Melatonin Hormone Raws li Kev Kho Riam Phom Tawm Tsam Cov Kab Mob Neurodegenerative

Paub meej: Cov kab mob hauv hlwb xws li Alzheimer's thiab Parkinson's disease (PD) yog cov xwm txheej uas tsis muaj peev xwm rov qab los nrog ntau yam teeb meem kev txawj ntse, suav nrog kev kawm tsis taus, nco tsis tau, kev txav tsis zoo, thiab teeb meem hais lus. Cov teeb meem no yog tshwm sim los ntawm ntau yam, feem ntau yog vim muaj cov pa phem uas tshwm sim los ntawm kev hloov pauv biochemical hauv kev tsim cov protein, tsis muaj kev tswj xyuas hluav taws xob neuronal, thiab cov qib neurotransmitter hloov pauv. Oxidative kev nyuaj siab thiab toxicity txuam nrog nce glutamate theem txo qis acetylcholine, thiab lub hlwb o yog qhov tseem ceeb tshaj plaws. Melatonin hormone yog suav tias yog ib qho ntawm cov kev kho mob muaj zog rau cov kab mob neurodegenerative.

Nyem mus xyuas Cistanche tubulosa nco extract

Melatonin raug tso tawm los ntawm lub caj pas pineal thiab tseem ceeb heev rau kev tswj lub hlwb. Membrane receptors, khi qhov chaw, thiab tshuaj lom neeg sib cuam tshuam kho cov tshuaj hormonal uas muaj ntau yam phenotypic. Nws ua raws li tus neeg sawv cev neurodegenerative tiv thaiv qee cov kab mob neurological xws li Alzheimer's disease (AD), PD, kev nyuaj siab, thiab migraines. Melatonin inhibits neurotoxic pollutants-induced Tau protein hyperphosphorylation, tshwj xeeb tshaj yog nyob rau hauv AD. Lwm yam tseem ceeb ntawm melatonin yog nws cov khoom tiv thaiv kab mob, uas txo cov kev mob cytokines qhia thiab yam xws li IL-8, IL-6, thiab TNF. Melatonin kuj txo NO (ib qho mob tshwm sim). Hauv qhov kev tshuaj xyuas no, peb tau hais txog kev tiv thaiv cov teebmeem ntawm melatonin, feem ntau tsom pom nws cov txheej txheem tiv thaiv neuroprotective uas yuav muaj txiaj ntsig zoo hauv kev ntsuas nws cov teebmeem hauv ib puag ncig muaj kuab paug-induced neurodegenerative pathology.

Ntsiab lus: Alzheimer's disease; Kev mob; Melatonin; Tus kab mob Parkinson; Neurodegenerative tus neeg sawv cev

Taw qhia

Alzheimer's disease (AD) yog ib qho kab mob neurodegenerative uas cuam tshuam rau 2 feem pua ​​​​ntawm cov neeg laus thoob ntiaj teb (1). Amyloid plaques thiab filamentous sheaths nrog lub paj hlwb amyloid angiopathy yog ob yam tsos mob loj hauv cov neeg mob AD. Qhov tsis sib xws ntawm beta-amyloid (A) synthesis los ntawm amyloid precursor protein thiab nws lub hlwb clearance yog lub ntsiab ua rau A tsub zuj zuj thiab nws pathogenicity (2). Intracellular A assemblages rhuav tshem cov endolysosomal-autophagic system thiab tom qab synthesis ntawm autophagic vacuole thiab malformed mitochondria nyob rau hauv lub neuron (3). Muaj kev sib cuam tshuam tseem ceeb ntawm A thiab Tau cov proteins, uas yog cov protein tseem ceeb ntawm cov kab mob microtubule ntawm cov neuron paub tab uas khi rau microtubules thiab stabilizes tag nrho microtubule network (4). Beta-amyloid sib sau ua ke sab hauv thiab sab nraud cov neurons.

Ntawm qhov tod tes, intra-neuronal hyperphosphorylated Tau, dendritic spines tsom, thiab synapse degradation thaum kawg tuaj yeem ua rau nco tsis tau hauv cov neeg uas raug AD. Amyloid plaques raug txheeb xyuas nyob rau theem pib ntawm AD hauv cortex thiab hippocampus thaum lawv kis tau los ntawm theem ua ntej mus rau theem kho mob, nthuav tawm hauv nruab nrab paj hlwb lossis CNS (5). Glia-koom nrog kev mob thiab kev tuag neuronal hauv AD txo qis kev ua haujlwm neuronal thiab yog li kev paub tsis meej (6). Parkinson's disease (PD) yog lwm yam kab mob neurodegenerative uas cuam tshuam txog 1.8 feem pua ​​​​ntawm cov neeg laus. Nws yog tshwm sim los ntawm kev poob ntawm dopaminergic neurons nyob rau hauv substantia nigra pars compacta (SNpc) nyob rau hauv nruab nrab lub hlwb thiab ib tug successive poob ntawm dopamine thiab kho mob tshwm sim los ntawm lub cev muaj zog ua hauj lwm, txo kev txawj ntse zog, thiab kev nyuaj siab. Cov tshuaj biochemical tsom xam pom tias cov pa oxygen reactive (ROS) lossis hom reactive nitrogen (RNS) yog cov neeg sib koom ua ke hauv PD. Tus kab mob qee zaus muaj kev sib txuas ntawm caj ces, thiab cov cim qhia, thiab cov tsos mob ntawm PD yuav tsim, tsawg kawg ntawm ib feem, tom qab dawb radical puas rau SNpc. Tsis tas li ntawd, qhov o ntawm cov neurons thiab malfunctioning ntawm mitochondria pab txhawb rau etiology ntawm tus kab mob no thiab txhim kho oxidative puas tsuaj rau dopaminergic neuronal pejxeem.

