Lub luag hauj lwm ntawm Glucagon-zoo li Peptide-1 Receptor Agonists (GLP-1 RA) nyob rau hauv Diabetes-Related Neurodegenerative Diseases Part 2
Aug 15, 2023
GLP-1 RA thiab Central Nervous System (CNS) Inflamation
Nws paub zoo tias CNS qhov mob ua lub luag haujlwm tseem ceeb hauv pathophysiology ntawm NDs.82 Hauv hom 2 mob ntshav qab zib mellitus-kev paub txog kev puas siab puas ntsws tsiaj cov qauv thiab cov kev tshawb fawb siab-glucose hauv vitro, cov cim neuroinflammatory, xws li IL-1 , TNF- , IL-6, thiab MCP-1, thiab cov lus teb inflammatory, xws li tus xov tooj hu ua receptor 4, cyclooxygenase 1 (COX1), COX2, NF-κB, leukocyte ntau antigen, thiab inducible nitric oxide synthase yog nce hauv lub hlwb.83–88 Ntawm cov neeg koom nrog dementia thiab AD pathology, hom 2 mob ntshav qab zib muaj kev sib raug zoo nrog JNK.89
Tsis nco qab los ntawm lub hauv nruab nrab paj hlwb kab mob los yog o yog vim o tuaj yeem ua rau kev puas tsuaj thiab kev tuag ntawm cov neurons hauv lub hlwb, rhuav tshem cov kev sib txuas neuronal, thiab ua rau cov neurons poob lawv lub peev xwm xa thiab tau txais cov cim ib txwm. Cov no yuav cuam tshuam rau kev khaws cia thiab khaws cia ntawm lub cim xeeb, ua rau nco tsis tau.
Hmoov zoo, txawm li cas los xij, muaj ob peb kauj ruam zoo uas peb tuaj yeem ua los tiv thaiv thiab kho qhov mob ntawm lub hauv paus paj hlwb o los txhim kho peb lub cim xeeb.
Ua ntej tshaj plaws, tswj lub sijhawm pw tsaug zog txaus thiab ua haujlwm zoo thiab so txhua hnub. Cov kev tshawb fawb tau pom tias tib neeg lub peev xwm los tswj thiab sib sau ua ke kev nco thaum pw tsaug zog ntau dua li nyob rau hauv lub xeev waking. Kev pw tsaug zog txaus tuaj yeem muab sijhawm txaus rau lub hlwb los ua cov ntaub ntawv nco.
Qhov thib ob, kev noj zaub mov zoo thiab kev noj qab haus huv ntawm lub neej kuj tseem muaj txiaj ntsig zoo rau kev tiv thaiv lub hauv paus paj hlwb thiab kev nco. Noj ntau cov zaub mov uas nplua nuj nyob rau hauv antioxidants thiab fatty acids, xws li ntses, zaub, thiab txiv ntseej. Tsis tas li ntawd, ib tug yuav tsum nyob kom deb ntawm tej yam teeb meem xws li haus luam yeeb, cawv, thiab tshuaj los tswj lub cev thiab lub hlwb.
Thaum kawg, lub hauv paus paj hlwb kuj tuaj yeem txhim kho los ntawm kev tawm dag zog lub hlwb. Kawm tej yam tshiab, ua kev puas siab puas ntsws thiab kev ua si nco, thiab lwm yam, tuaj yeem siv lub hlwb, txhawb kev sib txuas ntawm neuronal thiab txhim kho lub peev xwm nco.
Nyob rau hauv luv luv, kev noj qab haus huv ntawm lub hauv paus paj hlwb yog ze ze rau kev txhim kho kev nco. Peb yuav tsum ua tib zoo ntsuas los tiv thaiv lub hauv paus paj hlwb, txhim kho kev nco, ua tib zoo saib xyuas kev noj qab haus huv, thiab siv lub hlwb hauv peb lub neej txhua hnub kom peb muaj lub cev thiab lub hlwb zoo dua. Los ntawm qhov kev xav no, peb yuav tsum txhim kho peb lub cim xeeb. Cistanche tuaj yeem txhim kho peb lub cim xeeb zoo vim tias Cistanche yog cov khoom siv tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm cov nqaij minced yog los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog carboxylic acid, polysaccharides, flavonoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.
