Ntu Ⅰ Molecular Mechanisms Thiab Therapeutic Potential Of - Thiab -Asarone hauv Kev Kho Mob Neurological Disorders

Abstract

Cov kab mob neurological yog qhov tseem ceeb ua rau muaj kev mob nkeeg thiab kev tuag thoob ntiaj teb. Kev nce ntxiv ntawm cov kab mob neurological, cuam tshuam nrog cov neeg laus, tau ua rau lub neej muaj kev cuam tshuam nrog cov kab mob no, uas tsis muaj cov tswv yim kho mob tam sim no. Yog li ntawd, kev txheeb xyuas thiab kev txhim kho ntawm cov txheej txheem kho tshiab, tuaj yeem nres lossis thim rov qab neuronal poob los ntawm kev tsom mus rau cov laj thawj tseem ceeb uas ua rau neurodegeneration thiab neuronal cell tuag, yog qhov tsim nyog sai. Nroj tsuag thiab lwm yam khoom ntuj tsim tau raug tshawb nrhiav los ua qhov chaw nyab xeeb, ib txwm tshwm sim tom qab metabolites nrog cov khoom muaj peev xwm neuroprotective. Cov metabolites theem nrab - thiab -asarone tuaj yeem pom nyob rau hauv cov qib siab hauv cov rhizomes ntawm cov nroj tsuag tshuaj Acorus calamus (L.). - thiab -asarone nthuav tawm ntau yam khoom siv tshuaj xws li tshuaj tua kab mob antioxidant, tshuaj tiv thaiv kab mob, antiapoptotic, anticancer, thiab cov teebmeem neuroprotective. Daim ntawv no yog lub hom phiaj los muab cov ntsiab lus ntawm cov kev tshawb fawb tam sim no txog kev kho lub peev xwm ntawm - thiab -asarone hauv kev kho mob ntawm cov kab mob neurological, tshwj xeeb tshaj yog cov kab mob neurodegenerative xws li Alzheimer's disease (AD), Parkinson's disease (PD), nrog rau cov kab mob cerebral ischemic. , thiab mob qaug dab peg. Cov kev tshawb fawb tam sim no qhia tau hais tias - thiab -asarone tawm dag zog los ntawm kev txo qis oxidative kev nyuaj siab, txawv txav ntawm cov protein ntau ntxiv, neuroinflammation, neurotrophic yam tsis txaus, thiab txhawb nqa neuronal cell ciaj sia taus, thiab ua kom muaj ntau yam neuroprotective signaling pathways. Txawm hais tias cov txiaj ntsig tau txais txiaj ntsig los ntawm - thiab -asarone tau tshwm sim los ntawm kev tshawb fawb hauv vitro thiab hauv vivo tsiaj, kev tshawb fawb ntxiv yog xav tau los txhais cov txiaj ntsig hauv chav kuaj kom muaj kev nyab xeeb thiab zoo rau cov neeg mob AD, PD, thiab lwm yam kab mob neurological thiab neurodegenerative.

Ntsiab lus

-asarone; -asarone; neuroprotection; neuroinflamation; molecular luag hauj lwm; kho mob; neurological mob;Cov txiaj ntsig Cistanche.

Nyem qhov no kom tau txaisQhov zoo ntawm Cistanche yog dab tsi

Taw qhia

Lub paj hlwb, ib qho kev sib txuas ntawm cov paj hlwb thiab cov hlwb tshwj xeeb, yog lub luag haujlwm rau kev tswj hwm lub cev thiab kev sib txuas lus ntawm nws qhov chaw. Raws li Lub Koom Haum Saib Xyuas Kev Noj Qab Haus Huv Ntiaj Teb (WHO), cov kab mob neurological tau txhais tias yog cov kab mob ntawm lub hauv nruab nrab thiab cov hlab ntsha peripheral [1]. Cov kab mob neurological tuaj yeem cuam tshuam rau lub hlwb, cov hlab ntsha cranial, cov hlab ntsha peripheral, thiab txha caj qaum thiab suav nrog cov kab mob neurotraumatic, xws li mob stroke thiab txha caj qaum; Cov kab mob neurodegenerative, xws li Alzheimer's disease (AD) thiab Parkinson's disease (PD); nrog rau cov kab mob neuropsychological, xws li kev nyuaj siab thiab schizophrenia [2]. Feem ntau, cov kab mob neurological yog tus cwj pwm los ntawm kev mob hnyav thiab kev loj hlob ntawm cov neuron degeneration, thaum kawg ua rau lub hlwb tsis ua haujlwm thiab neuronal cell tuag [3]. Lub hauv paus molecular mechanisms ntawm neurodegeneration muaj xws li kev hloov pauv hauv phospholipid metabolism, tsub zuj zuj ntawm lipid peroxides, mitochondrial ua haujlwm tsis zoo, protein misfolding, txawv txav protein ntau, txo qis cellular zog, cuam tshuam calcium (Ca^{2 plus}) homeostasis, excitotoxicity, oxidative stress, neuroinflammation, dysregulated hormonal signaling, thiab apoptosis [4-6].