Thaum feem pua ​​​​ntawm cov hlwb no ploj lawm, cov cim PD tshwm sim (7). Melatonin (N-acetyl{2}}methoxy tryptamine) cov tshuaj hormones raug tso tawm los ntawm midbrain pineal caj pas thiab qee cov ntaub so ntswg peripheral. Cov tshuaj no yog ib qho ntawm G-protein ua ke receptors tsev neeg, ua kom cov kab mob hauv lub cev (8). Melatonin, tryptophan metabolite, muaj ntau lub luag haujlwm ntawm lub cev xws li circadian rhythms kev cai, dawb radicals scavenging, kev tiv thaiv kab mob, thiab feem ntau inhibiting biomolecule oxidation (9). Cov tshuaj no muaj kev tiv thaiv zoo rau cov kab mob neurodegenerative (10). Kev txo qis hauv melatonin serum qib thiab cerebrospinal kua (CSF), thiab kev txo qis hauv melatonin txhua hnub tau tshaj tawm hauv cov neeg mob AD.

Ntxiv mus, melatonin qib hauv CSF txo qis tom qab tsim AD neuron-based pathologies (11). Melatonin cov ntsiab lus hauv CSF thiab tib neeg cov qog ntshav qab zib tau txo qis nrog thawj cov tsos mob ntawm AD neuropathology (12). Muaj kev sib koom ua ke ntawm cov ntsiab lus pineal, CSF, thiab plasma melatonin qib, uas tej zaum yuav yog ib qho cim ntxov hauv AD's thaum ntxov (13). Lwm cov yam ntxwv ntawm AD tuaj yeem ua tus cwj pwm los ntawm kev ua kom tsis zoo, neurites lossis neuronal degeneration, endosome aggregation, lysosomes, thiab mitochondria txawv txav (xws li extracorporeal aneurysms). Synapses deterioration thiab neuron apoptosis nyob rau hauv lub limbic system ua rau kev txawj ntse nyob rau hauv cov neeg mob AD (Daim duab 1) (14). Melatonin muaj ntau hom kev ua haujlwm tuaj yeem lees paub qhov tseeb tias melatonin receptors nyob hauv ntau cov ntaub so ntswg (15). Lub hlwb melatonin receptors tuaj yeem pom nyob rau hauv prefrontal cortex, cerebellum, hippocampus, basal nucleus, substantia nigra, nucleus accumbens, retina, thiab kuj nyob rau hauv ntau yam hypothalamus hlwb.

Ntxiv mus, cov receptors no tau tshwm sim nyob rau hauv cov ntaub so ntswg peripheral xws li lub plab zom mov, cov ntaub so ntswg adipose, pancreas, zes qe menyuam, tawv nqaij, ntsws, plawv, thiab lymphocytes (16). Melatonin muaj ob chav kawm receptors, uas suav nrog G-tsev neeg receptors [(melatonin receptor 1 (MT1) thiab melatonin receptor 2 (MT2)] thiab quinone reductase [melatonin receptor 3 (MT3)] enzyme tsev neeg. Lub MT1 thiab MT2 tuaj yeem pib ntawm tes kev taw qhia txoj hauv kev tom qab khi rau lawv cov ligand, txhua qhov ua rau cov lus teb tshwj xeeb (15, 16). Kev tiv thaiv qis qis ntawm MT2 thiab nce kev tiv thaiv ntawm MT1 tau tshaj tawm hauv AD cov neeg mob hippocampus (17). MT1 thiab MT2 yog. MT1 thiab MT2 receptors yog 350 thiab 362 amino acids nyob rau hauv ntev, feem, nrog rau molecular masses ntawm 39-40 kDa (18).