Nyem paub ntxiv los txhim kho kev nco
Hauv vitro, cov piam thaj siab tau nce qhov kev qhia ntawm inflammasome recombinant NLR Tsev Neeg, pyrin domain-muaj protein ntau 3 (NLRP3) cov cim hauv hippocampal cells.90 Tsis tas li ntawd, CNS o yog ib qho kev tiv thaiv kab mob los ntawm microglia thiab astrocytes. Cov ntaub ntawv pov thawj pom tau tias mob ntshav qab zib hloov pauv ua rau muaj kev ntxhov siab uas hloov cov kev ua haujlwm ntawm microglial (xws li, kev ua kom mob plab lossis kev ua rau tus kheej), uas tej zaum yuav yog ib qho ntawm cov txheej txheem ntawm kev paub tsis meej hauv cov neeg mob ntshav qab zib.91 Cov nas mob ntshav qab zib kuj qhia cov kev hloov astrocyte hauv hippocampus.92. ,,93 ib
Txij li thaum astrocytes yog ib qho tseem ceeb ntawm cov hlwb txhawb nqa neuronal, kev hloov astrocyte tuaj yeem ua rau muaj kev ua haujlwm tsis zoo ntawm cov neuronal. Peb pab neeg yav dhau los tau tsim ib qho qauv IR induced los ntawm palmitic acid nyob rau hauv vitro thiab tsim ib tug neuron-microglia-astrocyte co-culture system, paub meej tias IR-induced microglial activation thiab lub secretion ntawm cytokines tau ho nce. Txoj kev tshawb no kuj tau lees paub tias activated microglia tuaj yeem qhib txoj hauv kev NF-κB hauv astrocytes, qhib astrocytes, thiab txo kev txhawb nqa rau cov neurons (cov ntaub ntawv tsis qhia). Txawm li cas los xij, kev sib koom ua ke ntawm hyperglycemia thiab neuroinflamation tsis meej meej. Qee cov kws tshawb fawb tau hais tias oxidative kev nyuaj siab-mediated mitochondrial dysfunction txhawb lub upregulation ntawm mitochondrial HSP60 thiab thaum kawg pib mob ntshav qab zib induced inflammatory pathways los ntawm activating qauv paub receptors.94
GLP-1 RA tau pom tias muaj kev tiv thaiv kab mob hauv CNS. Nyob rau hauv cov kab mob inflammatory hauv vitro, GLP-1 suppressed qhov tso tawm ntawm TNF- -sociated cytokines thiab chemokines hauv BV-2 microglia.95 Liraglutide kuj txo qis microglia thiab astrocyte load nyob rau hauv lub hlwb induced los ntawm ntev. o nyob rau hauv nas.96 Tsis tas li ntawd, kev kho liraglutide tiv thaiv cov txheej txheem neuroinflammatory, txhawb kev tsim cov tshuaj tiv thaiv kab mob xws li IL10, TGF, thiab arginase 1.97 Hauv cov qauv ntawm lipopolysaccharide (LPS)-induced o, liraglutide inhibited polarization ntawm pro- inflammatory microglia thiab txhawb lub polarization ntawm anti-inflammatory microglia, txo qis inflammatory cytokine qhia, thiab txo NF-κB txoj kev activation.98 Ib yam li ntawd, exendin -4 kuj txo mRNA theem ntawm IL-1 thiab TNF- nyob rau hauv LPS-stimulated microglia thiab txo qis qhov ua rau ntawm NF-κB signaling pathway.99 Cov tshuaj tiv thaiv kab mob ntawm GLP-1 kuj tshwm sim hauv ntshav qab zib mob neuroinflammation. Thaum lub sij hawm exendin{25}} kev kho mob, IL- 1b tau nce ntxiv hauv cov nas normoglycemic thiab txo qis hauv cov nas hyperglycemic.88 Liraglutide kuj tiv thaiv astrocytes tiv thaiv cov khoom kawg glycation (AGE)-induced TNF thiab IL{{29} } secretion.100
Muaj ob peb lub tswv yim ua tau los ntawm GLP-1 RA tswj neuroinflamation. Ua ntej, GLP-1 RA inhibited LPS-induced IL-1 mRNA qhia, whereas adenylate cyclase inhibitor preconditioning inhibited cov nyhuv no, qhia tias cAMP-mediated nws anti-inflammatory effect.101 Txoj kev cAMP/PKA kuj yog koom nrog kev tiv thaiv astrocytes los ntawm AGE-induced inflammatory teb.100 Thib ob, cov tshuaj tiv thaiv kab mob ntawm GLP-1 RA yog ib feem ntawm nws cov metabolite nyob rau hauv phosphorylated AMPK-raws li. Cov kev kho mob uas inhibit GLP-1 degradation tuaj yeem ua rau cov teebmeem metabolite-mediated tsis muaj zog.102
GLP-1 RA thiab Neurogenesis
