-O-methyl transferase inhibitors (COMTIs), anticholinergic, beta- blocker, antipsychotic, thiab amantadine [10]. Kev cuam tshuam kev phais dhau los ua ib qho kev xaiv nrog lub hlwb sib sib zog nqus (DBS) raws li qhov cuam tshuam ncaj qha rau cov neeg mob PD xaiv [11,12]. Feem ntau, tag nrho cov tshuaj muaj yog tsim los hloov cov kev ua ntawm depleted DA nyob rau hauv lub striatum yam tsis muajneuroprotectivekev ua si. Txawm li cas los xij, kev kho mob ntev nrog cov neeg ua haujlwm no feem ntau muaj cov teebmeem kev kho mob sib txawv thiab ua rau muaj kev cuam tshuam tsis zoo. Nrog rau lub sijhawm, kev kho mob pib poob qis thiab cov neeg mob cov tsos mob thiab kev xiam oob khab hnyav zuj zus, cuam tshuam rau lub neej zoo nrog kev xav tau kev saib xyuas hauv tsev thiab kev mus pw hauv tsev kho mob ntau zaus [13,14]. Raws li ntau qhov kev tshawb fawb, lub neej expectancy ntawm PD cov neeg mob, tom qab pib ntawm tus kab mob, yog li ntawm 6.9 mus rau 14.3 xyoo [15].

Raws li tau hais dhau los, mitochondrial tsis ua haujlwm, oxidative kev nyuaj siab, thiab kev hloov pauv hauv kev tuav cov protein yog peb lub ntsiab pathophysiological derangements hauv PD uas cuam tshuam rau cellular functions [2,3,5]. Yog li, txhawm rau kom ntseeg tau tias muaj kev phiv tsawg dua thiab txhawm rau tsom mus rau txoj hauv kev sib txawv ntawm lub cev hauv lub cev, yuav tsum muaj kev qhuab qhia ntau yam uas siv ntau yam tshuaj lossis cov tshuaj sib xyaw ntawm cov koob tshuaj tsawg kawg nkaus. Ntuj polyphenol tebchaw muab tau los ntawm cov nroj tsuag, xws li curcumin, muaj ntau yam khoom noj khoom haus zoo. Curcumin tau tshwm sim los ua tus neeg sib tw muaj txiaj ntsig rau kev siv cov tswv yim tshiab ntawm ntuj molecules nrogneuroprotectivecov khoom raws li kev kho mob adjuvant hauvParkinson tus kab mobkab mob.

Hauv cov ntsiab lus no, qhov kev tshuaj xyuas no tsom mus rau qhovneuroprotectivekev ua ub no ntawm curcumin hauv PD thiab ntau yam kev koom tes. Curcumin's pharmacokinetics, pharmacodynamics, lom, cellular, thiab molecular zog yog tag nrho hais txog. Ib qho tshwj xeeb tseem ceeb yog muab rau curcumin'sneuroprotectivekev ua ub no los ntawm 7-nAChR-mediated mechanism, kev ruaj ntseg profile, tam sim no thiab yav tom ntej kev sim tshuaj rau daim ntawv thov kho mob.

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2. Curcumin ua ib tug muaj peev xwm Neuroprotective Agent

Curcumin tau muaj npe tom qab Vogel thiab Pelletier, thawj zaug cais cov "daj xim-cov khoom" los ntawm rhizomes ntawm Curcuma longa hauv (turmeric) 1815. Tom qab ntawd, xyoo 1842, lawv pom tias turmeric yog cov khoom sib xyaw ua ke thiab ua tiav hauv cais cov ntshiab curcumin roj. Xyoo 1910, Milobedeska thiab Lampe qhia nws cov qauv ua diferuloylmethane, lossis 1,6-heptadiene-3,5-dione-1,7-bis ({{10}) }hydroxy-3-methoxyphenyl) (Daim duab 1), thiab peb xyoos tom qab ntawd lawv tau tsim cov curcumin [16].

2.1. Cov khoom siv tshuaj thiab lub cev ntawm Curcumin

Curcumin yog ib qho symmetric molecule uas muaj peb yam tshuaj loj: ob lub nplhaib aromatic uas muaj O-methoxy phenolic pawg txuas los ntawm xya-carbon linker uas muaj , -unsaturated diketone moiety (Daim duab 2). Curcuminoid (cov xim daj-pigmented turmeric npaj) suav rau 3-5 feem pua ​​​​ntawm cov turmeric thiab feem ntau yog tsim los ntawm peb derivatives: curcumin (diferuloylmethane, curcumin I ~ 77 feem pua), dimethoxy- curcumin (DMC, curcumin II), bisdemethoxycurcumin (BDMC, curcumin III), thiab cyclo-curcumin [17,18]. Tag nrho peb derivatives yog suav tias yog ntuj turmeric analogs. Curcumin nthuav tawm keto-enol tautomerism, nrog cov ntawv enol predominating hauv alkaline media thiab keto cov ntaub ntawv predominating hauv acidic lossis nruab nrab media [17]. Curcumin yog ib qho hydrophobic compound uas yog insoluble hauv polar lossis nruab nrab cov kuab tshuaj xws li dej. Nws tuaj yeem yaj hauv cov kuab tshuaj organic lossis hydrophobic xws li dimethylsulfoxide (DMSO), ethanol, thiab acetone [19]. tetrahydrocurcumin (THC), dimethyl curcumin, di-dimethyl curcumin, Vanillylidenacetone, Di-(tert-butyl-dimethylsilyl) curcumin, O-tert-butyl-dimethylsilyl curcumin, thiab curcumin-d6 yog tag nrho cov khoom lag luam muaj curcumin metabolites.