Cov receptors teeb liab los ntawm kev sib txuas nrog heterotrimeric Gi protein uas muaj , , thiab subunits. Ua kom cov receptors no txhawb kev sib cais ntawm G cov proteins rau hauv , , thiab dimers uas cuam tshuam nrog downstream cell signaling molecules (19). Hauv qab cov molecules hauv MT1 thiab MT2 receptors signaling los ntawm G protein coupling koom nrog adenylyl cyclase, phospholipase C, phospholipase A2, poov tshuaj raws, guanylyl cyclase, thiab calcium channels (20). Cov ntaub so ntswg enriched nrog MT1 thiab MT2 receptors suav nrog retina, hlwb, suprachiasmatic nucleus, pars tuberalis, zes qe menyuam, raum, pancreas, adipocytes, thiab lub cev tiv thaiv kab mob (21). Lwm yam khoom uas xav txog melatonin tiv thaiv ntau yam kab mob xws li mob qog noj ntshav lossis kab mob neurodegenerative yog nws cov khoom tiv thaiv apoptotic.

Txawm hais tias melatonin anti-apoptotic signaling pathways tseem tsis tau pom tag nrho, nws tau pom tias melatonin tuaj yeem qhib tau los ntawm qee txoj kev tiv thaiv, xws li nce Bcl-xL, Bcl-2, super oxidase dismutase, thiab glutathione peroxidase, los yog tshem tawm cov dawb radicals (22). Inhibition ntawm qee yam cuam tshuam nrog apoptosis xws li caspase, txo MAPK, thiab ERK kev ua haujlwm tiv thaiv qhov nce ntawm Rip txheej txheem hauv cov hlwb kom nplij siab tiv thaiv apoptosis (23). Ntau cov kev tshawb fawb tau pom tias muaj kev cuam tshuam melatonin rau AD, kab mob hauv lub hlwb, Amyotrophic Lateral Sclerosis (ALS), thiab PD. Cov kev tshawb fawb pom tias qhov tshwm sim ntawm cov kab mob no feem ntau yog nrog los ntawm kev poob ntawm melatonin lossis nws cov receptors (24). Lwm cov kev ua haujlwm melatonin suav nrog cov tshuaj tiv thaiv kab mob.

Melatonin tuaj yeem cuam tshuam ntau yam mob xws li TSIS TAU thiab NOS (25). Cov tshuaj no tswj cov cytokines synthesis xws li IL-6, IL-8, thiab lwm yam inflammatory parameters. Melatonin slows cia tej yam kab mob kev loj hlob (26). El-Shenawy et al. (25) pom cov nyhuv anti-apoptotic ntawm melatonin ntawm cov kab mob neurodegenerative. Melatonin tuaj yeem siv los txo cov tsos mob Huntington (27). Ntxiv mus, nyob rau hauv vitro melatonin tau unraveled los tiv thaiv ALS, Parkinson's, mob stroke, thiab AD txoj hauv kev uas melatonin tiv thaiv mitochondrial-dependent apoptotic txoj hauv ob qho tib si hauv vitro thiab hauv vivo thiab cuam tshuam nrog cell ciaj sia (28).

Kev cuam tshuam ntawm ib puag ncig yam

Ntau yam kev ua qias tuaj ib puag ncig tau pom tias muaj kev sib haum xeeb los ntawm kev hloov pauv hauv Tau phosphorylation, kev sib sau ntawm cov protein xws li -synuclein (-syn), mitochondrial dysfunction, thiab kev hloov pauv hauv cov hlau homeostasis (29). Cov kev tshawb fawb tau qhia tias A 42 thiab cyclooxygenase 2 (qhov taw qhia neuroinflammation) ntau dua nyob rau hauv lub hippocampus thiab frontal cortex ntawm cov neeg raug pa phem (30). Cov pa phem hauv huab cua ua rau microglia thiab tsim cov cytokines pro-inflammatory uas ua rau ventriculomegaly (los ntawm toxicity rau oligodendrocytes) thiab hypomyelination (30). Yav dhau los hauv vivo cov kev tshawb fawb ntawm Tg2576 nas pom tau tias qhov mob subcutaneous kev tswj hwm ntawm organophosphate tshuaj tua kab chlorpyrifos (50 mg / kg) nce kev nco thiab A qib hauv hippocampus thiab cortex thiab txo lub cev muaj zog ua haujlwm tom qab 6 lub hlis (31).