Neurogenesis yog cov txheej txheem tiav uas cov neural stem cells (NSCs) proliferate, muaj kev sib npaug thiab tsis sib npaug los ua cov hlwb progenitor thiab maj mam tsiv mus rau thaj chaw ua haujlwm, hloov pauv plasticity, thiab tsim kom muaj kev sib txuas synaptic nrog lwm cov neurons los tsim kev ua haujlwm neural. Cov neeg laus neurogenesis yog tsim nyob rau hauv ob feem ntawm lub hlwb: lub subventricular cheeb tsam ntawm lub lateral ventricle thiab subgranular cheeb tsam ntawm lub dentate gyrus nyob rau hauv lub hippocampus. Kev koom ua ke ntawm cov neeg laus yug los neurons rau hauv circuitry ntawm cov neeg laus hippocampus qhia lub luag haujlwm tseem ceeb rau cov neeg laus hippocampal neurogenesis hauv kev kawm thiab kev nco.103 Txoj hauv kev zoo li insulin / insulin-zoo li kev loj hlob (IGF) txhawb nqa NSC kev loj hlob, sib txawv, thiab ciaj sia taus; 104 Yog li ntawd, qhov tsis zoo ntawm cov tshuaj insulin tuaj yeem cuam tshuam rau neurogenesis. Kev txo qis ntawm cov ntshav qab zib hauv cov neurogenesis hauv hippocampal dentate txhais tau hais tias muaj peev xwm ua rau muaj feem cuam tshuam rau cov ntshav qab zib kom paub txog kev poob qis.105–110 Cov lus piav qhia ua tau yog tias cov teeb meem uas tshwm sim hauv hom 2 mob ntshav qab zib mellitus cuam tshuam endothelial caveolin-1, ib daim nyias nyias intrinsic protein nyob rau hauv lub caveolae ntawm lub xovtooj ntawm tes, ua rau vascular dysfunction, cuam tshuam rau neurogenesis, thiab tom qab ntawd ua rau AD.111 IKK / NF-κB-mediated impairment112 thiab -aminobutyric acid thiab glutamate transporter systems113 kuj tuaj yeem koom nrog hauv kev puas tsuaj rau ntshav qab zib. ntawm neurogenesis.
Txhim kho GLP-1R teeb liab txoj hauv kev ua rau kev loj hlob ntawm cov hlwb neuronal114 thiab neuronal sib txawv.115 Hauv cov nas rog rog thiab insulin-resistant, liraglutide elicits muaj txiaj ntsig zoo ntawm kev tswj cov metabolism thiab synaptic plasticity thiab txhim kho hippocampal neurogenesis.116
Lub tshuab uas GLP-1 RA cuam tshuam rau neurogenesis tseem tsis meej. Ib qho kev ua tau zoo yog, ib feem, los ntawm kev nthuav qhia ntawm mammalian achaete-scute homolog 1 (Mash1), uas ua lub luag haujlwm tseem ceeb hauv kev sib txawv ntawm cov neuronal thiab ntseeg tias yuav txhim kho hippocampal neurogenesis. Active Akt nce qib protein ntau thiab kev ua haujlwm hloov pauv ntawm Mash1,117 qhia txog qhov muaj peev xwm ua haujlwm ntawm GLP-1- qhib PI3K-Akt txoj hauv kev.
GLP-1 RA thiab Synaptic Plasticity
Synaptic plasticity yog hais txog lub zog kho tau ntawm kev sib txuas ntawm cov paj hlwb, hu ua synapses. Nws tau lees paub tias ntshav qab zib muaj feem cuam tshuam rau hippocampal synaptic plasticity, thiab qhov kev cuam tshuam ntawm synaptic plasticity no cuam tshuam nrog kev paub.118 Reisi li al qhia tias ob qho tib si presynaptic thiab postsynaptic Cheebtsam cuam tshuam rau cov ntshav qab zib ua rau kev puas tsuaj rau synaptic plasticity.119 Hauv tsiaj qauv ntawm ntshav qab zib. nrog kev paub tsis meej, synaptic plasticity tau raug cuam tshuam rau hauv ob txoj kev sim ntawm kev txhim kho mus sij hawm ntev (LTP) 120-124 thiab kev nyuaj siab ntev (LTD).125,126 Ntxiv mus, lub ultrastructure ntawm hippocampal synapses raug rhuav tshem, 127 yog li txo cov hippocampal dendritic. spine density.123 Tsis tas li ntawd, synaptic plasticity-related proteins, nrog rau CREB, pCREB, hlwb-derived neurotrophic factor (BDNF), thiab kev ua ub no-regulated cytoskeleton (Arc) cov proteins, yog txo qis.128 Peb cov ntaub ntawv yav dhau los pom tau tias hauv nruab nrab IR tuaj yeem ua tau zoo heev. cuam tshuam rau kev nthuav qhia ntawm synaptic plasticity proteins, xws li postsynaptic density protein-95 (PSD95), Arc, synapsin1, thiab BDNF, ua rau muaj qhov tsis zoo ntawm synaptic plasticity ntawm neurons thiab txo kev kawm