2.2. Pharmacokinetics thiab Pharmacodynamics ntawm Curcumin

Tib neeg kev tshawb fawb ntawm curcumin's pharmacokinetics tau txais txiaj ntsig zoo ib yam li cov tau txais los ntawm kev tshawb fawb tsiaj. Vim nws txoj kev nqus tsis zoo, curcumin muaj qhov tsis muaj bioavailability hauv plasma thiab cov ntaub so ntswg, cov metabolism hauv lub siab sai, nrog rau kev tshem tawm sai sai ntawm cov plab hnyuv siab raum nrog tib neeg cov ntshav plasma ntawm 0.41-1.75 umol / L tom qab qhov ncauj. kev tswj hwm ntawm 4-8 g ntawm curcumin [20,21]. Ntau cov kev tshawb fawb tau pom tias curcumin feem ntau yog metabolized nyob rau hauv daim siab, qhov uas nws txo qis ntawm cawv dehydrogenase, ua raws li glucuronate thiab sulfate conjugation [8,21]. Tsis tas li ntawd, Perkins thiab cov npoj yaig tau tshaj tawm tias tib neeg xav tau koob tshuaj txhua hnub ntawm 1.6 g curcumin kom ua tiav cov txiaj ntsig xav tau [22].

Yuav luag txhua qhov kev tshawb fawb tau lees paub tias curcumin unformulated muaj tsawg bioavailability ntawm cov tsiaj thiab tib neeg [23,24]. Ntau yam formulations tau tsim los txhim kho curcumin bioavailability. Nano curcumin, piv txwv li, tau tsim los txhim kho curcumin solubility hauv cov kua dej. Cheng et al. tsim ib daim ntawv nanoparticle ntawm curcumin uas ua rau cov ntshav plasma ntau dua thiab ntau dua rau AUC nrog lub sijhawm nyob ntev dua hauv cov hlwb nas. [25]. Polylactic-co-glycolic acid (PLGA) thiab liposomal-formulated curcumins txhim kho cov dej solubility ntawm compound [26–28]. Hais txog curcumin permeability, cyclodextrin (CD) encapsulated curcumin txhim kho curcumin permeability piv rau unformulated curcumin [29]. Concomitant kev tswj hwm ntawm piperine nrog curcumin tseem ceeb txo kev tshem tawm thiab ib nrab lub neej tshem tawm ntawm curcumin [23,24]. Alginate-curcumin nanoparticles (Alg-NP-Cur) [30], glyceryl mono-oleate nanoparticles loaded nrog piperine thiab curcumin (GMO-NP-Pip/Cur) [31], curcumin-loaded lactoferrin nanoparticles (Lf-NP-Cur) [32], thiab curcumin-loaded polysorbate 80- hloov kho keratome (CPC) nanoparticles (NPs) [33], yog cov kev npaj sib txawv tsim los ua kom muaj txiaj ntsig zoo ntawm curcumin bioavailability.

2.3. Biological Properties ntawm Curcumin

Curcumin, ntau lub hom phiaj, tau ib txwm siv los ua cov txuj lom thiab tshuaj ntsuab hauv cov teb chaws Esxias rau ntau yam pathologies vim nws cov khoom tiv thaiv kab mob [34], thiab antioxidant zog [35,36]. Tsis tas li ntawd, curcumin muaj cov tshuaj tua kab mob [37], tshuaj tua kab mob [38], tshuaj tua kab mob [39], tshuaj tiv thaiv kab mob [40], hepatoprotective [41], anti-thrombotic [42], cardio-tiv thaiv [43], hypoglycemic [44], anti-allergic [45,46], qhov txhab kho [47], thiab chemo-tiv thaiv thiab anticancer zog [48-50]. Curcumin's anti-inflammatory thiab antioxidant teebmeem, ntawm lwm tus, tsim lub hauv paus ntawm curcumin qhov tseem ceeb.neuroprotectivecuam ​​tshuam rau ntau yam kab mob neurological cuam tshuam rau ob qho tib si hauv nruab nrab thiab peripheral paj hlwb. Ntau lub hom phiaj molecular ntawm curcumin tau raug txheeb xyuas raws li cov pov thawj dav dav los ntawm kev tshawb fawb hauv vitro thiab hauv vivo.