AD, ib qho ntawm cov kab mob neurodegenerative feem ntau, yog tus cwj pwm los ntawm kev loj hlob zuj zus ntawm kev kawm, kev nco, thiab lwm yam kev txawj ntse nrog lub hnub nyoog. Ntawm qib cellular, AD yog txuam nrog kev tsim cov plaques extracellular plaques uas muaj amyloid-beta (A) thiab neurofibrillary tangles uas ua rau muaj kev puas tsuaj loj heev. Los ntawm kev txo cov qib cellular zog thiab nce oxidative kev nyuaj siab, o, thiab apoptosis, cov "senile" plaques thiab aggregates ua rau neuronal cell tuag [7-9].

PD, qhov thib ob feem ntau cov kab mob neurodegenerative, yog tus yam ntxwv pathologically los ntawm kev poob ntawm dopaminergic neurons hauv substantia nigra pars compacta (SNpc) [10,11]. Qhov no nigral neuronal poob thiaj li ua rau dopamine (DA) tsis muaj peev xwm hauv striatum (ST), uas cuam tshuam nrog lub cev muaj zog xws li tshee, nruj, bradykinesia, postural instability, thiab gait impairment [12]. Dopaminergic cell tuag nyob rau hauv PD yog txuam nrog kev loj hlob ntawm intracellular -synuclein aggregates hu ua Lewy lub cev [13].

Cerebral ischemic kab mob, ib hom mob stroke, yog thib tsib ua rau tuag thiab kev tsis taus cuam tshuam rau ib lab tus neeg Asmeskas txhua xyoo [14]. Nws yog tshwm sim los ntawm kev txhaws ntawm cov hlab ntsha vim yog thrombus lossis embolus [15]. Thaum so, lub paj hlwb tau txais kwv yees li 20 feem pua ​​​​ntawm lub cev cov ntshav tag nrho thiab yog li ntawd, muaj kev cuam tshuam rau cov xwm txheej ischemic, thiab txawm tias luv luv ischemia tuaj yeem ua rau muaj kev puas tsuaj rau lub hlwb [15]. Thaum lub sij hawm cerebral ischemia, ib feem ntawm lub hlwb yog deprived ntawm oxygen thiab as-ham, uas pib ib tug cascade ntawm cellular thiab metabolic txheej xwm uas yuav ua rau lub hlwb puas. Muaj ntau cov pov thawj qhia tau hais tias qhov kev tso tawm ntawm glutamate ntau dhau lub sijhawm thiab tom qab kev thuam ntawm ischemic ua rau glutamate receptor hyperactivity, ua rau muaj kev phom sij hauv lub cev, suav nrog calcium overload thiab tsim cov tshuaj reactive oxygen (ROS). Qhov kev cuam tshuam ntawm cellular homeostasis nws thiaj li ua rau neurodegeneration [16,17].

Epilepsy yog ib qho kev puas siab puas ntsws uas tshwm sim los ntawm kev ua haujlwm tsis zoo ntawm hluav taws xob ib ntus hauv cov paj hlwb [18]. Xyoo 2015, nyob ib ncig ntawm 70 lab tus tib neeg tau kuaj pom tias muaj mob vwm thoob ntiaj teb, nrog 80 feem pua ​​​​ntawm cov xwm txheej no pom hauv cov teb chaws tsim kho [19]. Oxidative stress, glutamate excitotoxicity, thiab mitochondrial dysfunction, ntawm lwm tus, tau cuam tshuam rau hauv cov kab mob ntawm kev qaug dab peg [20].