thiab kev nco muaj peev xwm (cov ntaub ntawv tsis qhia). Sasaki-Hamada qhia tau hais tias kev cuam tshuam ntawm synaptic plasticity tshwm sim nyob rau hauv cov kab mob prediabetes thaum cov piam thaj tsis txaus siab.129 Tsis tas li ntawd, qhov pib muaj hnub nyoog 130 thiab lub sijhawm ntawm ntshav qab zib mellitus131 yuav muaj qee yam cuam tshuam rau synaptic plasticity. Txawm li cas los xij, lub sijhawm luv luv ntawm kev hloov pauv ntawm cov piam thaj hauv cov ntshav tuaj yeem tsis ncaj qha rau cov synaptic plasticity cuam tshuam nrog ntshav qab zib, tshwj tsis yog mob hnyav heev.132
Glutamate receptors, suav nrog cov amino-3-hydroxy-5-methyl-4-isoxazolepro-pionicacid (AMPA) thiab N-methylD-aspartate (NMDA) receptors, mediate excitatory synaptic kis hauv CNS, thiab nws kev qhia hauv postsynaptic membrane yog txuam nrog LTP thiab LTD thiab koom nrog hauv kev tswj hwm ntawm kev kawm thiab kev nco ua haujlwm. Cov kev cai txawv txav ntawm glutamatergic receptors zoo nkaus li koom nrog hauv kev mob ntshav qab zib vim kev puas tsuaj ntawm synaptic plasticity.120,122,125,133,134 Tsis tas li ntawd, kev taw qhia cov tshuaj insulin yog qhov tseem ceeb rau synaptic plasticity. IR -subunit heterozygous nas135 thiab ua tiav kev cuam tshuam ntawm IRS2 hauv nas136 cuam tshuam LTP ntawm synaptic kis tau tus mob hauv hippocampus. Histone deacetylases (HDAC2), ib tug tswv cuab ntawm tsev neeg HDAC, muaj feem cuam tshuam nrog cov khoom siv tshuaj insulin hauv postsynaptic glutamatergic neurons ntawm cov neeg laus nas hippocampus, thiab hyperactivity ntawm HDAC system (xws li HDAC2) tuaj yeem ua rau muaj kev cuam tshuam ntawm insulin signaling system thiab kev cuam tshuam ntawm synaptic plasticity hauv hom 2 diabetes.137
GLP-1 RA muaj qhov cuam tshuam rau kev txhim kho synaptic plasticity. Exendin-4 inhibits qhov txo qis ntawm LTP hauv lub hlwb ntawm tus nas noj cov zaub mov muaj roj ntau 138 thiab nce qib phosphorylation ntawm CREB thiab qib qhia ntawm BDNF. Tsis tas li ntawd, exendin -4 tau nce qib membrane protein ntau ntawm AMPA receptor GluR1 subunit thiab PSD95.139 Liraglutide kuj tau cawm cov teebmeem ntawm cov rog rog ntawm hippocampal LTP ntawm neurotransmission140 thiab txhim kho tus naj npawb ntawm hippocampal thiab cortical synapses hauv AD model nas.141
Cov nyhuv ntawm GLP-1 RA ntawm synaptic plasticity yog ib feem ntawm GLP-1R. Hauv GLP-1R knockout nas qauv, LTP hauv thaj tsam CA1 ntawm hippocampus tau raug mob hnyav heev.142 Tsis tas li ntawd, GLP-1 RA upregulated neurotrophic tyrosine kinase receptor type 2 thiab mTOR genes hauv hippocampus ntawm Cov nas uas muaj roj ntau, uas koom nrog hauv kev tswj cov synaptic plasticity thiab LTP.143 Los ntawm kev hloov cov calcium cov lus teb rau glutamate thiab membrane depolarization, 144 thiab AMPA receptors, 139,145 GLP-1 RA tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tswj cov kab mob neural plasticity.
GLP-1 RA hauv Diabetes-Related AD thiab PD
AD yog ib qho insidiously progressive ND clinically characterized by memory impairment, aphasia, apraxia, agnosia, impaired executive function, cwm pwm thiab cwj pwm hloov, thiab lwm yam dementia manifestations. PD yog lwm hom kab mob degenerative, thiab lub ntsiab pathology yog degeneration thiab tuag ntawm dopaminergic (DA) neurons nyob rau hauv lub substantia nigra ntawm lub midbrain, uas ua rau ib tug tseem ceeb txo nyob rau hauv DA cov ntsiab lus nyob rau hauv lub striatum. Ob leeg AD thiab PD yog NDs cuam tshuam nrog ntshav qab zib; Txawm li cas los xij, tam sim no kev kho mob ntawm ob kab mob no tseem tsom mus rau kev txhim kho cov tsos mob. Nws yog ib qho tsim nyog kom nkag siab zoo dua lawv cov txheej txheem kom tau txais cov tshuaj zoo dua ntawm lawv cov kab mob.
