Melatonin Yuav Ua Li Cas Neuroprotective Lub luag haujlwm hauv Mitochondria?

Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com

Lindsay M. Melhuish Beaupre1,2, Gregory M. Brown1,3, Vanessa F. Gonçalves1,2,3 thiab James L. Kennedy1,2,3

Abstract

Melatoninyog ib qho qub molecule uas pom tseeb nyob rau hauv siab concentrations nyob rau hauv ntau yam ntaub so ntswg thoob plaws lub cev. Nws tuaj yeem muab cais ua ob lub pas dej; ib qho yog synthesized los ntawm pineal thiab tuaj yeem pom hauv cov ntshav, thiab qhov thib ob los ntawm ntau cov ntaub so ntswg thiab muaj nyob rau hauv cov ntaub so ntswg. Pineal melatonin qib qhia txog circadian atherosclerosis thaum cov ntaub so ntswg melatonin tsis. Tau ntau xyoo tam sim no, melatonin tau cuam tshuam rau kev txhawb nqa thiab tswj kev pw tsaug zog. Tsis ntev los no, cov pov thawj qhia tau hais tias nws kuj ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob. Qhov pib ntawm peb qhov kev tshuaj xyuas yuav xaus cov ntaub ntawv no. Raws li ib qho amphiphilic, pleiotropic indoleamine, melatonin muaj ob qho tib si ncaj qha ua thiab receptor-mediated teebmeem. Piv txwv li, melatonin tau tsim cov teebmeem ua antioxidant thiab dawb radical scavenger ob leeg hauv vitro thiab hauv cov qauv tsiaj. Qhov no kuj pom tseeb hauv melatonin lub luag haujlwm tseem ceeb hauv mitochondria, uas tau tshuaj xyuas hauv ntu tom ntej. Melatonin yog synthesized nyob rau hauv, coj los ntawm, thiab concentrated nyob rau hauv mitochondria, lub zog ntawm lub cell. Mitochondria tseem yog qhov tseem ceeb ntawm cov pa oxygen reactive raws li cov khoom ntawm mitochondrial oxidative metabolism. Tshooj kawg ntawm peb qhov kev tshuaj xyuas qhia txog melatonin lub luag haujlwm hauv kev laus thiab kev puas siab puas ntsws. Pineal thiab cov ntaub so ntswg melatonin qib ob leeg poob qis thaum muaj hnub nyoog. Pineal melatonin poob rau cov tib neeg uas muaj kev puas siab puas ntsws. Melatonin lub peev xwm los ua tus neuroprotectant qhib txoj hauv kev tshiab ntawm kev tshawb nrhiav rau cov molecule vim nws yuav yog ib qho kev kho mob rau cov neeg mob neurodegenerative.

cistanche tubolosa cov txiaj ntsig kev noj qab haus huv

Taw qhia

Melatoninyog ib qho pleiotropic indoleamine uas yog amphiphilic kom nws nkag tau los ntawm cov ntshav los yog lub hlwb txha caj qaum (CSF) mus rau hauv cov ntaub so ntswg thiab hlwb, nrog rau los ntawm cov ntshav-hlwb barrier.

Rau xyoo tam sim no, ncigmelatonintau paub zoo los txhawb kev pw tsaug zog, tswj kev pw tsaug zog, rov pib lub moos circadian, thiab nkag mus rau kev khiav dawb-khiav circadian rhythms1-7. Txawm li cas los xij,melatoninthiab nws cov derivatives tam sim no tau lees paub los kuj muaj cov txiaj ntsig zoo li dawb radical scavengers thiab antioxidants8. Melatonin yog tam sim no dav heev nyob rau hauv lub cev.

Cov ntawv xov xwm: James L. Kennedy (jim.kennedy@camh.ca)

1Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada

2Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada Tag nrho cov npe ntawm cov ntaub ntawv sau muaj nyob rau hauv qhov kawg ntawm cov ntaub so ntswg thiab hauv yuav luag tag nrho lawv, cov synthesizing enzymes arylalkylamine N-acetyltransferase (AANAT) thiab acetylserotonin O-methyltransferase (ASMT) tau pom 9. Vim tias mitochondria yog lub zog ntawm lub cev, ua ke ATP ntawm oxidative phosphorylation, muaj covmelatonintau nrhiav thiab pom nyob rau hauv lub organelle10. Qhov tseeb, mitochondria los ntawm nas niam oocytes tuaj yeem ua kemelatoninlos ntawm serotonin, uas yog raws li qhov tseeb tias mitochondria yog leej niam los ntawm 11,12. Yog li, qhov no haib antioxidant muaj ib qho tseem ceeb tiv thaiv muaj nyob rau hauv lub cev lub ntsiab qhov chaw ntawm dawb radicals13-15.

Peb lub hom phiaj los muab cov ntsiab lus luv luv ntawmmelatoninthiab nwsneuroprotectiveLub luag haujlwm, nrog rau qhov tseem ceeb ntawm mitochondrial melatonin. Vim muaj ntau cov pov thawj cuam tshuam txog mitochondria hauv cov txheej txheem kev laus, nrog rau kev puas siab puas ntsws 16, peb yuav muab kev sib tham txog kev sib tham ntawmcov tshuaj melatoninmuaj peev xwm ua lub luag haujlwm ua qhov tseem ceeb thiab cim ntawm kev laus thiab kev puas siab puas ntsws los kaw qhov kev tshuaj xyuas no.

cistanche phelypaes

Keeb kwm thiab lub ntsiab lus ntawm melatonin

Melatoninyog ib qho qub molecule, pom nyob rau hauv cov kab mob, nroj tsuag, thiab pwm17. Hauv ntau hom, ua ntej ib qho lus qhia ntawm lub luag haujlwm hormonal nws muaj kev tswj hwm hauv zos 18. Hauv cov tsiaj reptiles thiab noog, nws muaj nyob rau hauv ntau qhov chaw nrog rau qhov muag. Qhov thib peb lub qhov muag parietal uas yog ib qho sensor rau lub xub ntiag ntawm lub teeb yog ib qho ntawm cov qhov muag uas muaj melatonin19.