Txawm hais tias nanoparticles tau cog lus cov cuab yeej kho mob rau cov kab mob neurodegenerative, qee cov pov thawj koom nrog lawv nrog kev hloov pauv ntawm cov txheej txheem molecular tau koom nrog hauv cov kab mob ntawm cov kab mob neurodegenerative (32). Ze et al (33) tau pom tias kev tswj hwm qhov ntswg ntawm 2.5–10 mg / kg TiO2 nanoparticles rau 90 hnub ua rau oxidative kev nyuaj siab, cell tuag nyob rau hauv lub hippocampus, thiab poob rau hauv kev txawj ntse thiab kev nco-txuas nrog cov noob. Tsis tas li ntawd, kev txo qis hauv electrophysiological endpoints thiab spatial cognition tau pom nyob rau hauv lwm txoj kev tshawb fawb ntawm cov nas raug rau 0.5 mg / kg CuO-NPs (14 hnub, ip) uas ua raws li qib siab ntawm ROS tsim thiab lipid peroxidation thiab txo qis antioxidants enzymes qib ( 34). Ntau qhov kev sim thiab kev tshawb fawb txog kab mob kis tau hais txog qhov muaj feem cuam tshuam ntawm kev cuam tshuam rau ib puag ncig cov pa phem xws li nanoparticles, tshuaj tua kab, hlau, thiab kev txhim kho cov kab mob neurodegenerative (35). Vim muaj cov tshuaj lom neeg zoo sib xws raws li kev txo qis ntawm cov enzymes antioxidant thiab oxidative kev ntxhov siab tsim los ntawm cov pa phem no, cov tshuaj antioxidants ntuj xws li melatonin, curcumin, resveratrol, thiab lwm yam, thiab lawv cov nanoformulations tau txais kev saib xyuas ntau dua (35-37).

Melatonin induces kev txhim kho hauv cov kab mob neurodegenerative

Ntau cov kev tshawb fawb qhia txog cov nyhuv ntawm melatonin ntawm AD. Txhim kho kev nco hauv Alzheimer's nas thiab hauv vitro txo ​​qis hauv beta-amyloid apoptosis los ntawm melatonin tau kawm (27). Hauv lwm txoj kev tshawb fawb, melatonin tuaj yeem tiv thaiv Tau protein hyperphosphorylation los ntawm inhibiting cAMP, txo PKA kev ua, thiab txo CREB phosphorylation hauv vitro (38). Melatonin muaj zog tiv thaiv kab mob, uas inhibit pro-inflammatory cytokines thiab yam xws li IL-8, IL-6, thiab TNF qhia (39). Txij li thaum melatonin yog ib qho zoo tshaj plaws antioxidant cov neeg ua haujlwm raws li nws ncaj qha scavenges dawb radicals, nws yog siv nyob rau hauv ntau heev ntawm kev sim ua qauv nyob rau hauv uas cov pathogenicity yog xav kom kho los ntawm dawb radicals nyob rau hauv ib txoj kev los yog lwm yam (7, 40).

Tsis tas li ntawd, melatonin txo NO (ib qho tseem ceeb cuam tshuam rau kev mob o. Tsis tas li ntawd, raws li Tan et al. (41) AFMK metabolism, uas muaj peev xwm zoo li melatonin, tau siab dua hauv cov neeg mob meningitis dua li cov tib neeg ib txwm muaj. Korkmaz li al. (42 ) kuj tau tshaj tawm tias melatonin inhibited inflammatory enzyme activation (Daim duab 2). Melatonin txo nitrate los ntawm kev txo cov iNOS hauv PSLPS / IFN U los ntawm inhibiting NFkB kev ua.Melatonin tuaj yeem ua rau muaj kev tiv thaiv hauv kev puas tsuaj CNS (43). Raws li Hong li al. . (44) nyob rau hauv tus qauv SCI (Spinal Cord Injury), melatonin txo qis kev raug mob thiab ua kom rov zoo los ntawm inhibiting lipid peroxidation induced los ntawm neutrophils.

Cov nyhuv ntawm melatonin ntawm Akt / Protein Kinase (PKB) B Pathway

Txoj hauv kev no yog qhov tseem ceeb ntawm kev ciaj sia ntawm tes nruab nrab thiab apoptotic stimuli yam. PI3K / Akt txoj hauv kev muaj lub luag haujlwm tseem ceeb hauv cov paj hlwb ciaj sia (45). Thaum PI3K yog activated membrane phospholipids tsim phosphatidylinositol, uas nyob rau hauv lem induces Akt phosphorylation, ua tiav cov yam xws li Bcl -2 yog qhib thiab inhibiting apoptosis (46). Cov proteins no yog anti-apoptotic. Kev tshem tawm 2-Bcl endogenous paj paj qhia ncaj qha rau kev nplij siab neuron apoptosis hauv cov kab mob neurodegenerative. JNK txoj kev tiv thaiv apoptosis hauv kab mob neurodegenerative (47). Melatonin suppresses apoptosis los ntawm kev cuam tshuam ntawm cellular signaling thiab downregulates cov txheej txheem apoptosis. Thaum lub sij hawm cov kab mob neurodegenerative kev loj hlob, cov teeb liab cascades yog kho los ntawm neuronal tiv thaiv yam xws li phospho-inositol 3 kinase activator txoj kev thiab N-kinase 3 protein kinase (48).