Mob ntshav qab zib thiab Alzheimer's Disease
Mob ntshav qab zib muaj ze rau AD, thiab ib qho kev ntsuas ntsuas pom tau tias cov neeg mob ntshav qab zib muaj qhov tshwm sim ntawm AD ntau dua li cov uas tsis muaj ntshav qab zib (tus txheeb ze pheej hmoo [RR], 1.53; 95% CI, 1.42–1.63), 146 qhia tias ntshav qab zib. tuaj yeem txhawb txoj kev loj hlob ntawm AD. Insulin ua rau -site amyloid precursor protein cleaving enzyme 1 thiab -secretase los tswj cov qib A thiab degrades ntau tshaj A los ntawm kev hloov kho cov tshuaj insulin-degrading enzyme.147 Kev ua kom cov insulin signaling pathway PI3k/Akt ua rau Ser9 phosphorylation ntawm GSK3 thiab nws cov kinase ua haujlwm tsis zoo. rau phosphorylation ntawm tau.148 Li no, IR txhawb cov pathology ntawm AD los ntawm kev txo cov amyloid clearance thiab nce tau hyperphosphorylation neurofibrillary tangles, 149 ob qho tib si yog txuam nrog kev paub tsis meej.150,151
Nws tau lees paub tias kev hloov pauv hauv mitochondria tau koom nrog hauv kev txhim kho AD. Cov kev tshwm sim ntawm mitochondrial dysfunction nyob rau hauv AD feem ntau muaj xws li nce oxidative kev nyuaj siab thiab ROS ntau lawm, 152,153 mitochondrial DNA puas, 154 mitochondrial ua pa raug mob, thiab 155 calcium abnormalities.156 Mitophagy, 157 mitochondrial 58drial cov neeg mob thiab dynamics, , thaum kawg ua rau tsub zuj zuj ntawm dysfunctional mitochondria thiab mitochondrial fragmentation. Mitochondrial puas yuav tsis tsuas yog cov txheej txheem pathological ntawm ntshav qab zib thiab AD tab sis kuj yog qhov tseem ceeb ntawm kev sib tham ntawm lawv. Ob tug ADrelated markers, A -production thiab tau phosphorylation induced los ntawm IR, tej zaum lub upstream mechanisms ntawm AD-txog mitochondrial puas tsuaj.159–161 Tsis tas li ntawd, kev puas tsuaj mitochondrial tej zaum yuav yog ib qho tseem ceeb rau kev mob ntshav qab zib rau AD, raws li raug rau A. Ua kom muaj qhov tsis zoo ntawm lub hlwb mitochondria hauv cov nas mob ntshav qab zib.162
ER, kev ntxhov siab ua lub luag haujlwm nyuaj hauv kev tswj hwm ntawm neuronal ciaj sia taus, amyloid cascade, neurodegeneration, thiab synaptic muaj nuj nqi hauv AD.163 Hauv vitro, cov lus hais saum toj no ER kev nyuaj siab / JNK / IRS1 txoj hauv kev tau koom nrog A 1-42 oligomer-induced tau hyperphosphorylation, uas tej zaum yuav qhia tau hais tias IR txhawb lub luag hauj lwm ntawm ER kev nyuaj siab nyob rau hauv AD.164 de la Monte et al qhia tias nyob rau hauv AD, ib tug triangulated Mal-signaling network pib los ntawm lub hlwb cov insulin / IGF tsis kam yog kis los ntawm cov ceramides thiab ER kev nyuaj siab. homeostasis tsis meej, uas nyob rau hauv lem txhawb IR.165
Cov kev tshawb fawb tau pom tias qhov mob ua rau muaj qhov tshwm sim ntawm AD. Nyob rau hauv AD, A puas microglia tsim inflammatory cytokines thiab chemokines, thiab cuam tshuam rau ib puag ncig CNS cov neeg nyob hauv hlwb (astrocytes, oligodendrocytes, thiab neurons), uas tej zaum yuav ua rau cov kab mob loj zuj zus thiab thaum kawg ua rau neurodegeneration thiab neuron poob.166 Kev mob plab kuj tseem yog qhov sib txuas ntawm ntshav qab zib thiab AD. Takeda et al hla Alzheimer transgenic nas (APP23) nrog ob hom kab mob ntshav qab zib nas (ob/ob thiab NSY nas) thiab pom muaj qhov nce ntxiv hauv IL-6 hauv lub hlwb ntawm cov nas hybrid noj nrog cov zaub mov muaj roj ntau. 167 Tsis tas li ntawd, nws tau pom tias noj AD qauv nas (triple transgenic AD [3xTgAD]) noj cov rog rog yuav ua rau kom cov microglia nce ntxiv.168 Cov kev tshawb fawb no qhia tias cov ntshav qab zib mellitus thiab cov zaub mov muaj roj ntau tuaj yeem ua rau AD mob. .