Muaj pov thawj tias lub qhov muag thib peb pib hloov mus rau hauv lub caj pas pineal hauv cov tsiaj nyeg20. Nws tseem txuas nrog lub teeb-sensing system los ntawm kev sib txuas neural tab sis tom qab ntawd dhau cov ntaub ntawv los ntawm cov teeb liab neuroendocrine,melatonin. Nyob rau hauv cov ntaub so ntswg ntawm lub cev, nws muaj nyob rau hauv siab concentration nyob rau hauv ntau cov ntaub so ntswg nrog rau lub hardline caj pas, retina, hypothalamus, daim siab, txoj hnyuv, tag nrho cov plab hnyuv siab raum, thiab lub cev tiv thaiv kab mob 9,19,21-25. Ob lub tshuab no, hormonal thiab cov ntaub so ntswg yog cov pas dej sib cais. Nws tau paub txij li xyoo 1980 tias cov ntaub so ntswg hauv plab yog ywj siab ntawm cov ntshav; pinealectomy tsis txo qis cov ntaub so ntswg tab sis tshem tawm tag nrho cov ntshav qib 23,26. Ib lub pas dej ua ke yog tsim nyob rau hauv pineal, lwm qhov yog tam sim no nyob rau hauv txhua tus neeg cov ntaub so ntswg 9,27-29. Lub pas dej ntawm cov ntaub so ntswg melatonin ntau dua (10-400 ×) tshaj qhov uas tau los ntawm pineal caj pas 26,30,31.

Pinealmelatonincov qib hauv cov ntshav thiab cov ntshav ntshav tso tawm ib qho circadian (txog 24 h) atherosclerosis nyob rau hauv uas theem qis qis thaum nruab hnub thiab nce thaum lub sijhawm tsaus ntuj, nce siab nyob ib ncig ntawm 2-4 teev sawv ntxov ua ntej yuav rov qab los dua 32-34. Lub synthesis thiab secretion ntawmmelatoninyog tswj los ntawm suprachiasmatic nucleus (SCN), lub moos tswv ntawm lub cev. SCN muaj cov noob caj noob ces sib cuam tshuam hauv tus kheej-muaj cov ntawv txhais lus tsis zoo nrog lub voj voog 24-h cycle35,36. Lesioning SCN tshem tawm endogenous melatonin rhythmicity thiab ua rau tsis muaj peev xwm rau exogenous melatonin rau resynchronize lub system37,38. Qhov no atherosclerosis yog synchronized nrog lub teeb-dub (LD) voj voog los ntawm cov tswv yim los ntawm lub retina ntawm lub retinohypothalamic ib ntsuj av, uas tshwm sim los ntawm ib tug me me txheej ntawm innately photosensitive ganglion hlwb (IPGCs). Cov IPGCs no muaj cov photopigment melanopsin, uas yog tshwj xeeb tshaj yog rhiab rau lub teeb nyob rau hauv xiav spectrum. Cov neurons no xa cov ntaub ntawv ntawm LD voj voog mus rau SCN, mus rau thaj chaw uas tswj cov lus teb rau cov menyuam yaus nrog rau kev pw tsaug zog thiab waking systems39. Qhov projection mus rau pineal yog multi-synaptic pib mus rau autonomic seem ntawm lub hypothalamic paraventricular nucleus, ces ua rau ib tug projection mus rau sab sauv thoracic inter-mediolateral cell kem. Los ntawm qhov ntawd, preganglionic sympathetic noradrenergic fibers taug kev mus rau lub ncauj tsev menyuam zoo tshaj plaws uas xa cov post- ganglionic fibers mus rau lub caj pas pineal, yog li pib.melatoninsynthesis. Muaj cov lus teb sai heev hauv AANAT los tsim N-acetylserotonin, nce 10– 100-fold thaum hmo ntuj-40. Cov tshuaj ntawd hloov mus rau melatonin los ntawm enzyme ASMT [yav tas los hu ua hydroxy indole O-methyl transferase (HIOMT)] 41.Melatonintsis khaws cia, raug tso ncaj qha mus rau hauv cov hlab ntsha uas nws tau khi rau albumen.

MelatoninKev ntsuas nyob rau hauv CSF qhia tau hais tias cov ntsiab lus nyob rau hauv lub thib peb ventricle tsis tsuas yog siab tshaj nyob rau hauv lub ventricle lateral tab sis kuj siab tshaj nyob rau hauv cov ntshav, qhia tau hais tias muaj ncaj qha nkag los ntawm lub pineal rau CSF thiab tsis yog los ntawm cov ntshav nyob rau hauv lub choroid plexus yog probable42, 43.

Ob G1-protein txuasmelatoninCov receptors MT1, thiab MT2 paub txog 44,45. Zoo li lwm yam G1-protein-linked receptors (GPCR), lawv nquag koom ua dimers; lub heterodimer MT1 / MT2 yog nquag npaum li homodimer ntawm MT1, thaum homodimer ntawm MT2 yuav luag 4-fold tsawg dua. Ib tus neeg txais thib peb, GPR-50, muaj ib ntus uas yog 45 feem pua ​​​​txog tab sis yuav tsis khimelatonin. Txawm li cas los xij, nws yuav tsim heterodimers nrog MT1 uas tshem tawm

kev khi thiab yog li ntawd yuav ua haujlwm tseem ceeb. Txawm li cas los xij plaub yam tsiaj txhumelatoninqhov chaw khi tau pom. Nws muaj nanomolar es tsis yog picomolar affinity rau melatonin thiab tau tam sim no tau tus yam ntxwv raws li cov analog ntawm quinone reductase hom 2 nyob rau hauv hamster menyuam yaus-46. Ob leeg MT1 thiab MT2 receptors muaj nyob hauv SCN. MT1 inhibits filring, thaum ob qho tib si yuav ua rau theem hloov thiab sib txawv tswj GABAA function47,48. Ob leeg MT1 thiab MT2 receptors tau dav dav hauv lub hlwb thiab zoo li muaj qhov sib txawv hauv qhov muag nrawm (REM) piv rau cov tsis-REM pw tsaug zog, ntxhov siab, thiab ceev faj49-53. Ob leeg receptors kuj pom muaj nyob hauv ntau qhov chaw ntawm lub cev thiab tau pom tias muaj kev sib haum xeeb / qhib qee qhov melatonin'sneuroprotectiveua 54,55.