2.4. Molecular thiab Cellular Neuroprotective Mechanisms ntawm Curcumin hauv PD

Qhov kev tshuaj xyuas tam sim no tsom mus rau kev nce qib tsis ntev los no thiab cov txheej txheem hauv qab ntawm ntau yam kev lom zem ntawm curcumin tawm tsam cov kab mob neurodegenerative, tshwj xeeb.Parkinson tus kab mobkab mob. Curcumin lub peev xwm los hloov kho cov haujlwm ntawm ntau lub teeb liab kev hloov pauv txoj hauv kev tau txuas rau kev txo qis ntawm kev kis kab mob. Curcumin cuam tshuam nrog cov kev hloov pauv xws li z transcription (STAT) cov proteins [51], cov yam ntxwv loj hlob thiab lawv cov receptors, xws li, epidermal growth factor receptors thiab HER2 [52,53], cytokines, eg, interleukin 1b (IL-1). b), interleukin 6 (IL-6) [54], enzymes, eg, hex (HO-1) [55], thiab cov noob uas tswj cov cell proliferation thiab apoptosis [56]. Lub peev xwm ntawm curcumin los hloov kho thiab cuam tshuam nrog ntau lub xov tooj ntawm tes taw qhia txoj hauv kev thiab cov proteins qhia tau hais tias cov polyphenol no yog ib qho txiaj ntsig zoo rau ntau lub hom phiaj [57-59]. Qhov kev txiav txim siab no yog nyob rau hauv txoj kab nrog ntau cov ntawv tshaj tawm tsis ntev los no qhia txog curcumin raws li lub zog muaj zog epigenetic regulator [60,61]. Interestingly, curcumin's inhibitory nyhuv ntawm MOA-B enzyme [62], uas yuav ua rau kom nce qib thiab muaj DA hauv lub hlwb, tau txais kev mloog ntau hauv xyoo tas los, raws li tau tham hauv qab no.

Qhov kev xav tau tseem ceeb hauv kev tswj hwm ntawm PD yog qhov kev tshawb pom ntawm txoj hauv kev tshiab uas tuaj yeem ua rau qeeb, nres, lossis rov qab zoo tshaj, cov txheej txheem ntawm neurodegeneration. Curcumin covneuroprotectivepeev xwm tau pom nyob rau hauv ntau qhov kev tshawb fawb tsis ntev los no siv ntau yam tsiaj qauv ntawmParkinson tus kab mobkab mob [63–70]. Piv txwv li, Zbarsky tau piav qhia txog kev tiv thaiv cov txiaj ntsig ntawm curcumin ntawm tus lej ntawm TH-zoo neurons nrog rau qib striatal DA thiab nws cov metabolites; dihydroxyphenylacetic acid (DOPAC) thiab homophilic acid (HVA) tawm tsam 6-hydroxy dopamine (6-OHDA) induced neurodegeneration hauv tsiaj qauv ntawm PD [71]. Qhov kom zoo dua ntawm curcumin tshaj lwm yam derivatives, xws li demethoxycurcumin (DMC) thiab bisdemethoxycurcumin (BDMC), tau tshaj tawm ntawm DA receptor (D2) khi kev ua ub no thiab ntawm tus naj npawb ntawm TH plus ve neurons [72]. Yang et al. tau piav qhia txog kev tiv thaiv ntawm curcumin ntawm cov neeg raug mob hippocampus hauv 6-OHDA qauv ntawm PD, suav nrog kev txhim kho tseem ceeb hauv kev puas siab puas ntsws, hnyav nce, neurobehaviors, kev kawm thiab kev nco, qib ntawm dopamine thiab norepinephrine, neural regeneration hauv hippocampal cov ntaub so ntswg. , thiab cell survival-related signaling pathways xws li BDNF, TrkB, thiab PI3K [73]. Ntxiv mus, lub hlwb-derived neurotrophic factor (BDNF), ib tug tswv cuab ntawm tsev neeg neurotrophin loj hlob, uas koom nrog ntau yam paj hlwb, cuam tshuam hauv PD [74]. Curcumin restores neuronal regeneration los ntawm stimulating Trk/PI3K signaling cellular cascade, txo theem ntawm qog necrosis factor- (TNF- ) thiab caspase kev ua, li no nce qib ntawm BDNF nyob rau hauv 6-OHDA qauv ntawm PD [73,75]. Tsis ntev los no, peb tau tshawb xyuas cov teebmeem neuroprotective ntawm curcumin hauv 6-OHDA tsiaj qauv ntawm PD [70]. Cov txiaj ntsig tau qhia tias curcumin txhim kho txoj sia nyob ntawm striatal TH fibers thiab SNpc neurons, txo qis tus cwj pwm hloov pauv, thiab tawm dag zog.neuroprotectiveyam tsawg kawg yog ib feem ntawm 7- nAChR-mediated mechanism. Cov kev tshawb pom no muab pov thawj tias 7-nAChRs tuaj yeem yog lub hom phiaj kho mob thiab curcumin yuav yog thawj tus neeg sawv cev uas tau tshaj tawm los hloov kho nicotinic receptors hauv PD.