Neurogenesis yog qhov tsis zoo hauv AD qauv, uas yog tus cwj pwm los ntawm kev txo qis kev loj hlob thiab kev sib txawv, txo qis kev loj hlob ntawm lub paj hlwb, thiab txo qis kev ciaj sia, ua ntej cov txheej txheem uas yuav cuam tshuam rau neurogenesis, xws li neuronal poob, amyloid deposition, thiab mob.169 Chronic hyperglycemia txo qhov nyuaj. thiab kev sib txawv ntawm 3xTg-AD cov menyuam yug tshiab neurons thiab kev nyuaj siab synaptic yooj yim, nrog rau kev nco tsis zoo hippocampal-dependent, 109 qhia tias ntshav qab zib txhawb kev hloov pauv hauv AD neurogenesis uas thaum kawg exacerbates kev paub tsis meej.
Mob ntshav qab zib thiab Parkinson's Disease
Kev tshuaj xyuas thiab kev tshuaj ntsuam xyuas meta tau qhia tias ntshav qab zib yog qhov muaj feem pheej hmoo rau PD (RR=1.37, 95% CI, 1.21–1.55; P < {0}.0001).170 Ntshav Qab Zib tuaj yeem ua rau hnyav dua. Kev loj hlob ntawm PD, suav nrog kev paub tsis meej thiab cov tsos mob ntawm lub cev muaj zog.171 IR tseem yog qhov tseem ceeb ntawm kev sib txuas ntawm ntshav qab zib thiab PD thiab tuaj yeem cuam tshuam nigrostriatal dopamine kev ua haujlwm, 172 exacerbate nigrostriatal DA depletion, 173 thiab txhim kho kev txawj ntse 174 thiab kev coj cwj pwm txawv.175
Mitochondrial dysfunction yog qhov tsis xws luag nyob rau theem pib ntawm PD thiab feem ntau suav nrog kev cuam tshuam ntawm mitochondrial electron thauj saw, hloov pauv hauv mitochondrial morphology thiab dynamics, kev hloov pauv hauv mitochondrial DNA, thiab kev tsis txaus ntseeg hauv calcium homeostasis, 176 uas muaj feem cuam tshuam nrog PD. Mitochondrial puas kuj yog vim li cas vim li cas IR mob ntshav qab zib txhawb kev txhim kho PD. Nyob rau hauv vitro, nyob rau hauv sib txawv tib neeg DA neurons, IR tau txuam nrog nce -synuclein thiab ROS ntau ntau, nrog rau mitochondrial depolarization, uas tej zaum yuav kho los ntawm polo-zoo li kinase -2.177 Nyob rau hauv vivo, mitochondrial dynamics-txog yam. Parkin tau txo qis hauv substantia nigra ntawm cov nas noj cov zaub mov muaj roj ntau thiab cov nas mob ntshav qab zib, ua rau muaj kev sib txuam ntawm Parkin-interacting substrate thiab txo qis ntawm PGC-1 .41 Tsis tas li, cov piam thaj ntau tuaj yeem hloov pauv Parkin/ PINK1-mediated mitochondrial autophagy hauv DA hlwb los ntawm thioredoxin-interacting protein.178 Tag nrho cov txheej txheem saum toj no qhia tau hais tias cov mob ntshav qab zib muaj feem xyuam rau cov metabolic yam yuav txhawb nqa PD los ntawm kev tswj cov mitochondria.
Txhua ceg ntawm UPR hauv ER kev ntxhov siab yuav cuam tshuam rau hauv PD etiology.179 Tam sim no, kev tshawb fawb txog seb mob ntshav qab zib thiab IR ua rau ER kev nyuaj siab hauv PD muaj tsawg. Txawm li cas los xij, muab qhov chaw ntawm ER txoj kev ntxhov siab ntsig txog txoj hauv kev thiab IR crosstalk tau hais los saum toj no, IR mob ntshav qab zib yuav muaj feem cuam tshuam rau tiam ER kev ntxhov siab hauv PD.