Muaj ntau txoj hauv kev tau npaj rau kev tswj hwm ntawm neuronal dysfunction thiab cell tuag txuam nrog neurological ntshawv siab. Txawm li cas los xij, cov kev qhia tam sim no feem ntau pab txo lossis tswj cov tsos mob, thiab tsis muaj kev kho mob tau qhia uas tuaj yeem ua rau qeeb, tiv thaiv, lossis rov qab kab mob kev loj hlob [21].

Qhuav CistanchethiabCistanche ntsiav tshuaj

Cov nroj tsuag tshuaj, pom thoob plaws hauv ib puag ncig ntuj, sawv cev rau qhov loj ntawm bioactive compounds nyob rau hauv daim ntawv ntawm cov metabolites theem nrab thiab lwm yam bioactive constituents [22]. Cov metabolites thib ob muab tau los ntawm cov nroj tsuag tshuaj tau pom tias muaj txiaj ntsig zoo ntawm cov tshuaj sib npaug hauv lub hlwb los ntawm kev cuam tshuam kev ua haujlwm ntawm ntau cov neurotransmitter receptors, nrog rau cov txiaj ntsig zoo ntawm kev paub tsis meej [23]. Tsis ntev los no, peb cov kev tshawb fawb tau txheeb xyuas - thiab -asarone, pom nyob rau hauv cov qib siab hauv cov rhizomes ntawm cov nroj tsuag tshuaj Acorus calamus (L.), uas yog ib qho tseem ceeb theem nrab metabolites uas muaj peev xwm kho cov txiaj ntsig zoo rau kev kho mob ntawm AD, PD, thiab lwm yam kev puas hlwb. Cov txheej txheem hauv qab - thiab -asarone-mediated neuroprotection yog multiproged, thiab suav nrog antioxidant, antiapoptotic, thiab anti-neuroinflammatory teebmeem, nrog rau kev hloov kho ntawm ntau lub hom phiaj ntawm tes thiab molecular; Cov kev ua no thaum kawg yuav ua rau muaj peev xwm ntawm - thiab -asarone kom txo qis qhov mob ntawm cov hlab ntsha tsis zoo [24–27] (Daim duab 1). Qee qhov tshwj xeeb lub hom phiaj molecular koom nrog - thiab -asarone-mediated neuroprotection tsis ntev los no tau pib nthuav tawm. Piv txwv li, - thiab -asarone tau tshaj tawm los txhawb kev sib cais ntawm cov protein sib sau ua ke (tau, A , thiab -synuclein) cuam tshuam nrog neurodegenerative disorders [28,29], attenuate lipopolysaccharide (LPS)-mediated neuroinflammation, txhawb nqa neuronal cell ciaj sia, txhim kho lub cev muaj zog thiab tsis yog lub cev muaj zog, thiab tiv thaiv cov neurodegeneration ntawm dopaminergic neurons hauv lub hlwb (24,25. Antidepressant-zoo li cov teebmeem ntawm a- thiab B-asarone kuj tau piav qhia (30l, thaum Pan et al. [31] pom tias B-asarone tiv thaiv cortical neurons thiab txo qhov ntim ntawm infarction hauv kev sim qauv ntawm ischemic stroke.

Ntawm no, peb tshuaj xyuas cov kev tshawb fawb tsis ntev los no ntawm cov txheej txheem uas a- thiab p-asarone siv cov teebmeem neuroprotective hauv vitro thiab hauv vivo, kom paub meej lawv cov khoom siv tshuaj thiab tshuaj xyuas lawv lub peev xwm los kho cov kab mob neurological.