cistanche kev paub

Melatonin thiab neuroprotection

Muaj pov thawj txaus los txhawbcov tshuaj melatoninlub luag haujlwm hauv neuroprotection. Lub tswvyim yog thawj tsim los ntawm Tan et al. (1993) 56 leej twg nrhiav tau nws lub peev xwm mus khawb dawb radicals, tshwj xeeb tshaj yog, hydroxyl radicals nyob rau hauv vitro56. Lub tswv yim ntawm melatonin muaj peev xwm tshem tawm cov dawb radicals ntxiv tau pom ob qho tib si hauv vitro thiab siv tsiaj qauv57,58. Qhov tseeb, kev tshawb fawb tsiaj tau pom tias melatonin muaj txiaj ntsig zoo hauv kev tshem tawm cov dawb radicals thaum ob qho tib si postischemic reperfusion thiab tom qab lub taub hau raug mob 59,60. Nws yuav tsum tau muab sau tseg tias lub sij hawm ntawmmelatoninkev tswj hwm yog qhov tseem ceeb thaum kho mob taub hau. Melatonin tsuas yog txo cov malondialdehyde, ib qho cim ntawm oxidative kev nyuaj siab, thaum melatonin tau siv nyob rau hauv thawj ob teev tom qab raug mob. Yog tias muab 8 teev lossis 48 teev tom qab raug mob, cesmelatonintsuas yog nce malondialdehyde ntau ntau, tab sis yog vim li cas thiaj li tseem tsis meej txog 60,61. Interestingly, Zang et al. (1998) 62 tsis tuaj yeem rov ua dua cov txiaj ntsig nrog hydroxyl radicals. Lawv postulate tias qhov kev pom tsis zoo no yog vim tias txhua qhov kev sim ua tau nyob rau hauv lub xub ntiag ntawm hydrogen peroxide, uas melatonin yog ib koob tshuaj scavenger 62. Txawm li cas los xij, kev nce qib melatonin ua rau muaj peev xwm scavenger ntau dua 62.

Serummelatoninkuj tau pom tias muaj peev xwm antioxidant, thiab raws li, lub ncov hauv kev tiv thaiv oxidant muaj peev xwm yog nyob ntawm qhov nce hauv melatonin63. Antioxidant muaj peev xwm kuj tseem muaj qhov cuam tshuam tseem ceeb rau neurocognition hauv cov neeg uas muaj kev nyuaj siab nyuaj siab 64-66.

Melatonintseem tuaj yeem pom thoob plaws hauv lub cev tiv thaiv kab mob thiab tam sim no paub tias kuj yog ib qho kev tiv thaiv kab mob, ib qho nrog ob qho kev ua 67. Ntawm qhov tod tes, nws txhawb kev tiv thaiv kev tawm tsam txawv teb chaws thaum nyob rau lwm qhov, nws hloov kho cov ntaub so ntswg teb, txo qis-regulating proinflammatory thiab up-regulating anti-inflammatory cytokines.Melatonintau pom tias txhim kho morbidity thiab tuag ob leeg nyob rau hauv sepsis nyob rau hauv cov tsiaj thiab cov me nyuam68. Nws kuj tau pom tias muaj kev nyab xeeb loj heev thiab hauv cov tsiaj, kev tswj hwm tsis tau ua rau tuag taus thaum muab qhov ncauj lossis subcutaneously, yog li LD50 tau hais tias yog infinity68,69.

Hauv kev tshuaj xyuas dav dav tsis ntev los no, nws tau taw qhiamelatoninua ob qho tib si los ntawm receptor-dependent thiab ywj siab txoj hauv kev los tiv thaiv neurodegeneration55. Piv txwv li, agomelatine, uas tsis yog tshwj xeeb MT1/2 receptor agonist yog siv los kho cov kev nyuaj siab loj (MDD), thiab nws kuj txhim kho cov qauv kev pw tsaug zog thiab normalizes circadian rhythms54,70,71. Ntxiv rau,

kev tswj hwm ntawmmelatoninrau MT1/2 knock-out nas tom qab lub hlwb perfusion (kom induce focal cerebral ischemia) coj mus rau ib co neuroprotection, raws li ntsuas los ntawm qhov txo ntawm infarct volume72. Melatonin receptors kuj tseem tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv neurodegeneration. Hauv tib neeg SH-SY5Y cell kab (uas muaj cov lus qhia protein zoo ib yam li Alzheimer's dis-ease), nws tau pom tias kev tswj hwm melatonin inhibited -secretase -site APP-cleaving enzyme 1

(BACE1) thiab Presenilin 1 (PS1) qhia thaum nce ib qho disintegrin thiab metalloproteinase 10

(ADAM10), txhua tus uas koom nrog hauv kev tsim ntawm Alzheimer-txog amyloid-peptides. Txhua qhov kev hloov pauv uas pom hauv BACE1, PS1, thiab ADAM10 tau txais kev sib kho; kev tswj hwm ntawm G protein inhibitor ua ntejmelatoninKev kho mob tshem tawm cov teebmeem ntawm melatonin. Qhov no qhia txog qhov tseem ceeb ntawm covmelatoninreceptors hauv inhibiting neurodegeneration ntawm kev ua kom melatonin73. Txawm li cas los xij, muaj ntau ntawm receptor-mediatedneuroprotectiveCov kev cuam tshuam uas tau tshuaj xyuas tsis ntev los no nyob rau lwm qhov (thov saib refs. 74,75) yog li qhov seem ntawm qhov kev tshuaj xyuas yuav raug tsom rau kev ua mitochondrial-mediated.