2.4.1. Curcumin Anti-Inflammatory Effects

Kev kis kab mob yog ib qho kev hloov kho lub cev uas peb lub cev tawm tsam kev raug mob lossis kis kab mob, thiab ua rau muaj kev tiv thaiv kab mob. Kev kis kab mob ua lub luag haujlwm tseem ceeb hauv ntau yam kab mob xws li neurodegenerative (PD thiab AD), autoimmune, plawv plawv, endocrine, thiab neoplastic disorders [76,77]. Nws yog ib qho kev sib cuam tshuam uas lub hom phiaj ntawm kev tshem tawm tus neeg sawv cev los yog cov ntaub so ntswg puas los ntawm kev ua kom muaj ntau yam kab mob sib kis. Kev ua kom lub cev tiv thaiv kab mob ntau dhau thiab cov lus teb tshwm sim tuaj yeem ua rau cov ntaub so ntswg puas tsuaj ntxiv [78,79]. Neuroinflammation tau txuas nrog cov kab mob neurodegenerative, suav nrog PD, tab sis txawm tias neuroinflammation yog qhov tshwm sim los yog tshwm sim los ntawm kev poob neuronal tseem muaj teeb meem [78,79]. Kev nce qib tam sim no hauv molecular biology muab pov thawj tias neuroinflammation plays lub luag haujlwm tseem ceeb hauv cov kab mob ntawm PD [80,81]. Cov tshuaj tiv thaiv kab mob hauv daim ntawv ntawm glial activation thiab cov txheej txheem inflammatory kuj tuaj yeem koom nrog hauv cov xwm txheej cascade, ua rau neuronal degeneration hauv PD. Activated microglia nthuav qhia ntau yam ntawm cov cell-surface receptors, ua rau nce qib ntawm cytokines xws li TNF- , interleukin -1 (IL-1 ), thiab interferon-y hauv substantia nigra ntawm PD cov neeg mob [82]. Cov no tswj kev mob ntev ntawm lub hlwb, neuronal tsis ua haujlwm, thiab kev poob ntawm cov neurodegenerative hauv PD [79,82]. Zoo kawg nkaus, curcumin nthuav tawm cov haujlwm tiv thaiv kab mob los ntawm inhibiting inflammatory cytokines, interleukins (ILs), chemokines, thiab inflammatory enzymes, cycloxygenase-2 (COX-2), GFAP qib, thiab cyclin D18 [3] 84] ib. Tsis tas li ntawd, curcumin inhibits qhov kev qhia ntawm inducible nitric oxide protein (iNOS mRNA qhia), LPS-induced TNF- , IL-1 , IL-6 ntau lawm, thiab JNK phosphorylation, collectively inhibiting cell apoptotic txoj kev thiab pab kom ciaj sia. [85,{29}}]. Kev cuam tshuam nrog thiab kev hloov kho ntawm cov teebmeem ntawm ntau yam kab mob sib kis los ntawm curcumin txheeb xyuas nws cov khoom tiv thaiv kab mob [16,65].