Kev tshwm sim, Bioavailability, thiab Pharmacokinetics ntawm - thiab -Asarone

Cov metabolites theem nrab a- thiab B-asarone ((E-/(Z)-124-trimethoxy-5-prop-1-enylbenzene) yog cov concentrated hauv cov rhizomes ntawm Acorus mlamus Linn, Acorustatarinowii Schott, thiab Acorus gramineus Solander, uas belongs rau Acoraceae plantfamily (feem ntau hu ua "sweet flag") (32). a-asarone raws li ib tug active phytochemical kuj muaj nyob rau hauv cov tawv ntoo ntawm Mexican ntoo Guatteria gamers Greenman los ntawm tsev neeg Annonaceae [33 A. calamus, ib leeg lossis ua ke nrog lwm cov tshuaj ntsuab, tau cog qoob loo ntau hauv ntau thaj chaw sov thiab subtropical thoob ntiaj teb [32,34,35] thiab dav siv los ua tshuaj ib txwm muaj rau ntau pua xyoo [32] A. calamus muaj Ob peb phytoconstituents, suav nrog alkaloids, volatile roj, tannins, glycosides (xanthone), tseem ceeb roj, flavonoids, monoterpenes, steroids, lignin, sesquiterpenes, saponins, mucilage, thiab polyphenolic compounds [36,37]. yog dav siv los kho ntau yam kab mob inflammatory [36,38–40], thiab hauv Suav teb, cov kws kho mob ib txwm muab tshuaj A. calamus los kho cem quav, digestive teeb meem, thiab lwm yam teeb meem kev noj qab haus huv [41]. A. calamus thiab nws cov ntsiab lus bioactive tseem tau pom los txo cov kev ntxhov siab vim kev tiv thaiv kab mob hauv nas, ua rau muaj kev tiv thaiv kab mob zoo dua [42]. Ob leeg - thiab -asarone tau kawm dav bioactive theem nrab metabolites, featuring ntau yam ntawm pharmacological zog, xws li antioxidant, anti-inflammatory, neuroprotective, antidiabetic, anticancer, antifungal, antimicrobial, anti-ulcer, anti-allergic, qhov txhab kho, tshuaj tua kab, insecticidal, thiab radioprotective zog, thiab lwm yam [36,43–47].