suab puam cistanche cov txiaj ntsig

Melatonin thiab mitochondria

Qhov tseem ceeb,melatonintso saibneuroprotectivecuam ​​tshuam rau mitochondria ntawm nws cov dawb radical scavenging peev xwm. Piv txwv li, nws tau pom tias kev tswj hwm ntawm melatonin tiv thaiv mitochondrial DNA (mtDNA) kev puas tsuaj uas muaj feem cuam tshuam los ntawm ROS76. Kev tswj hwm ntawm melatonin rau tus poj niam cev xeeb tub nas kuj nce kev ua haujlwm ntawm glutathione (GSH) peroxidase, tus cim tshuaj tiv thaiv kab mob, hauv fetal hlwb77. Mitochondria pom nyob rau hauv lub hlwb thiab daim siab muaj ntau ntawm melatonin23,78. Martin et al. (2000) 79 pom tias 100 nanomolar koob tshuaj melatonin muab rau mitochondrial membranes los ntawm nas hlwb thiab daim siab ua rau intramitochondrial theem uas yog 100 npaug ntau dua li cov qib hauv plasma. Muab mitochondria lub luag haujlwm hauv kev tsim ROS, nws ua rau kev nkag siab tias qhov siab tshaj plaws ntawm melatonin yuav nyob hauv mitochondria,

Qhov chaw ntawm mitochondrial oxidative metabolism. Qhov no txhais tau hais tias qhov loj tshaj ntawm ROS thiab oxidative kev nyuaj siab tshwm sim ntawm qhov chaw uas melatonin siab tshaj plaws, thiab yog li nyob rau hauv ib qho chaw zoo tshaj plaws los ua tus scavenger ntawm cov dawb radicals23.

Nws tau raug suav hais tias qhov siab ntawm melatonin hauv mitochondria tuaj yeem raug ntaus nqi rau (1) oligopeptide transporters (PEPT1/2) thiab / lossis (2) mitochondria synthesizing lawv tus kheej.melatonin78. Qhov tseeb, kev tshawb fawb tsis ntev los no pom tias ob lub enzymes koom nrogmelatoninsynthesis, AANAT thiab ASMT muaj nyob rau hauv lub hlwb mitochondria10,12,13,80. Txawm li cas los xij, nws tseem ceeb heev uas yuav tsum nco ntsoov tias qib melatonin hauv mitochondria zoo li mus txog qhov saturation point23. Yog tias melatonin tuaj yeem ncav cuag saturation, puas txhais tau tias nws cov dawb radical scavenging kev ua si kuj tuaj yeem ncav cuag qhov siab tshaj plaws? Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, qhov no tseem tsis tau tshawb xyuas.

Ntxiv nrog rau nws cov haujlwm antioxidant,melatonintxhawb kev ua haujlwm ntawm cov enzymes antioxidant thiab txo cov oxidant enzymes78. Ib qho piv txwv ntawm cov enzyme antioxidant yog GSH uas nws cov synthesis yog txhawb los ntawm melatonin81. Kev ua haujlwm ntawm cov enzyme antioxidant, superoxide dismutase 2 (SOD2) yog upregulated los ntawmmelatoninlos ntawm kev nce qib ntawm kev ua sirtuin 3 (SIRT3) uas deacetylates SOD2, yog li ua kom nws 82,83. Nws yuav tsum tau muab sau tseg tias ib nrab-lub neej ntawm reactive ROS yog heev, luv heev (piv txwv li rau -OH, 10 −9 s) yog li lawv mus deb heev luv luv ua ntej oxidizing nyob ib sab molecules81. Yog li, qhov sib xyaw ntawm cov tshuaj tua kab mob antioxidants thiab cov khib nyiab nrog qhov chaw ntawm ROS ntau lawm hauv mitochondria, zoo li cov ntaub ntawv rau melatonin thiab nws cov teebmeem thib ob, yog qhov tseem ceeb rau lawv kom ua tau zoo.

Melatonin covCov teebmeem ntawm mitochondria tuaj yeem kho ncaj qha los ntawm MT1/2 receptors. Piv txwv li, kev kho cov nas tsuag nrog agomelatine tom qab cerebral ischemia, ua rau txo qis ROS ntau lawm hauv lub hlwb, muaj zog antioxidant ntau dua, thiab tsawg dua neuronal apoptosis vim tias muaj kev nce hauv nuclear erythroid 2-txog yam 2 (NRF2)84.Melatoninactivates NRF2, uas yog suav hais tias yog ib tug tiv thaiv mechanism tiv thaiv ROS raws li nws tswj cov kev qhia ntawm ib tug sau ntawm noob koom tes nyob rau hauv antioxidant tiv thaiv thiab inflammatory teb 85-88. Kev kho melatonin tiv thaiv apoptosis thiab mitochondrial kev puas tsuaj los ntawm hydrogen-peroxide nyob rau hauv retinal pigmented epithelial hlwb los ntawm kev ua kom covmelatoninlos ntawm MT1 receptor89. Remarkably, nws kuj tau pom tias melatonin receptor MT1 yog tam sim no nyob rau hauv mitochondrial txheej membranes thiab hais tias melatonin ua rau tus receptor ntawd inhibit kev ntxhov siab-mediated cytochrome C tso tawm, yog li qhia txog lwm yam.neuroprotectiveCov khoom ntawm melatonin 10.

Melatonin qib raws li biomarker muaj peev xwm?

Hmoov tsis zoo,melatoninqib tsis nyob tas mus li thoob plaws lub neej los sis tej zaum yuav hloov. Qhov no pom thaum muaj hnub nyoog thiab hauv cov neeg uas muaj kev puas siab puas ntsws 90-92. Cov no yuav tau tham hauv qab no.