Cov nyhuv ntawm melatonin txo qis A toxicity

Ib qho molecule (39-43 amino acids), ib daim ntawv derivative ntawm amyloid precursor protein (APP), muaj lub luag haujlwm tseem ceeb hauv AD. APP yog ib tug tswv cuab ntawm amyloid precursor protein tsev neeg APLP1 thiab APLP2. Tag nrho cov proteins no dhau los ntawm daim nyias nyias ntawm ib zaug thiab muaj thaj tsam loj sab nrauv. Tag nrho cov tswv cuab ntawm tsev neeg no tuaj yeem tsim cov amyloid fragments thiab mRNA down-regulation theem los ntawm APP, ua rau isoform ntau lawm, uas yog cov feem ntau cov ntaub ntawv nyob rau hauv lub paj hlwb (49, 50). 695 amino acid variants ntawm APP yog feem ntau nyob rau hauv CNS, tab sis 751 thiab 770 amino acid variants tau qhia lwm qhov. Cov kev tshawb fawb zoo sib xws tau qhia txog cov khoom muaj peev xwm rau A , uas tuaj yeem qhib tau los ntawm kinetic enzymes hauv oxidative stress regulation (51).

Melatonin's anti-fibrillogenic cov teebmeem tau raug tshem tawm los ntawm ntau yam kev siv tshuab microscopic thiab spectroscopic (52). Tsis tas li ntawd, cov tshuaj tiv thaiv ntawm melatonin thiab A tau raug suav tias yog txuam nrog cov qauv thiab cov khoom melatonin (53). Kev tshawb fawb los ntawm cov txheej txheem spectrometric tau txheeb xyuas tias melatonin cuam tshuam nrog txog 40 amino acid residues ntawm A, tshwj xeeb tshaj yog aspartate, thiab histidine, uas yog qhov zoo rau kev tsim daim ntawv. Kev rhuav tshem cov ntawv cog lus no ua rau A molecule dissolution. Melatonin kev sib cuam tshuam nrog succinate imidazolecarboxylate txuas txuas coj mus rau cov qauv hloov pauv mus rau hauv cov coils random. Yog li melatonin tsis tsuas yog tiv thaiv kev tsim-daim ntawv thiab txo cov neurotoxicity tab sis kuj txo A peptide secretion los ntawm kev nce proteolytic degradation (54).

Ib qho molecule's over-expression coj mus rau cellular puas xws li lipid peroxidation, nce intracellular dawb calcium concentration, mitochondrial DNA oxidative puas, thiab tso tawm apoptosis indicators. Cov kev tshawb fawb tau pom tias melatonin tswj cov mitochondrial hauv daim nyias nyias fluidity thiab khi rau mitochondrial membrane. Kev Tiv Thaiv Kev Sib Koom Tes yog suav tias yog qhov tseem ceeb hauv kev kho AD. Tsis ntev los no, ntau hom kev tshawb fawb tau pom tias melatonin tuaj yeem hnov ​​​​mob A 40 thiab A 42 molecules los tiv thaiv lawv cov kev loj hlob zuj zus mus rau -sheet lossis amyloid fiber (Table 1) (54, 55).

Melatonin suppresses Tau proteins synthesis

Tau yog cov protein ntau pom nyob rau hauv axon uas stabilizes neural pathways, microtubules, thiab neural kis tau tus mob. Cov noob no nyob ntawm chromosome 17 ntev caj npab thiab muaj 16 exons (56). Tau yog tam sim no tsis tsuas yog nyob rau hauv neuron axons tab sis kuj nyob rau hauv oligodendrocytes. Tau hyperphosphorylated daim ntawv yog tsis soluble, nyob rau hauv uas nws propensity rau microtubules yog txo thiab spontaneously tsim complex interconnected lug (57). Tau cov proteins sib sau sab nraud ntawm AD thiab lwm yam kab mob CNS (39). Cov kab mob no hu ua Tauopathy. Tus nqi ntawm cov hlua neurofibrillary yog ib qho ntawm AD prognosis markers (58). Lub ntsiab Cheebtsam ntawm cov coils yog hyperphosphorylated thiab sau tau cov ntaub ntawv protein.

Zoo li A oligomers, qhov txawv txav tau cov protein nruab nrab sib xyaw ua ke kuj muaj kev cuam tshuam rau cov hlwb thiab ua rau muaj kev puas hlwb. Insoluble complex strands tej zaum yuav tsis muaj kev phiv tab sis txo qis synaptic kis tau tus mob thiab cov xov tooj neuron yog vim neurofibrillary coils 'detrimental teebmeem. Tus kab mob Parkinson tau txheeb xyuas ntau dua 30 qhov kev hloov pauv hauv cov noob taum ntawm chromosome 17 (59). Hauv qhov sib piv, tsis muaj kev hloov pauv hauv Tau protein hauv AD, thiab kev tsim cov kab mob neurofibrillary tsis yog los ntawm Tau protein hloov pauv. Txawm li cas los xij, qhov nce ntawm Tau phosphorylation hauv cerebrospinal kua yog ncaj qha ntsig txog qhov txo qis hauv cov qhab nia xeem.