Zoo ib yam li AD, neuroinflammation yog koom nrog hauv kev degeneration ntawm DA neurons, uas feem ntau yog kho los ntawm activated glial hlwb thiab ib puag ncig lub cev tiv thaiv kab mob. Cov lus teb ntawm tes no thaum kawg tuaj yeem ua rau tuag ntawm DA hlwb, ua rau muaj kab mob.180 Kev tshawb fawb uas siv 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP) rau kev ua raws li PD-zoo li neural raug mob pom tias neuroinflammation yog aggravated nyob rau hauv lub midbrain ntawm hom 2 mob ntshav qab zib nas, uas muaj ntau raug rau cov neurotoxicity induced los ntawm MPTP.181 Qhov no tej zaum yuav qhia tau hais tias mob ntshav qab zib exacerbates DA neuronal degeneration thaum lub sij hawm kev loj hlob ntawm cov kab mob. PD, uas tuaj yeem kho los ntawm neuroinflamation.
Cov neeg laus neurogenesis muaj kev cuam tshuam loj heev hauv PD, thiab txawm hais tias qhov tseeb mechanisms thiab cov txiaj ntsig ntawm cov kev hloov pauv no tsis to taub tag nrho, tej zaum yuav muaj kev sib cuam tshuam ntawm lawv thiab PD-txog pathology.182 Txawm hais tias nws tsis paub meej tias puas muaj kev sib tham ntawm cov ntshav qab zib. thiab PD hauv neurogenesis, kev hloov pauv pathophysiological zoo sib xws yuav qhia tau tias muaj kev sib raug zoo ntawm ob kab mob.
GLP-1 RA Qhia cov teebmeem
Qee cov txheej txheem zoo sib xws lossis sib tshooj yeej muaj nyob nruab nrab ntawm ntshav qab zib thiab AD lossis PD, xws li mitochondrial tsis ua haujlwm, oxidative kev nyuaj siab, thiab mob, uas tuaj yeem ua rau muaj kev sib raug zoo. Tsis tas li ntawd, cov txheej txheem no yuav ua rau muaj kev siv cov tshuaj ntshav qab zib GLP-1 RA los kho AD thiab PD. Hauv qee tus qauv AD thiab PD, ntau qhov kev tshawb fawb tau qhia meej txog lub luag haujlwm ntawm GLP-1 RA hauv cov txheej txheem ntawm tes. Txawm li cas los xij, GLP-1 RA kuj muaj qee yam kab mob tshwj xeeb hauv AD thiab PD, xws li txo qis A qib, tau hyperphosphorylation hauv AD, thiab txo cov synuclein pathology thiab DA neuronal poob hauv PD, qhia tias GLP{{4} } RA muaj zog neuroprotective muaj nuj nqi (Tables 1 thiab 2).
Lub tshuab ntawm GLP-1 RA ntawm A tsis meej. Ib qho ua tau yog tias amyloid precursor protein (APP) khi rau GLP-1 ua G-protein-coupled receptor, ua rau txo qis APP synthesis.183 GLP-1 RA txo tau phosphorylation tsis yog hauv AD qauv xwb. tab sis kuj hauv ntshav qab zib.32,33,184,185 Txawm li cas los xij, cov txheej txheem uas GLP-1 RA txo tau hyperphosphorylation yuav nyuaj. Nws tau raug tshaj tawm tias GLP-1 RA txo tau phosphorylation los ntawm Akt thiab GSK-3, ib txoj hauv kev muaj feem xyuam rau cov teeb liab insulin, uas kuj tau lees paub tias cov tshuaj insulin tsis kam yog tus yuam sij rau tau phosphorylation.186–188 Nws muaj kuj tau tshaj tawm tias cov teebmeem ntawm liraglutide ntawm kev txo qis hyperphosphorylation ntawm tau los ntawm kev txhim kho O-glycosylation ntawm neuronal cytoskeleton protein, txhim kho JNK thiab ERK signaling pathway.189,190 Tsis tas li ntawd, mitochondrial PGC-1 kev taw qhia txoj hauv kev kuj yog cov txheej txheem. ntawm GLP-1 RA los tiv thaiv cov neurons los ntawm tau hyperphosphorylation, qhia tias mitochondrial dysregulation muaj crosstalk nrog tau pathology.46 Lub hom phiaj ntawm GLP-1 RA txo nyob rau hauv A overproduction thiab tau hyperphosphorylation tej zaum yuav yog lub restoration ntawm protein. phosphatase 2A kev ua thiab inhibition ntawm - thiab secretase.191 Cov txheej txheem ntawm GLP-1 RA txhawm rau txhim kho dopaminergic degeneration thiab pathological -synuclein aggregation hauv PD qauv yuav cuam tshuam rau inhibiting PI3K/Akt/mTOR pathway192 thiab txhim kho AMPK/PGC. -1ib txoj kev taw qhia.193
Txawm hais tias qee qhov txiaj ntsig tau ua tiav hauv cov qauv tsiaj, kev tshawb fawb soj ntsuam ntawm GLP-1 RA tseem txwv. Qhov kev tshuaj xyuas no nthuav tawm qee cov ntaub ntawv kho mob ntawm GLP-1 RA (Table 3), nrog qee qhov txiaj ntsig zoo siab. Tab sis qee qhov kev tshawb fawb tsis pom qhov ua tau zoo vim yog qhov kev txiav tawm ntxov194 lossis qee qhov kev tshawb fawb yuav tsis pom cov tshuaj cuam tshuam vim lub sijhawm luv luv los yog cov ntaub ntawv qis qis.195 Ntau qhov kev tshuaj xyuas lossis kev tshuaj ntsuam xyuas meta tau sim ua kom tiav cov ntaub ntawv soj ntsuam ntawm GLP. -1 RA hauv kev kho mob ntawm AD lossis PD, tab sis cov txiaj ntsig tseem tsis tau lees paub, 196–200 tej zaum vim qee qhov kev tshawb fawb soj ntsuam tseem tab tom ua thiab xav tau kev saib xyuas tsis tu ncua.201,202 Vim muaj kev txwv ntawm kev tshawb fawb soj ntsuam, kev tshuaj xyuas cov tshuaj yuav tsum tau cia siab rau qee txoj kev tshuaj ntsuam xyuas tshiab, xws li imaging.203 Muaj laj thawj ntseeg tias nrog kev txhim kho thev naus laus zis tsis tu ncua, kev txiav txim siab ntawm kev siv tshuaj yuav yooj yim dua thiab muaj ntau haiv neeg.