2.4.2. Curcumin Antioxidant teebmeem

Oxidative stress plays lub luag haujlwm tseem ceeb hauv kev mob hnyav, mob ntev, thiab degenerative kab mob. Oxidative kev ntxhov siab tshwm sim los ntawm qhov tsis sib xws ntawm kev tsim thiab nruab nrab ntawm cov pa oxygen reactive hauv peb lub cev, ua rau lub cim ntawm cov dawb radicals thiab lub zog tsis ua haujlwm [87]. Qhov kev loj hlob ntawm dopaminergic neurotoxicity hauv SNpc tau txuas ncaj qha rau oxidative kev nyuaj siab raws li lub hauv paus tseem ceeb hauv degenerating cascade hauv qab neuronal degeneration hauv PD. ROS oxidative kev nyuaj siab yog qhia meej meej txog kev ua haujlwm ntawm mitochondrial enzyme tsis ua haujlwm ntawm cov kab mob ua pa, uas yog, complex I, uas ua rau feem ntau ntawm kev puas tsuaj neuronal degeneration hauv PD [5,65]. Tsis tas li ntawd, cov nplua nuj ntawm polyunsaturated fatty acids nyob rau hauv lub hlwb, uas undergoes lipid peroxidation nyob rau hauv oxidative kev nyuaj siab, liberates ntau toxic by-products. Tsis tas li ntawd, qhov kev puas tsuaj ntawm cov kab mob reactive nitrogen xws li nitric oxide (NO) thiab peroxynitrite ntawm ob peb kauj ruam ntawm dopamine synthesis, mitochondrial tsis ua haujlwm, thiab yog li dopaminergic cell aging thiab tuag hauv PD, tau tshaj tawm [88,89]. Lub zog ua haujlwm ntawm curcumin tawm tsam pro-oxidants xws li superoxide radicals, hydrogen peroxide, thiab nitric oxide radicals, nrog rau kev txhim kho cov oxidant enzymes xws li catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), thiab heme oxygenase{ {8}} (OH-1), ua rau txo qis hauv lipid peroxidation thiab lub cev puas tsuaj [90–92]. Los ntawm nws cov teebmeem antioxidant, Nkauj thiab al. tau tshaj tawm tias curcumin muaj kev cuam tshuam rov qab rau cov neurons degenerated hauv substantia nigra, thiab ua kom pom kev txhim kho hauv lub cev muaj zog, cellular, thiab biochemical hloov pauv hauv PD nas [93]. Ib yam li ntawd, Khawaja muab cov pov thawj dav dav ntawm cov haujlwm muaj zog ntawm curcumin tiv thaiv pro-oxidants xws li superoxide radicals thiab hydrogen peroxide radicals, nrog rau kev txhim kho antioxidant enzymes xws li catalase, superoxide dismutase (SOD), thiab glutathione peroxidase (GPx), uas ua rau. hauv kev txo qis hauv lipid peroxidation thiab tom qab ntawd neuronal puas tsuaj hauv SNpc hauv 6-OHDA qauv ntawm PD [94]. Cov txiaj ntsig zoo sib xws ntawm cov tshuaj antioxidantneuroprotectiveCov khoom ntawm curcumin thiab, rau qhov tsawg dua, lwm yam curcuminoid derivatives xws li demethoxycurcumin thiab bisdemethoxycurcumin, tom qab ntawd tau lees paub [72]. Tsis tas li ntawd, curcumin antioxidant kev ua ub no rov qab dopamine nrog rau qib tyrosine hydroxylase hauv MPTP qauv ntawm PD [95]. Ib qho ntawm cov ntsiab lus tseem ceeb hauv kev txhim kho lub paj hlwb thiab kev tswj hwm ntawm lub hlwb neurogenesis yog kev ua kom muaj Wnt / -catenin signaling pathway [96]. Curcumin tau pom tias tiv thaiv oxidative stress-induced neurodegeneration hauv 6-OHDA PD los ntawm stimulating Wnt/ -catenin txoj kev, uas yog li ua rau kev txhim kho cell viability, ciaj sia taus, thiab txo neuronal apoptosis [97]. Kev hloov kho ntawm cov neeg nyob nruab nrab ntawm cov neeg nruab nrab, xws li c-Myc thiab cyclin D1 hauv Wnt signaling cascade, kuj tuaj yeem ua lub luag haujlwm tseem ceeb hauvneuroprotectiveKev ua haujlwm ntawm curcumin [98] Cov methoxy thiab phenolic pawg ntawm benzene rings thiab -diketone moiety nyob rau hauv cov qauv curcumin (Daim duab 2) yog xav tias yog ib qho tseem ceeb rau nws cov khoom tiv thaiv oxidant [17,99]. Interestingly, curcumin nthuav tawm lub zog tiv thaiv oxidant txawm tias piv nrog vitamin C thiab E [92].

2.4.3. Curcumin Dawb Radicals 'Kev Ua Si Kev Ua Si

Oxygen yog lub zog quab yuam rau feem ntau ntawm kev raug mob ntawm tes tsis tuaj yeem thiab cov kev hloov pauv neurodegenerative tshwm sim hauv PD. Txawm hais tias cov pa oxygen yog qhov tseem ceeb heev rau txhua qhov kev ua neej nyob, nws muaj kev phom sij rau tib lub sijhawm, qhov tshwm sim hu ua "cov pa oxygen paradox" [100,101] . Cov pov thawj ua ntej rau lub luag haujlwm ntawm oxygen paradox hauv PD tau txhawb nqa los ntawm kev soj ntsuam tom qab lub hlwb ntawm PD cov neeg mob uas pom tau tias muaj cov oxidized DNA, protein ntau, thiab lipid [102,103]. Txoj kev xav tom qab cov pa oxygen tsis txaus ntseeg yog nyob ntawm qhov tsis zoo ntawm cellular scavenging kev ua si, nrog rau qhov kawg ntawm cov protein carbonylation, tsim ntawm nitrotyrosine, thiab tom qab protein aggregation [104,105]. Hauv kev txhawb nqa ntawm qhov ntawd, cov kab mob pathological aggregates xws li -synuclein, ubiquitin-proteasome system (UPS), thiab cov kws kho mob tau tshaj tawm hauv PD [106]. Curcumin suav nrog ntau pab pawg ua haujlwm lub luag haujlwm rau nws cov haujlwm antioxidant. Tsis tas li ntawd, curcumin tuaj yeem tshem tawm cov khoom siv hluav taws xob ncaj qha thiab rhuav tshem cov saw hlau oxidation [107]. Kev kho curcumin tseem ceeb txo qis carbonylated proteins thiab nitrotyrosine-hloov cov proteins hauv rotenone-induced qauv ntawm PD [104]. ROS muaj ob qho tib si dawb radical oxidants thiab non-radical molecular oxidants. Dawb radical oxidants koom rau hauv ib qho kev hloov pauv hluav taws xob thiab hydrogen atom abstraction. Peb qhov chaw ua haujlwm, methoxy thiab phenolic pawg ntawm benzene rings thiab -diketone moiety ntawm curcumin, tuaj yeem raug oxidation los ntawm kev hloov hluav taws xob thiab hydrogen abstraction, thiab yog li tsim cov phenoxyl radicals stabilized. Curcumin yog ib qho zoo heev scavenger rau feem ntau ROS nyob rau hauv ib tug concentration los yog koob tshuaj-dependent yam [92]. Remarkably, curcumin inhibits oligomerization ntawm -synuclein, protein aggregation, thiab thiaj li neural toxicity [65,108], thiab tsim muaj peev xwm inhibitory cuam tshuam rau astrocytic ua kom zoo li NADPH oxidase system [65]. Kev tsim kho cov txheej txheem oxidative ntawm curcumin tuaj yeem ua tiav los ntawm kev sib tsoo lossis hydrogen pub dawb antioxidant, xws li vitamin E lossis ascorbic acid (Daim duab 3).