cistanche extract: tshem tawm dawb radicals

Kev laus thiab hnub nyoog txog kev paub txog kev poob qis

Ib phau ntawv tseem ceeb tau qhia tiasmelatoninCov qib tau paub tias poob qis thaum muaj hnub nyoog 92-96. Cov teebmeem putative tshwm sim los ntawm cov kev hloov pauv no tuaj yeem cuam tshuam nrog kev hloov pauv hauv ob lub pas dej ntawm melatonin97,98. Kev soj ntsuam cov zis pom, qhov nruab nrab, cov neeg muaj hnub nyoog 20 thiab 39 xyoo tso tawm txog 12 micrograms ntawm 6- sulpha-to melatonin (6SMT), cov metabolite ntawm melatonin, thiab qhov no tsis tu ncua mus txog 6 ug hauv qee tus neeg. tshaj 8094. Qhov tseeb, nws tau pom thaum nruab hnubmelatoninCov qib hauv CSF poob li ib nrab ntawm cov hnub nyoog 15 thiab 5092. Saib thoob plaws lub neej tag nrho, cov ntshav ntshav melatonin tshwm sim nyob rau hauv thawj 6 lub hlis ntawm lub neej, tom qab ntawd lawv nce siab thaum muaj hnub nyoog 1-3 xyoos. Los ntawm cov neeg muaj hnub nyoog 15-20 xyoo twb dhau los lawm, qhov nruab nrab, 80 feem pua ​​​​ntawm cov qib melatonin poob qis thiab qhov kev poob qis no txuas ntxiv mus rau hnub nyoog laus (70-90 xyoo) 95. Cov tib neeg hluas kuj tau ntsib lawv qhov siab tshaj plaws melatonin secretion tom qab pw tsaug zog dua cov neeg laus 99,100. Tej zaum qhov no yog vim hais tias melatonin secretion muaj feem cuam tshuam nrog cov neeg koom nrog lub sijhawm pw tsaug zog, uas yog tom qab rau cov neeg laus 99. Lwm txoj kev tshawb nrhiav pom tias qhov nocturnal serum melatonin qib yog qhov sib txawv ntawm cov tib neeg.<60 and="" those="" over="" 60="" years="" of="" age="" when="" multiple="" samples="" are="" drawn="" throughout="" the="" night.="" when="" only="" one="" sample="" was="" looked="" at="" (2:00="" a.m.),="" the="" differences="" were="" abolished96.="" daytime="" serum="" levels="" also="" display="" mixed="" results.="" one="" study="" found="" that="" daytime="" serum="" levels="" display="" a="" negative="" correlation="" with="" age="" but="" another="" study="" was="" unable="" to="" replicate="" this="">

Tseem muaj cov piv txwv uas muaj kev sib raug zoo ntawmmelatoninqib thiab kev laus tsis pom txhua. Zeitzer et al. (1999) 101 postulate tias lawv qhov kev pom tsis zoo hauv plasma yog vim lawv cov neeg yau thiab cov laus tau txais kev kuaj mob hnyav thiab tsis muaj kev kuaj mob, tshuaj, nicotine, cawv, thiab caffeine, cov kauj ruam uas tsis tau sau tseg los ntawm lwm cov kev tshawb fawb. Txoj kev tshawb no los ntawm Zeitzer et al. (1999) 101 tsuas yog suav nrog cov tib neeg hnub nyoog 18 thiab 81, feem ntau ntawm lwm cov kev tshawb fawb suav nrog cov tib neeg sab nraud ntawm lub hnub nyoog 93,94,96. Ib yam uas yuav tsum nco ntsoov txog tag nrho cov kev tshawb fawb no yog tias melatonin qib sib txawv ntawm tib neeg-rau-tus neeg thiab tag nrho cov kev tshawb fawb no siv tus qauv tsim 102-105. Qhov kev hloov pauv ntawm tus neeg-rau-tus neeg no tuaj yeem piav qhia qee yam los ntawm genetics106.

Cov kev tshawb fawb tsiaj kuj pom tias muaj hnub nyoog hloov pauv tsis yog nyob rau hauv xwbmelatoninmuab tau los ntawm pineal tab sis kuj nyob rau hauv cov ntaub so ntswg melatonin. Kev txo qis mRNA kev ua ntawm AANAT thiab ASMT tau pom nyob rau hauv situ107. Txo AANAT

mRNA theem tau tshwm sim nyob rau hauv tus po thiab daim siab ntawm 12- nas hnub nyoog (piv rau 3-cov nas hnub nyoog hli) thaum txo qis ASMT qib muaj nyob rau hauv tus po xwb. Nce mRNA qhia theem ntawm ob enzymes tau pom nyob rau hauv lub plawv. Ntxiv mus, nce AANAT enzyme kev ua haujlwm tau pom nyob rau hauv daim siab thiab lub raum uas cov kws sau ntawv hais tias yuav yog ib qho kev them nyiaj yug mechanism107.

Raws li Free Radical Theory of Aging tau npaj los ntawm Harman, cov tshuaj tiv thaiv dawb radical tsim cov dawb radicals, xws li ROS, uas ua rau cov txheej txheem kev laus ntawm oxidative hloov nrog rau kev puas tsuaj rau nuclear DNA thiab mtDNA108. mtDNA yog peb zaug ntau dua rau oxidative kev nyuaj siab uas tuaj yeem ua rau mitochondrial tsis ua haujlwm thiab apoptosis109. Qhov no yog vim hais tias mtDNA tsis muaj histones thiab vim nws qhov sib thooj rau cov saw hlau thauj electron110. Antioxidants xws limelatoninthiab lwm yam uas pom nyob rau hauv mitochondria (xws li GSH per- oxidase) yog cov kev tiv thaiv uas tau tsim nyob rau hauv lub sij hawm mus ncaj qha scavenge dawb radicals los yog indirectly metabolize lawv los yog lawv intermediates rau neutralize lawv, yog li tiv thaiv cov deleterious teebmeem lawv yuav ua rau 110-113. Txawm hais tias lwm yam, xws li mitochondrial transcription factor A kuj tseem ceeb 15. Hmoov tsis zoo, kev laus kuj ua rau poob ntawm tag nrho cov antioxidant muaj peev xwm ua ke nrog melatonin poob 63.