Kev nce qib ntawm Tau phosphorylated nyob rau hauv cov kua cerebrospinal tuaj yeem raug tswj hwm raws li biomarker tsim nyog hauv kev kwv yees thiab kuaj xyuas AD thaum ntxov hauv cov neeg mob kev paub tsis meej. Melatonin synthesis inhibition ua rau spatial nco impairments nyob rau hauv nas thiab elevated Tau phosphorylation ntawm PP-2Ib qho kev tawm tsam (60). Melatonin supplementation nrog 5-hydroxyindoleO-methyltransferase ua rau muaj kev cia siab ntau ntxiv tau raug ntes Tau, thiab txo qis hyperphosphorylation, oxidative stresses, thiab PP-2A dej num (60).

Kev tiv thaiv ntawm melatonin rau neuroinflamation

Hauv qee hom, pinealectomy thiab lwm yam kev sim ua haujlwm uas cuam tshuam cov melatonin secretions txhawb lub immunosuppression theem uas yog ntxiv thim rov qab los ntawm kev tswj cov melatonin (61). Hauv ntau yam hauv vivo sim ua qauv thiab hauv vitro kev tshawb fawb, melatonin induces inflammatory cytokines thiab nitric oxide synthesis. Melatonin induces T-lymphocytes, monocytes, ntuj killer hlwb, granulocytes, cell-dependent cytotoxicities, thiab cov tshuaj tiv thaiv-dependent teb (62). Tsis tas li ntawd, NF-κB DNA binding inhibition los ntawm melatonin txo qis cov lus teb pro-inflammatory thiab ua rau txo qis 50 feem pua ​​ntawm A-induced pro-inflammatory cytokines. Txawm li cas los xij, T-lymphocyte thiab NK hlwb yog qhov txaus siab rau kev mob neural. Melatonin muaj cov tshuaj tiv thaiv kab mob los ntawm kev tsom IL-6, IL-2, IL-1b, IL-12, IL-1, TNF- , thiab IFN - cytokines (63).

Melatonin nyob rau hauv monocytes tsub kom ROS tsim thiab cellular toxicity, qhia tau hais tias lub dual teebmeem ntawm melatonin rau o (64). Txawm li cas los xij, nws cov txiaj ntsig ntawm kev sib txuas ntawm monocytes thiab microglial hlwb tsis tau tshaj tawm. Melatonin muaj kev cuam tshuam tseem ceeb ntawm kev hloov pauv ntawm lymphocytes thiab lwm yam leukocytes hauv cov ntaub so ntswg tiv thaiv kab mob. Txawm li cas los xij, cov kev hloov pauv hauv lub cev tiv thaiv kab mob thaum hluas tuaj yeem cuam tshuam kev noj qab haus huv thiab cuam tshuam tsis ncaj rau CNS. Tsis tas li ntawd, melatonin coj cov inhibition ntawm prostaglandin E2 (PGE2) ntawm IL-2 synthesis. Nws upregulates anti-inflammatory yam dab tsi L-10 thiab IL-2 (65).

Ob qho tshuaj tiv thaiv kab mob ntawm melatonin hauv macrophages yog kho los ntawm kB-NF txoj hauv kev, uas cuam tshuam nrog cyclo oxidase 2 (COX 2) qhia los ntawm iOS ua kom. Cov ntawv ceeb toom tau qhia tias melatonin inhibits apical apoptosis thiab DNA fragmentation los ntawm inhibiting caspase-1 kev ua thiab IL-1 zais cia hauv hlwb hlwb. Nws tseem tiv thaiv kev mob los ntawm Akt / K-PI3, JNK, thiab Akt phosphorylation txoj hauv kev. Melatonin tswj apoptotic signals los ntawm downregulating phosphorylation / MEK1, 1-Raf, thiab ERK1, yog li tiv thaiv cellular puas (66).

Melatonin li dawb radicals scavenger

ATP yog tsim nyob rau hauv mitochondrial electron hloov saw hlau thaum lub sij hawm cellular respiration. Hauv cov xwm txheej ib txwm muaj, 5.5 feem pua ​​​​ntawm cov pa oxygen hloov mus rau kwv yees li ib hom oxygen (67). Qhov siab tshaj plaws ntawm ROS radicals yog superoxide anion (O2) uas yog tsim los ntawm electron keeb kwm ntawm oxygen (O2) molecule. Lwm cov ROS tus nqi qis uas muaj anion nitrite peroxide yog hydroxyl radicals, carbonate radicals, thiab nitrogen dioxide (NO2) uas yog synthesized los ntawm cov cellular Cheebtsam thiab muaj deleterious teebmeem ntawm protein synthesis (67). Txij ntawm no mus, cov dawb radical scavenging muaj lub luag haujlwm tseem ceeb hauv ntau lub paj hlwb, kev tiv thaiv kab mob, thiab inflammatory, thiab kab mob mitochondrial.