2.4.4. Kev Tiv Thaiv Mitochondrial

Mitochondria ua lub luag haujlwm tseem ceeb hauv kev tswj hwm cellular homeostasis [100]. Neuronal hlwb muaj kev vam khom rau mitochondrial zog ntau lawm [109,110]. Cov ntaub ntawv dav dav los ntawm cov xov tooj ntawm tes, noob caj noob ces, kev tshawb fawb tsiaj txhu lom thiab tom qab tib neeg lub hlwb ua rau pom kev ua haujlwm ntawm mitochondrial hauv PD hauv daim ntawv ntawm inhibited complex I thiab tom qab mitochondrial electron chain inhibition, lub zog tsis ua haujlwm, oxidative stress, thiab dopaminergic cell tuag hauv PD [3,1109,111. 113] ib. Curcumin yog ntau lub hom phiaj sib xyaw uas tuaj yeem ua haujlwm ua ib qhoneuroprotectivetus neeg sawv cev. Kev tswj hwm qhov ncauj ntawm curcumin tiv thaiv Swiss albino nas tawm tsam rotenone-vim kev ua haujlwm tsis zoo hauv mitochondrial respiratory saw thiab txuag cov mitochondrial enzyme complex, uas yog qhov cuam tshuam rau kev txhim kho cov cwj pwm ntawm cov tsiaj tom qab peb lub lis piam ntawm kev tswj hwm curcumin [114]. Tsis tas li ntawd, curcumin tau txais txiaj ntsig zoo hloov kho mitochondrial malfunction thiab tsis paub qab hau senescence [115,116]. Nws ua tau zoo txhim kho mitochondrial enzyme complex kev ua ub no hauv rotenone-induced PD qauv [114]. Tsis tas li ntawd, nyob rau hauv PTEN-induced putative kinase 1 (PINK1), ib tug genetic mutated qauv ntawm PD nyob rau hauv nas, pre-kho nrog curcumin im- proves cell viability, txhim kho mitochondrial membrane muaj peev xwm thiab txo apoptosis nyob rau hauv SH-SY5Y neuroblastoma hlwb [117] .

2.4.5 ib. Curcumin Iron-Chelating Properties

Hlau yog xav tau rau ntau lub hauv paus ua haujlwm hauv lub hlwb. Iron homeostasis tswj kev tswj hwm cov hlau nkag, ua kom zoo, thiab khaws cia. Cov hlau xws li hlau (Fe), zinc (Zn), thiab tooj liab (Cu) khaws cia hauv lub hlwb thaum peb muaj hnub nyoog [118]. Nrog rau lub hnub nyoog nce, muaj kev nce hauv lub hlwb hlau concentration thiab deposition raws li qhov tshwm sim ntawm hlau mismanagement, ua rau oxidative raug mob thiab neuronal degeneration [119]. Hlau yog khaws cia hauv lysosomes lossis khi rau neuromelanin thiab ferritin hauv cov hlwb hlwb. Cov tom kawg yog bio-vital chelator uas tswj los ntawm mitochondria [120,121]. Hlau deposition nyob rau hauv cov hlwb neuronal kuj tau raug suav hais tias yog ib qho ntawm cov kev tshawb fawb loj hauv postmortem PD lub hlwb, suav nrog substantia nigra [122,123]. Qhov tseem ceeb, kev ua haujlwm hlau-chelateing ntawm curcumin tau piav qhia yav dhau los [124]. Du et al. ua tiav qhov kev txo qis ntawm cov hlau-zoo hlwb tom qab kho curcumin hauv 6-OHDA induced qauv ntawm PD [125]. Kev txhawb nqa pov thawj ntawm kev kho curcumin ua ke thiab desferrioxamine, muaj zog hlau-chelating tus neeg saib xyuas, cuam tshuam qhov kev tiv thaiv ntawm curcumin ntawm dopaminergic neuronal poob hauv PD qauv [126]. Kev siv cov tshuaj deferoxamine ua ke nrog kev xa tawm tshiab; curcumin-loaded-nanocarrier nyob rau hauv rotenone-induced Parkinson tus kab mob qauv tau txais kev txhawb nqa tsis ntev los no, xws li kev sib xyaw ua ke tau muab kev tiv thaiv meej rau dopaminergic neurons tiv thaiv hlau deposition [127]. Sharma thiab cov npoj yaig tau txais txiaj ntsig zoo sib xws thaum inhibiting hlau deposition hauv dopaminergic neurons [65].