Lwm qhov tshwm sim ntawm kev laus yog kev paub tsis meej. Qhov kev poob qis hauv kev paub tau txuas rau ob qho tib si nce hauv oxidative kev nyuaj siab thiab txo qis hauv pineal.melatoninqib. Piv txwv li, ib txoj kev tshawb fawb tsis ntev los no tau pom qhov txo qis ntawm GSH ntawm lub hauv paus, uas yog qhov qhia tau tias muaj kev ntxhov siab oxidative ntau dua thiab kev poob qis hauv kev ua haujlwm ntawm 4 xyoo 114. Hauv lwm txoj kev tshawb fawb, cov tib neeg uas muaj kev puas siab puas ntsws tau ntsib ib qho kev nthuav dav hauv circadian nkhaus ntawm plasma.melatoninqib piv rau cov tib neeg lub hlwb noj qab haus huv ntawm tib lub hnub nyoog 115. Tsis tas li ntawd, qhov nocturnal plasmamelatoninQhov siab tshaj plaws tau cuam tshuam nrog kev paub tsis meej, raws li tau txiav txim los ntawm Mini-Mental State Examination116. Tseem muaj tshaj tawm qhov sib txawv ntawm salivarymelatoninqib. Waller et al. (2016) 117 tus neeg sib cais raws li lawv cov qhab nia Draft board txawj ntse; Cov neeg uas tau qhab nia siab heev tau raug cais raws li pab pawg neeg muaj peev xwm ua haujlwm siab, thiab cov neeg uas tau qhab nia qis tau raug cais raws li pab pawg neeg tsis paub qab hau. Siv cov qauv qaub ncaug uas tau sau dhau ib lub sijhawm 24-h, lawv pom tias qhov nruab nrab nocturnal melatonin teb thaum 4 teev sawv ntxov tau qis dua hauv cov pab pawg neeg tsis paub qab hau. Txawm li cas los xij, tsis muaj qhov sib txawv tseem ceeb ntawm lwm lub sijhawm point117. Cov lus nug tshwm sim: puas yog exogenous melatonin muaj txiaj ntsig? Txawm hais tias lo lus nug tsis tuaj yeem teb ncaj qha, peb muaj qee qhov kev pom los ntawm cov qauv tsiaj. Piv txwv li, cov nas raug rau formaldehyde raug kev txom nyem los ntawm kev paub tsis meej thiab muaj kev nce hauv oxidative kev nyuaj siab, raws li tau sau tseg los ntawm qib siab ntawm ROS, 50 feem pua ​​​​txo hauv GSH, thiab txo qis endogenous melatonin.

Txawm li cas los xij,melatoninKev kho mob muaj peev xwm ameliorate qhov txo qis hauv GSH, rov qab qib melatonin thiab txhim kho kev txawj ntse ua haujlwm118. Ua ke, cov pov thawj no txhawb kev poob qis hauv melatonin thiab nce oxidative kev nyuaj siab thaum lub sij hawm kev txawj ntse poob, tsis muaj hnub nyoog. Nws kuj tseem qhia tau tias exogenous melatonin tuaj yeem muaj txiaj ntsig zoo hauv kev tawm tsam cov kev hloov pauv no tab sis kev tshawb fawb ntxiv rau qhov teeb meem no tau lees paub. Hauv kev tshawb fawb tsis ntev los no, melatonin thiab nicotinamide mononucleotide (NMN) cais lossis ua ke rov qab muaj hnub nyoog ntsig txog kev paub tsis meej thiab txo cov mitochondrial ROS uas tsim nyob rau hauv prefrontal cortex thiab hippocampus ntawm cov laus nas119. NMN yog lub hauv paus rau nicotinamide adenine dinucleotide, uas ua lub luag haujlwm tseem ceeb hauv OXPHOS. Zuag qhia tag nrho, cov ntaub ntawv qhia tias kev sib raug zoo ntawm kev txo melatonin thiab nce oxidative kev nyuaj siab yog ib qho nyuaj uas yuav tsum tau kawm ntxiv.

cistanche tubolosa cov txiaj ntsig

Kev puas siab puas ntsws

Tshooj lus no tshuaj xyuas cov ntaub ntawv ntawm pinealmelatonin. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, tsis tau muaj kev tshawb fawb txog cov ntaub so ntswg melatonin hauv ib qho kev puas siab puas ntsws li tam sim no.

Kev nyuaj siab loj

Tau ntau xyoo lawm, txo qis nocturnalmelatoninCov qib tau raug tshaj tawm hauv cov ntshav thiab ntshav, txhais tau tias qis qis qis qis hauv MDD cov tib neeg 120–123. Txawm li cas los xij, muaj qhov tsis sib xws nyob rau theem sawv ntxov raws li ib txoj kev tshawb fawb pom tias lawv, ib yam nkaus, tau txo qis thaum txoj kev tshawb fawb thib ob pom tias lawv tau nce ntxiv hauv MDD cov tib neeg 121,124. Hauv cov tib neeg noj qab haus huv, txo qis melatonin theem nocturnal tau txuas rau kev pw tsaug zog tsis zoo, suav nrog REM pw tsaug zog hloov pauv 125. Qhov zoo siab, cov kev hloov pauv pw tsaug zog no kuj muaj nyob hauv MDD cov neeg mob126.

Tsis muaj kev hloov pauv hauvmelatoninQib hauv CSF tau txheeb xyuas hauv MDD cov neeg mob 2124

Schizophrenia

Ntau qhov kev tshawb fawb, suav nrog kev tshuaj ntsuam xyuas meta tsis ntev los no, tau tshaj tawm tias cov tib neeg uas muaj tus mob schizophrenia tau txo qis melatonin nyob rau hauv cov ntshav thiab ntshav, tsis hais seb lawv puas tau kho mob hlwb 127-131. Qhov txo qis hauv cov ntshav qab zib yog pom meej thoob plaws hauv 24 h128. Thaum sib piv cov qib ntawm pre-effective thiab post-effective antipsychotic kev kho mob, antipsychotics tsis hloov nocturnal.melatoninlus 129. Yuav tsum nco ntsoov, peb ntawm plaub qhov kev tshawb fawb zoo tsuas yog suav nrog cov tib neeg uas muaj tus mob schizophrenia. Ib txoj kev tshawb fawb uas suav nrog ob tus tib neeg uas muaj tus mob schizophrenia thiab cov neeg uas nyuam qhuav pib muaj cov tsos mob ntawm kev puas siab puas ntsws pom tias cov pab pawg uas nws cov tsos mob nyuam qhuav pib tau nce nocturnal secretion piv rau cov tib neeg uas mob ntev 127. Txoj kev tshawb fawb thib plaub, los ntawm Afonso et al. (2011) 132, uas tau pom qhov tsis zoo, tsis tau hais tias cov pab pawg neeg muaj tus mob schizophrenia puas raug kev txom nyem.