Cistanche ntxiv

1. Bioavailability thiab Pharmacokinetics ntawm - thiab -Asarone

Vim lawv cov lipophilic cwj pwm, - thiab -asarone muaj kev txwv qhov ncauj bioavailability, uas tuaj yeem txhim kho los ntawm kev ua kom lawv ruaj khov thiab solubility [48,49]. Lub plasma ib nrab-lub neej ntawm -thiab -asarone yog luv luv vim qhov kev faib tawm sai ntawm cov neeg ua haujlwm no rau cov kabmob tseem ceeb, xws li lub siab, tus po, lub plawv, lub raum, lub ntsws, thiab lub hlwb [25,48,5{16} ib., 51]. Kev tswj hwm qhov ncauj ntawm cov roj tseem ceeb (ib koob tshuaj ntawm 200 mg / kg) los ntawm A. tatarinowii Schott muaj 11 feem pua ​​-asarone thiab 74 feem pua ​​-asarone rau nas qhia tias qhov siab tshaj plaws ntawm cov ntshav plasma yog 0.5 µg / mL (tmax=11} min) rau -asarone thiab 2.5 µg / mL (tmax=14 min) rau -asarone, nrog ib nrab-lub neej hauv cov ntshav ntawm kwv yees li 1 h [52]. Qhov tseem ceeb, - thiab -asarone tau muab faib thoob plaws hauv lub hlwb, qhia tias lawv muaj peev xwm permeate cov ntshav-hlwb barrier (BBB), uas feem ntau yog ib qho kev txwv thaum tsim kho cov kab mob neurological, nrog rau cov kab mob neurodegenerative [24,25]. Lu et al. [49] kuj tau tshaj tawm qhov nqus sai thiab permeation ntawm BBB los ntawm -asarone hauv nas. Hauv lwm txoj kev tshawb fawb, kev tswj hwm qhov ncauj ntawm -asarone ntawm 80 mg / kg ua rau 34 feem pua ​​​​ntawm bioavailability [53]. Ib txoj kev tshawb fawb pharmacokinetic tsis ntev los no tau pom tias cov tshuaj intravenous (iv) kev tswj hwm ntawm lipid nanoparticles loaded nrog -asarone ua rau muaj kev nce ntxiv -asarone qib kuaj pom hauv murine plasma thiab hlwb parenchyma feem, piv nrog dawb -asarone, lees paub lub peev xwm los tsim thiab tswj kev kho mob. concentration ntawm -asarone nyob rau hauv plasma uas tuaj yeem thauj tau sai heev hla BBB [54]. Hauv lwm txoj kev tshawb fawb, kev xa tawm intranasal ntawm -asarone mus rau lub hlwb siv lactoferrin-hloov methoxy poly(ethylene glycol)-poly(lactide) copolymer (mPEG-PLA) nanoparticles pom zoo BBB permeability yam tsis muaj bioavailability tsis zoo, piv nrog iv tswj. Intranasal -asarone tus me nyuam txhim kho lub hlwb-targeting efficiency thiab txo lub siab tsub zuj zuj [55]. Lwm txoj kev tshawb fawb pom tau hais tias qhov tseeb bioavailability, lub hlwb-targeting efficiency, thiab feem pua ​​​​ntawm cov nasal-mediated hlwb xa ntawm nasally tswj PLA- -asarone nanoparticles yog 74.2 feem pua, 142.24 feem pua, thiab 29.83 feem pua, raws li, thiab qhov ntswg tswj tau txo cov tshuaj. -induced hepatotoxicity [56]. Nyob rau hauv ib qho in vitro BBB qauv, borneol thiab -asarone, siv los ua co-adjuvant agents, txhim kho lub hlwb xa ntawm lub hauv paus paj hlwb (CNS) tshuaj puerarin thiab tetramethylpyrazine. Vim tias cov nyhuv no tuaj yeem cuam tshuam los ntawm inhibitors ntawm adenosine receptors, cov kws sau ntawv xaus lus tias -asarone tuaj yeem nkag mus rau CNS los ntawm adenosine receptors (AR), uas sawv cev rau txoj hauv kev tseem ceeb rau kev xa tshuaj. Tsis tas li ntawd, kev sib koom ua ke ntawm borneol thiab -asarone txo qhov kev qhia ntawm zonula occludens 1 (ZO-1), ib qho tseem ceeb BBB hlws ris protein, tab sis nce A1AR thiab A2AAR qhia. Ib qho kev soj ntsuam hauv vivo pharmacokinetic tau lees paub tias kev sib koom ua haujlwm ntawm borneol thiab -asarone ua rau muaj kev nce ntxiv ntawm puerarin thiab tetramethylpyrazine hauv lub hlwb, qhia tias qhov koob tshuaj tsawg ntawm -asarone tsis tsuas yog txhim kho lub qhov ncauj bioavailability ntawm puerarin thiab tetramethylpyrazine tab sis kuj nce BBB. permeability, nrog -asarone nthuav tawm superior permeability li borneol [57].

Kev nqus, faib, metabolism, thiab tso tawm (ADME) hauv silico tsom xam qhia tias -asarone muaj qhov ncauj zoo bioavailability thiab khi affinity rau dopaminergic receptors [58]. Tsis tas li ntawd, hauv silico cov txiaj ntsig tau qhia tias -asarone yuav cuam tshuam nrog ntau yam amino acid residues hauv D2 thiab D3 dopamine receptors los ntawm hydrogen bonds [58]. Nyob rau hauv tib txoj kev tshawb no, cov tshuaj toxicity ntawm -asarone tau kwv yees siv Lazar thiab ProTox, cov cuab yeej suav siv los kwv yees cov khoom lom ntawm cov molecules. Lazar kwv yees tias -asarone yog carcinogenic nyob rau hauv ntau yam nas qauv. Kev txheeb xyuas ntawm kev mob toxicity siv ProTox pom tias -asarone muaj qhov siab LD50 tus nqi (418 mg / kg) thiab qhov tshwm sim ntawm qhov sib xyaw ua mutagenic hauv Salmonella typhimurium tau pom tias yog 0.573 [58]. Lwm txoj kev tshawb fawb qhia tias ib nrab-lub neej ntawm -asarone nyob rau hauv lub cerebellum, thalamus, hlwb, cortex, hippocampus, thiab ntshav yog 8.149, 2.832, 7.142, 1.937, 1.300, thiab 1.380 h, feem [59].