Kuv tuaj yeem yuav cistanche bark qhov twg

3. Neuroprotective Mechanisms ntawm Curcumin ntawm Nicotinic Acetylcholine Receptors

Curcumin cov tshuaj pharmacological yog xav tias yuav kho los ntawm ntau yam ligand-gated ion channels thiab receptors [128]. Cov kev tshawb fawb tsis ntev los no ntawm cov teebmeem ntawm lub ntuj polyphenol compound muab pov thawj tias curcumin muaj lub zogneuroprotectivecuam ​​tshuam raws li nws khaws cov kev ncaj ncees ntawm nigrostriatal dopaminergic system. Qhov no tau pom meej meej hauv kev txhim kho kev coj tus cwj pwm zoo hauv cov tsiaj kho curcumin los ntawm 7-nAChRs-mediated mechanism [70]. Txoj kev tshawb no ntxiv rau cov kev tshawb fawb hauv vitro yav dhau los uas qhia tau tias curcumin txhim kho cov teebmeem ntawm acetylcholine (ACh) los ntawm kev ua haujlwm ntawm 7-nAChRs nyob rau hauv ib tug concentration-dependent yam [129]. Tsis tas li ntawd, cov txiaj ntsig tau los ntawm lwm txoj kev tshawb fawb hauv vitro qhia txog lub luag haujlwm tseem ceeb ntawm curcumin hauv kev hloov pauv cov dej ntawm calcium (Ca2 ntxiv) ions ntawm 7-nAChRs [130]. Raws li qhov kev tshawb pom yav dhau los uas curcumin ua raws li hom II PAM ntawm 7-nAChRs thiab lub zog ntawm receptor muaj nuj nqi los ntawm kev txo qis desensitization [129], nws yog qhov tsim nyog los txiav txim siab tias curcumin's PAM ua ntawm 7-nAChRs muaj txiaj ntsig zoo hauv kev sib khoneuroprotectivecov teebmeem [131,132]. Curcumin lub sijhawm kuaj kev nyab xeeb,neuroprotectiveKev ua tau zoo, thiab kev kho mob ua ntej ua tiav ntawm cov neeg ua haujlwm tsom rau cov nicotinic receptors hauv PD ua rau nws yog ib tus neeg sib tw txaus nyiam rau kev tshawb nrhiav ntxiv thiab kev txhim kho hauv kev tshawb nrhiav PD kho.

Peb cov hauv vitro, hauv silico, thiab hauv vivo pom tau hais tias kev nce Ca2 ntxiv tuaj yeem muajneuroprotectivemechanism nyob rau hauv neuronal thiab non-neuronal hlwb ntawm ntau yam intracellular mechanisms, raws li qhia nyob rau hauv daim duab 4 [70,129,130]. Stimulation ntawm presynaptic 7-nAChR txhawb nqa vesicular DA tso tawm los ntawm Ca2 ntxiv rau -dependent kev yooj yim mechanism [133–135]. Extracellular signal-regulated mitogen-activated protein kinase (ERK/MAPK) activation can be triggered by protein kinase A (PKA) and/or calcium-calmodulin-dependent protein kinase (CaMK) [136]. Ib qho kev nce hauv intracellular Ca2 ntxiv rau qib yog suav tias yog qhov tshwm sim ntawm ob qho kev taw qhia cascades. Kev ua kom muaj zog ntawm (ERK/MAPK) yog qhov tseem ceeb tshaj tawm qhov tshwm sim hauv txoj kev ciaj sia ntawm tes los ntawm kev tswj hwm ntawm cov xov tooj ntawm tes; cAMP teb lub caij sib khi (CREB), nce cov noob qhia ntawm tyrosine hydroxylase thiab txhim kho DA tso tawm [137,138]. 7-nAChR kuj tau hais tawm ntawm microglia thiab astrocytes thiab ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob los ntawm "cholinergic anti-inflammatory pathway". Kev ua kom ntawm 7-nAChR ua rau muaj kev nce hauv intracellular Ca2 ntxiv rau cov concentration, thiab yog li hloov kho Janus kinase 2 (JAK2) thiab/los yog lub teeb liab transducer thiab activator ntawm transcription 3 (STAT3), xaus nrog kev nce qib ntawm cov protein kinase B. (PKB), ua rau inhibition ntawm nuclear factor-kB (NF KB) [139]. Lub lipid signaling cascade uas yog pib los ntawm protein kinase C (PKC), los ntawm phosphorylation ntawm phosphatidylinositol 3-kinase (PI3K/Akt), tau lees paub nrog kev hloov kho cov dej num ntawmneuroprotectivethiab apoptotic yam, xws li Bcl-2 thiab caspases, raws li [140–142]. Cov ntaub ntawv tsis ntev los no qhia tau hais tias kev tswj hwm ntawm cov tshuaj tiv thaiv neuroinflammatory los ntawm curcumin tshwm sim los ntawm kev hloov kho ntawm microglial JAK / STAT signaling pathway [143]. Sib sau ua ke, tag nrho lossis qee yam ntawm cov xwm txheej no ua rau txo qis apoptosis, txhim kho neuronal ciaj sia, hloov kho lub cev tiv thaiv kab mob, thiab tsim kev hloov pauv hauv synaptic plasticity [144].