(1982) 127 taw qhia tias lub cev hnyav kuj ua lub luag haujlwm hauvmelatoninzais cia. Qhov tseeb, thaum lub cev hnyav tau siv los ua covariate, qhov sib txawv ntawm melatonin qib ntawm cov rooj plaub thiab kev tswj hwm tau ua tsis tseem ceeb127. Interestingly, thaum muab piv rau nocturnal plasma theem ntawm cov neeg uas muaj tus mob schizophrenia thiab MDD, nws tau pom tias cov qib hauv MDD yog qis dua cov uas pom hauv schizophrenia130. Tsis muaj qhov sib txawv ntawm cov qib melatonin hauv CSF133. Muab melatonin lub luag haujlwm hauv kev pw tsaug zog thiab hloov pauv kev pw tsaug zog tau ntsib txog li 78 feem pua ​​​​ntawm cov neeg uas muaj tus mob schizophrenia, kev tshawb fawb melatonin hauv cov ntsiab lus ntawm tus mob schizophrenia yuav yog qhov tseem ceeb 125,134.

Kev puas siab puas ntsws Bipolar (BD)

Cov kev tshawb fawb thaum ntxov ntawm plasma melatonin concentrations hauv BD cov neeg mob qhia tias tsis muaj kev hloov pauv 135. Txawm li cas los xij, cov pov thawj ua ntej tam sim no qhia txog kev txo qis hauv cov ntshav melatonin ntawm cov neeg mob BD txhua lub sijhawm cov ntsiab lus hauv ib lub sijhawm 24-h. Thaum kawm nyob rau hauv ntau lub xeev mus ob peb vas, ib qho tseem ceeb txo nyob rau hauv melatonin theem ntawm BD cov neeg nyob rau hauv lawv lub xeev kev nyuaj siab tau tshaj tawm piv rau kev noj qab haus huv tswj ntawm 1 teev sawv ntxov (nce melatonin pib) thiab thaum sawv ntxov ntxov. Melatonin qib tsuas yog txo qis hauv cov neeg mob euthymic piv rau kev tswj hwm kev noj qab haus huv ntawm 1 teev sawv ntxov tab sis tsis pom muaj kev hloov pauv thaum piv rau cov neeg mob manic thiab tswj kev noj qab haus huv. Tsis muaj kev hloov pauv hauv cov zis melatonin qib tau sau tseg raws li qib 6SMT lossis 136. Cov kev tshawb fawb tsis ntev los no tau lees paub qhov txo qis melatonin thaum yav tsaus ntuj hauv cov qaub ncaug thiab CSF, tab sis kev tshawb fawb tsis tuaj yeem rov ua dua cov txiaj ntsig hauv ntshav 124,137.

Qhov tseeb, melatonin secretion hauv qaub ncaug yuav luag ob zaug qis dua thaum lub sijhawm pw tsaug zog hauv cov tub ntxhais hluas thiab cov hluas nrog BD piv rau MDD137. Cov qib melatonin txo qis tuaj yeem piav qhia los ntawm

nce qib ntawm interleukin -6, ib tug pro-inflammatory cytokine, uas induces monoamine oxidase A, uas ua rau kom nce nyob rau hauv kev puas tsuaj ntawm serotonin, precursor ntawm melatonin138,139.

Txawm hais tias nws tsis tuaj yeem hais qhov tseeb, ib qho kev piav qhia txog qhov txo qis hauv melatonin ntawm peb qhov kev puas siab puas ntsws uas tau tham tuaj yeem yog qhov sib txawv ntawm caj ces. Ntau qhov tshwj xeeb, cov noob caj noob cesmelatoninsynthesis. Ob lub noob tseem ceeb yog AANAT thiab ASMT, uas encode enzymes lub luag haujlwm rau hloov serotonin rau hauv melatonin. Soria et al. (2010) 140 tau txheeb xyuas ob lub cim ntawm AANAT, rs3760138 thiab rs4238969, ob qho tib si uas muaj allele thiab genotype (tus qauv tseem ceeb) qhov sib txawv ntawm cov neeg mob kev nyuaj siab (xws li cov neeg unipolar thiab bipolar) thiab tswj kev noj qab haus huv. Peb lub haplotypes kuj tau txheeb xyuas, ob ntawm cov uas tiv thaiv kev nyuaj siab thiab ib qho uas yog ib qho kev raug mob haplotype140. Hauv lwm cov kev tshawb fawb, cov cim ntawm ASMT kuj tau txuas rau kev nyuaj siab xws li 'AA' genotype ntawm rs4446909 thiab 'GG' genotypes ntawm rs5989681 yog kev tiv thaiv genotypes hauv ob qho piv txwv ntawm cov neeg ntawm Polish qhovntsej thiaj tsis mob 141,142. Txoj kev tshawb no kuj tau tshaj tawm qhov sib txawv ntawm mRNA qhia qib hauv cov ntshav rau ASMT, xws li cov neeg mob kev nyuaj siab uas muaj 'G'allele rau rs4446909 lossis 'G' allele rau rs5989681 tau txo qis mRNA qhia qib 141. Hauv BD, muaj qhov sib txawv ntawm qhov sib txawv ntawm cov xwm txheej thiab kev tswj hwm rau cov cim ntawm ASMT ('G' ntawm rs4446909, 'G' ntawm rs5989681, thiab 'A' ntawm rs56690322) txawm hais tias tsuas yog qhov kev tshawb nrhiav rau rs4446909 nyob rau hauv cov qauv kev ywj pheej. Kev tiv thaiv haplotype siv peb lub cim uas twb tau hais lawm thiab rs6644635 kuj tau txheeb xyuas. Cov tib neeg uas muaj 'GG' genotype ntawm rs4446909 tau pom cov kev ua haujlwm qis qis thiab mRNA qib 143.

Lub sijhawm no, nws tsis paub meej tias qhov kev tshawb fawb ntawm cov ntaub so ntswgmelatonintej zaum yuav nthuav tawm hauv cov pab pawg neeg mob no thiab peb tsuas tuaj yeem kwv yees txog lawv qhov muaj peev xwm kho mob qhov tseem ceeb. Txawm li cas los xij, nws yuav xav tias kev hloov pauv ntawm melatonin synthetic genes yuav cuam tshuam rau ob lub pas dej uas paub txog.melatoninzoo ib yam.