Cov txiaj ntsig ua ntej los ntawm cov kev tshawb fawb pharmacokinetic qhia tau hais tias lub hlwb permeability sai thiab tseem ceeb ntawm - thiab -asarone, xav tias yuav txaus siab ua rau muaj txiaj ntsig zoo rau kev ua haujlwm neuroprotective tsim nyog los tsim cov txiaj ntsig kho mob. Txawm li cas los xij, ntxiv hauv vivo cov kev tshawb fawb tseem tsim nyog los kos cov lus xaus hais txog ADME cov khoom thiab tag nrho kev nyab xeeb ntawm - thiab -asarone.

Cistanche tubulosa

2. Toxicology ntawm - thiab -Asarone: Preclinical Studies

Toxicity studies examining the effects of low doses of α- and β-asarone in rodent models have not revealed severe adverse effects. For instance, Chen et al. [60] reported that sub-chronic treatment with α-asarone (50 and 100 mg/kg, per os [p.o.], for 28 days) did not result in overt behavioral changes (walking, rearing, and grooming) in a seizure model generated in Swiss albino mice. However, α-asarone administered at a higher dose (200 mg/kg, p.o., for 28 days) significantly diminished spontaneous locomotor activity, although no mortality was observed. An acute toxicity test revealed that the oral median lethal dose (LD50) for α-asarone in mice was greater than 1000 mg/kg, with no deaths reported in any test groups [60]. In another study, mice were treated with α-asarone (150, 200, 250, 300, and 350 mg/kg) and survival was recorded for 14 days after treatment. The LD50 of α-asarone was calculated to be 245.2 mg/kg, with 95% confidence limits of 209.2–287.4 mg/kg. Deaths occurred mostly within 24 h after injection, and piloerection, ptosis, dyspnea, and ataxia were the most frequent clinical signs observed [61]. An in vivo subacute toxicity study revealed that the oral administration of β-asarone (100 mg/kg, for five consecutive days) reduced body weight and food consumption without causing mortality in pre-weanling rats [62]. Moreover, the weights of the adrenal glands and heart increased, the thymus weight decreased, and increased single-cell degenerative changes were observed in the thymus following β-asarone treatment. However, no significant changes in hematology or enzyme levels indicating hepatotoxicity were detected [62]. In yet another study, a long-term safety evaluation examining the effects of oral administration of β-asarone at 10 and 20 mg/kg p.o. for 90 days in mice did not reveal significant changes in any hematological parameters; however, blood concentrations of total bilirubin (BIL-T) increased following treatment with 20 and 50 mg/kg of β-asarone p.o. for 90 days; K+ concentrations decreased following treatments with 20 mg/kg/day of β-asarone p.o. for 90 days; and Cl− concentrations decreased following treatments with 50 mg/kg of β-asarone p.o. for 90 days [63]. Following the oral administration of β-asarone at 200 µg/kg for 20 weeks in mice, no obvious toxicity was observed. During an LD50 toxicity study, treatment with β-asarone (500, 750, 1000, 1250, 1500, 1750, and 2000 mg/kg, i.v., for 24 h) did not result in marked behavioral changes, and no obvious toxicity was observed [63]. Mice that died first appeared weak and less active, followed by gradual death, and the LD50 of β-asarone was calculated to be 1560 mg/kg [63]. Taken together, based on sub-acute toxicity tests, β-asarone at doses ≤ 100 mg/kg appears to be safe for clinical use, whereas the safety of doses >100 mg / kg tseem tsis paub meej. Yog xav paub ntxiv txog toxicology ntawm - thiab -asarone, peb xa tus nyeem ntawv mus rau cov kev tshuaj xyuas zoo hauv qab no [27,64].

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Rengasamy Balakrishnan 1,2, Duk-Yeon Cho 1, In-Su Kim 2, Sang-Ho Seol 3 thiab Dong-Kug Choi 1,2,

1 Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Kauslim; balakonkuk@kku.ac.kr (RB); whejrdus10@kku.ac.kr (D.-YC)

2 Department of Biotechnology, Research Institute of Inflammatory Disease (RID), College of Biomedical and Health Science, Konkuk University, Chungju 27478, Kauslim; kis5497@kku.ac.kr

3 Kev Tshawb Fawb thiab Kev Txhim Kho, Sinil Pharmaceutical Co., Ltd., Seongnam-si 13207, Kauslim; seol@sinilpharm.com