Kev ua haujlwm tsis tiav mitochondrial yog ib qho ua tau zoo tshaj plaws ntawm cov kab mob dawb-radicals hauv cov kab mob xws li cov kab mob neurodegenerative, ischemia, thiab cov txheej txheem kev laus. Yog li ntawd, cov dawb radicals ntau ntxiv, kev ua pa ua pa, kev ua haujlwm ntawm mitochondrial, thiab qhov tsis xws luag hauv cov saw hlau thauj hluav taws xob ua rau mitochondrial tsis ua haujlwm thiab cellular tuag. Melatonin induces glutathione synthesis, lwm antioxidant uas txo mitochondrial electron saw electron emission (68).

Melatonin yog xaiv absorbed los ntawm mitochondria thiab ua raws li ib tug muaj zog antioxidative tus neeg saib xyuas thiab tswj mitochondria lub bioenergetic functions (69). Nws tsub kom mitochondrial membrane permeability thiab stimulates disparate antioxidant enzymes. Yog li, melatonin tuaj yeem tiv thaiv oxidative puas tsuaj los ntawm kev kho cov kab mob microsomal. Melatonin txo cov dawb radical ntau lawm. Nws tiv thaiv electron emission nyob rau lub sij hawm ntev thiab yog li txhim kho mitochondrial muaj nuj nqi los ntawm inhibiting electron charging. Qhov siab tshaj plaws ntawm melatonin muaj nyob hauv mitochondria (70).

Lub luag haujlwm ntawm melatonin hauv kev kho PD

PD yog ib qho kev puas siab puas ntsws uas ua rau cov hlwb dopaminergic ua rau cov substantia nigra thiab striatum. Ntau cov ntaub ntawv tshawb fawb tau hais txog kev hloov pauv, oxidative stresses, thiab dawb radical-induced increment in mitochondrial thiab dopamine-metabolizing enzymes (74). Yog li, kev tswj hwm tshuaj tiv thaiv kab mob antioxidant tau raug pom zoo ua kev kho mob zoo rau PD (75). Singhal et al. (76) siv neurotoxin (MPTP) hauv nas PD qauv thiab pom qhov txo qis melatonin hauv MPTP-mediated lipid peroxidation thiab hypertriglyceridemia. Hauv kaum xyoo dhau los, ntau pua daim ntawv tshaj tawm nthuav tawm cov ntaub ntawv tshawb fawb txog kev kho lub luag haujlwm ntawm melatonin hauv ntau qhov kev cuam tshuam OS nrog cov kev tiv thaiv raug ntaus nqi rau qhov ncaj thiab tsis ncaj cov tshuaj tiv thaiv antioxidant ntawm indole. Melatonin tau raug siv nyob rau hauv ntau qhov kev sim ua qauv nyob rau hauv uas pathogeny xav tias yuav tsum tau kho los ntawm cov dawb radicals nyob rau hauv ib txoj kev los yog lwm yam.

Cov pov thawj tseem ceeb ntawm qhov tshwj xeeb ntawm melatonin thiab PD yog los ntawm kev tshawb pom ntawm cov kev ua pineal txo qis thiab kev txo qis hauv kev nthuav dav melatonin concentrations hauv PD-cov neeg raug cuam tshuam (40). Melatonin kuj nce qib antioxidant enzyme, dhau li ntawm kev tiv thaiv apoptosis hauv hippocampus. Qhov kev tiv thaiv kev tiv thaiv ntawm melatonin cuam tshuam nrog inhibition ntawm extracellular calcium txauv los ntawm mitochondrial membrane, stimulating mtPTP txoj kev, zam ROS tsim, thiab cytochrome C secretion txo. Lwm txoj kev tshawb fawb hauv nas tsiaj qauv qhia tau hais tias melatonin inhibited caspase -3 kev ua. MPTP exerts nws cov teebmeem neurodegenerative los ntawm nce NO synthesis, uas ua rau dopaminergic fiber ntau nyob rau hauv lub paj hlwb striatum kawg.

Melatonin ua los ntawm JNK txoj hauv kev los tiv thaiv dopaminergic apoptosis hauv substantia nigra thiab striatum thiab yog li, nws txo qis iNOS thiab tsis muaj qib hauv paj hlwb thiab cuam tshuam cov txheej txheem no (77). Melatonin kuj txhawb Mn-SOD, antioxidant, thiab GPx antioxidants hauv dopaminergic hlwb (78, 79). Tsis tas li ntawd, melatonin nce mitochondrial complexes 1 thiab 3 kev ua haujlwm thiab muaj txiaj ntsig zoo. Nws khaws cia mitochondrial homeostasis, txo cov dawb radicals synthesis, thiab txhim kho ATP synthesis. Yog li, melatonin tuaj yeem tiv thaiv apoptotic cascade thiab dedopaminergic neuron apoptosis (80). Contrary to saum toj no, ob peb cov kev tshawb fawb tau qhia tias txawv txav aggregation ntawm lub cytoskeleton cuam tshuam rau neurodegenerative kab mob pathogenesis. Levi lub cev, uas yog cov cim cytopathological ntawm PD, yog cov qauv txawv txav ntawm tubulin, ubiquitin, thiab microtubule proteins 1 thiab 2.