Xaus

Tsis muaj kev ntseeg li ntawdmelatoninyog ib qho indoleamine ntau yam, nrog rau ntau lub luag haujlwm thiab kev ua haujlwm nws muaj nyob rau hauv lub cev. Ntxiv nrog rau nws lub luag haujlwm paub zoo tias yog cov tshuaj hormones, ntau cov pov thawj tau muab tso rau hauv kev txhawb nqa ntawm nws lub luag haujlwm ua neuroprotectant, tiv thaiv kab mob, thiab txawm tias muaj antioxidant rau lub hlwb thiab lub cev. Peb tau muab cov ntsiab lus luv luv ntawm qee qhov kev tshawb fawb no. Rau kev yooj yim, peb tau tsim ib daim duab (daim duab 1) los sau cov ntsiab lusneuroprotectivecov khoom ntawmmelatonintshuaj xyuas hauv daim ntawv no. CovneuroprotectiveCov teebmeem melatonin cov lus qhia zoo ib yam ntawm cov receptor-ywj siab thiab nyob ntawm txoj kev. Ob txoj hauv kev tuaj yeem txhawb kev tiv thaiv antioxidant, muaj peev xwm dawb radical scavenging, thiab muaj peev xwm tiv thaiv mitochondria.Melatoninkev tswj hwm kuj tuaj yeem cuam tshuam nws cov teebmeem hauv receptor-ywj siab lossis kev vam meej. Ntxiv mus, vim tias lub luag haujlwm tshiab no nrhiav pom rau melatonin, nws yog ib qho tseem ceeb los tshawb xyuas qhov cuam tshuam nws yuav muaj raws li biomarker nyob rau hauv ntau qhov xwm txheej.

Raws li qhov loj ntawm cov ntaub ntawv, txo qis pineal thiab cov ntaub so ntswgmelatoninzoo li yog biomarker ntawm kev laus. Kev txo qis hauv pineal melatonin kuj zoo li yog biomarker ntawm kev puas siab puas ntsws, yam tsawg kawg ntawm peb qhov kev sib tham hauv qhov kev tshuaj xyuas no (MDD, schizophrenia, thiab BD), thiab tej zaum yuav qhia tau tias muaj cov txheej txheem neurodegenerative zoo sib xws rau aging144.

Ntawm kev txhawj xeeb txog kev puas siab puas ntsws, kev kuaj mob tam sim no pob ua ke nrog cov neeg mob hauv pawg nrog sib txawv pathological nta. Subtyping cov kab mob no yuav tsum tau ua kom coj cov kab mob pathophysiological suav nrogmelatoninmus rau hauv tus account thiaj li yuav kho thiab txiav kev kho mob. Muaj tsawg kawg yog peb qhov ua rau txo qismelatonin: kev hloov pauv hauv cov noob qoob loo melatonin tseem ceeb raws li tau sau tseg saum toj no; Kev txo qis ntawm serotonin vim muaj kev ntxhov siab ntau ntxiv thiab cov cytokines proinflammatory cytokines uas ncaj qha tryptophan mus rau txoj hauv kev kynurenine thiab nce hauv lub teeb raug thaum lub sijhawm pw tsaug zog 65. Cov no tuaj yeem txo cov neuroprotection pom hauv qee cov neeg mob. Txhawm rau kom tsis txhob ua rau muaj kev puas tsuaj, melatonin tuaj yeem muab los ua kev kho mob los kho cov kab mob neuroprotection.

Yog li ntawd, peb xav kom cov kev tshawb fawb yav tom ntej los tshuaj xyuas cov kev hloov pauv hauv cov genes koom nrogmelatoninsynthesis (piv txwv li ASMT), tshwj xeeb tshaj yog nyob rau hauv kev sib raug zoo rau cov tsos ntawm kev txawj ntse tsis txaus nyob rau hauv no psychiatric pejxeem 140-143. Tsis tas li ntawd, ib qho kev ntsuas thaum hmo ntuj 6SMT kuj tseem cuam tshuam rau kev kwv yees tag nrho lub cev nocturnalmelatoninntawm ob qho tib si nws cov khoom thiab pov tseg. Qhov no tuaj yeem ua tiav los ntawm kev tau txais cov qauv thawj zaug thaum sawv ntxov ntawm cov zis thiab txiav txim siab qib 6SMT thiab normalizing nws mus rau qhov concentration ntawm creatinine. Tsis tas li ntawd, kev sim kho mob tuaj yeem ua tiav rau cov neeg uas txo melatonin nrog lub hom phiaj ntawm kev sim tiv thaiv kev tsis zoo ntawm neuroprotection.

Thaum kawg, qib melatonin hauv mitochondria yog kwv yees li 100 × siab dua cov qib pom hauv cov ntshav. Thaum twgmelatonin, thiab tom qab ntawd nws cov kev tiv thaiv tsis muaj, kev puas tsuaj oxidative zoo kawg li 79. Yog li ntawd, lub teb yuav tsum nqis peev ntau zog rau lub luag hauj lwm muaj zog ntawm nomelatoninHauv kev tswj oxidative metabolism los ntawm kev tshuaj xyuas, piv txwv li, kev sib raug zoo ntawm cov theem ntawm melatonin metabolites thiab cov cim rau mitochondrial tsis ua haujlwm lossis oxidative stress145.

Cistanche muaj cov nyhuv neuroprotective

Kev lees paub

Frederick Banting thiab Charles Best Canada Graduate Scholarship Doctoral Award (LMMB), BBRF/NARSAD Young Investigator Grant, Miner's Lamp Innovation Fund, McLaughlin Center Accelerator Grant, Larry, thiab Judy Tanenbaum Family Foundation.

Sau Paub meej

1Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada. 2 Lub Tsev Haujlwm Saib Xyuas Kev Kho Mob, University of Toronto, Toronto, ON, Canada. 3 Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Kev tsis sib haum xeeb

Cov kws sau ntawv tshaj tawm tsis muaj kev sib tw txaus siab