Daim duab 4. Hypothetical qauv ntawm Ca2 ntxiv -dependent cell ciaj sia taus mechanism. Curcumin modulates 7-nAChR allosterically tso cai rau Ca2 ntxiv rau nkag mus rau hauv lub cell raws li tau piav qhia los ntawm cov ntaub ntawv electrophysiological. Kev nce hauv intracellular Ca2 ntxiv rau cov concentration yuav ua rau muaj kev cuam tshuam ntawm cov xwm txheej hauv dopaminergic neurons (los ntawm sab laug mus rau sab xis): Kev pab cuam ntawm dopamine tso tawm los ntawm synaptic vesicles. Ua kom ERK los ntawm PKA thiab / lossis CaMK, txhawb nqa CREB protein, nce tyrosine hydroxylase kev ua haujlwm, thiab qhib dopamine tso tawm. JAK2 / STAT3 signaling txoj kev ua rau inhibition ntawm NF-kB translocation ntawm PKB ua kom. Kev nce hauv IC Ca2 ntxiv rau attenuates inflammatory teb nyob rau hauv lub cev tiv thaiv kab mob activating protein kinase C, PKC zoo nkaus li ua kom downstream signaling PI3K/AKT txoj kev uas txhawb Nrf-2 translocation uas ua rau kev hloov ntawm cell ciaj sia taus proteins; Bcl-2 thiab caspase.

4. Kev Hloov Kho thiab Kev Pom Zoo tam sim no ntawm Curcumin

7-nAChR tau xav tias yog tus neeg sawv cev nutraceutical rau ntau yam kev puas hlwb, suav nrogParkinson tus kab mob, Alzheimer tus kab mob, thiab schizophrenia. Kev sim tshuaj kho mob tam sim no tab tom ua rau ntau tus 7-nAChR agonists thiab modulators [145]. Interestingly, 7-nAChR-positive allosteric modulators (PAMs) qhia tau zoo heev thiab muaj txiaj ntsig zoo. Curcumin, hom II PAM [129], yog ib qho khoom siv ntuj tsim nrog kev nyab xeeb siab thiab tsis muaj kev tshaj tawm txog tshuaj lom los ntawm hauv vitro mus rau hauv vivo, thiab kev sim tshuaj [20,146–150] yog siv ntawm cov tshuaj pom zoo [22,151]. Curcumin tau dhau los ua ntau qhov kev sim tshuaj rau kev kho mob ntawm cov kab mob neurodegenerative thiab pom tau tias muaj txiaj ntsig zoo hauv cov nas thiab tsis yog tib neeg primates [152-161].

Zuag qhia tag nrho, qhov kev tshawb pom tam sim no ntawm kev sim tshuaj ntsuam xyuas ntawm nicotinic receptors thiab PD lossis curcumin thiab neurodegenerative disorders xws li PD yog qhov zoo heev, tab sis ntau cov kev tshawb fawb ua ntej thiab kev sim tshuaj ntsuam xyuas yog xav tau los txhim kho curcumin's bioavailability thiab txheeb xyuas nws cov hom phiaj zais.

cistanche tubulosa

5. Cov lus xaus

Curcumin yog ibneuroprotectivetus neeg sawv cev nrog antioxidant [35,36], anti-inflammatory [86], dawb radical scavenging [107], mitochondrial tiv thaiv [62], thiab hlau-chelating zog [125], uas txhim kho DA qib hauv lub hlwb [ 62] ib. Kev sib cuam tshuam ntawm curcumin nrog 7-nACh receptors muab pov thawj ntxiv rau qhov muaj peev xwmneuroprotectiveLub luag haujlwm rau curcumin hauv PD. Tsis tas li ntawd, curcumin thiab derivatives qhia tau hais tias muaj kev nyab xeeb siab nrog qhov tsawg tshaj plaws qhia toxicity raws li tau pom ob qho tib si hauv vitro thiab hauv vivo kev tshawb fawb hauv PD qauv. Yog li ntawd, tau txais kev nkag siab zoo ntawm covneuroprotectiveCov khoom ntawm curcumin tuaj yeem muaj qhov cuam tshuam zoo rau kev kho mob. Cov pov thawj tshuaj xyuas txhawb nqa curcumin lub zog molecular thiab cellular cuam tshuam hauv cov kab mob neurodegenerative raws li lub tswv yim txaus siab rau kev txhim kho PD kev tswj hwm thiab kev soj ntsuam.

Cov Nyiaj Txiag: Cov haujlwm no tau txais kev txhawb nqa los ntawm lub chaw tshawb fawb ntawm DMC.

Institutional Review Board Statement: Tsis siv tau.

Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.

Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.

Kev lees paub: Tus sau ua tsaug lees paub Safa Shehab (College of Medicine thiab Health Sciences, United Arab Emirates University, Al-Ain, UAE) rau nws cov lus qhia tseem ceeb, thiab ua tsaug rau Hafez Abdel Fattah Ahmed (Dubai Medical College, Dubai, UAE) rau nws qhov tseem ceeb pab kho cov ntawv sau.

Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj kev cuam tshuam ntawm kev txaus siab.