Melatonin muaj txiaj ntsig zoo hauv kev tsim thiab rov tsim dua tshiab ntawm cytoskeleton tsim thiab yog li, nws yog ib qho ua tau los ua ib qho ntawm cov tshuaj muaj peev xwm hauv cov kab mob neurodegenerative. Ntau yam kev tshawb fawb tau qhia tias melatonin muaj lub zog kho qhov tseem ceeb ua tus neeg saib xyuas neuroprotective hauv PD, ALS, thiab mob hlwb. Ntxiv mus, kev sim tshuaj melatonin tau tsim nws cov teebmeem neuroprotective (81). Cov kev tshawb fawb tsis ntev los no tau qhia txog kev txhim kho cov peev txheej ntawm melatonin siv cov keeb kwm keeb kwm nanocarriers rau kev xa tshuaj (82). Cov nanoformulations no tuaj yeem muab cov txiaj ntsig zoo hauv kev hla cov ntshav-hlwb cov teeb meem thiab txuas ntxiv melatonin tso tawm (82, 83). Cov yam ntxwv sib txawv ua rau melatonin tiv thaiv neurodegeneration los ntawm kev tsom mus rau mitochondrial-txog txoj hauv kev (84). Tau kawg, nws yuav tsum raug sau tseg tias kev saib xyuas rau lwm yam xws li cov teeb meem caj ces, kev kho noob caj ces, thiab kev sib txawv ntawm caj ces hauv qhov no tseem ceeb heev (85-87).

Xaus

Melatonin yog endogenous, non-toxic, thiab antioxidative tus neeg sawv cev. Nws raug suav hais tias yog ib tus neeg muaj txiaj ntsig zoo hauv cov kab mob neurodegenerative sib txawv nrog rau AD thiab PD raws li kev kho mob nrog cov qauv kev kho mob. Ntau yam kev tshawb fawb ntawm melatonin qhia tias nws tuaj yeem siv tau los ua ib qho ntxiv hauv cov kab mob neurodegenerative los ntawm nws cov teebmeem ntau yam, tshwj xeeb tshaj yog anti-apoptotic thiab anti-inflammatory zog. Cov ntaub ntawv sim ua ke qhia tias kev siv melatonin yuav txo lawv cov kab mob. Vim tias cov kab mob neural feem ntau tshwm sim los ntawm kev puas tsuaj oxidative, melatonin tau raug tshawb xyuas hauv ntau hom kev sim. Melatonin-raws li kev kho mob zoo li yog ib txoj hauv kev zoo los txo cov kev xav tsis zoo hauv AD thiab cov neeg laus cuam tshuam PD.

Vim li cas noj Cistanche tuaj yeem kho AD&PD

Cistanche muaj cov tshuaj bioactive uas tau pom tias muaj cov teebmeem neuroprotective. Tshwj xeeb, nws muaj echinacoside thiab acteoside uas tau pom los txhim kho kev txawj ntse thiab tiv thaiv cov neurodegeneration hauv kev tshawb fawb tsiaj. Cov tebchaw no kuj tau pom tias muaj cov tshuaj tiv thaiv kab mob thiab cov tshuaj antioxidant uas tuaj yeem pab txo qis kev puas tsuaj rau lub hlwb thiab txhim kho lub hlwb. Tsis tas li ntawd, Cistanche tau pom tias nce qib ntawm cov neurotransmitters xws li dopamine thiab acetylcholine uas yog ib qho tseem ceeb rau kev tswj lub hlwb ua haujlwm thiab depleted hauv AD thiab PD.

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Zahra Asefy1, Ameer Khusro2*, Shakar Mammadova3, Sirus Hoseinnejhad1, Aziz Eftekhari1,4*, Saad Alghamdi5, Anas S. Dablool6, Mazen Almehmadi7, Elham Kazemi8, Muhammad Umar Khadayam Sahib*

1 Department of Pharmacology thiab Toxicology, Maragheh University of Medical Sciences, Maragheh, Iran

2 Kev Tshawb Fawb Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv thiab Biotechnology, Loyola College, Chennai, Tamil Nadu, India

3 Department of Physical Geography, Baku State University, Baku, Azerbaijan 4 Department of Biology thiab Chemistry, Drohobych Ivan Franko State Pedagogical University, Drohobych, Ukraine

5 Laboratory Medicine Department, Kws qhia ntawv ntawm Applied Medical Sciences, Umm Al-Qura University, PO Box.715, Makkah, 21955, Saudi Arabia

6 Department of Public Health, Health Sciences College ntawm Al-Leith, Umm Al-Qura University, Makkah, Saudi Arabia

7 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, PO Box 11099, Taif 21944, Saudi Arabia

8 Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

9 Department of Pharmacy, Sarhad University of Science & Information Technology, Peshawar 25100, Khyber Pakhtunkhwa, Pakistan