Xaus
Hauv xyoo tas los no, cov txheej txheem kho mob tau pib qhia txog qhov tseem ceeb ntawm NDs ntsig txog ntshav qab zib thiab lawv txoj kev pheej hmoo ntawm kev paub tsis meej, txawm tias muaj kev txhawj xeeb thoob plaws. Mob ntshav qab zib mellitus thiab lwm yam NDs sib koom cov txheej txheem sib xws, xws li hauv nruab nrab IR, oxidative kev nyuaj siab, thiab mob, uas ua rau lawv cov lus sib tham, uas tau tshwm sim rau kev tshawb nrhiav cov tshuaj hypoglycemic, tshwj xeeb tshaj yog GLP-1 RA, raws li kev kho mob ntshav qab zib thiab muaj feem xyuam. NDs.
Qhov kev tshuaj xyuas no piav qhia meej txog cov txiaj ntsig zoo ntawm GLP-1 RA ntawm lub hauv paus pathological mechanisms ntawm ntshav qab zib thiab lwm yam kab mob degenerative. Txawm li cas los xij, lub luag haujlwm ntawm GLP-1 RA hauv lub cev yog qhov nyuaj. Ua ntej, GLP-1 RA tau pom tias muaj cov nyhuv hypoglycemic muaj zog, thiab kev cuam tshuam ntawm cov ntshav qabzib ntawm cov txheej txheem no tsis tuaj yeem txiav tawm. Qhov thib ob, IR muaj nyob rau hauv lub hlwb ntawm cov neeg mob ntshav qab zib mellitus, AD, thiab PD thiab tseem yog ib qho tseem ceeb cuam tshuam rau cov txheej txheem no. Yog li ntawd, nws tsis paub meej tias GLP-1 RA ncaj qha txhim kho mitochondrial muaj nuj nqi, txo ER kev ntxhov siab, thiab txo qis neuroinflammation, lossis tsis ncaj qha txhim kho cov txheej txheem no los ntawm kev txo cov ntshav qabzib thiab txhim kho IR. Cov kev tshawb fawb ntxiv yog xav tau kom paub tseeb tias qhov kev tiv thaiv hauv nruab nrab ntawm GLP-1 RA, thiab kev sim tshuaj ntxiv yuav tsum tau ua kom nquag plias.
Cov ntawv luv
A, amyloid protein; AD, Alzheimer's kab mob; AGE, advanced glycation kawg khoom; Akt, protein kinase B; AMPA, amino-3-hydroxy-5-methyl-4-isoxazolepro-pionicacid; AMP, adenosine 5'-monophosphate; AMPK, AMP-activated protein kinase; Arc, kev ua haujlwm-tswj cytoskeleton; ATF6, activating transcription factor 6; APP, amyloid precursor protein; BDNF, hlwb-derived neurotrophic yam; BiP, khi immunoglobulin protein; CHOP, C / EBP homologous protein; CNS, central paj hlwb; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; CREB, cAMP teb cov ntsiab lus-binding protein; DA, dopaminergic; Drp1, dynamin-related protein 1; ER, endoplasmic reticulum; ERK-Yap, extracellular teeb liab-regulated kinase-Yes-sociated protein; GADD34, kev loj hlob ntes thiab DNA puas inducible noob 34; GLP-1, glucagon-zoo li peptide 1; GLP-1 RA, GLP-1 receptor agonists; GLP-1R, GLP-1 receptor; GRP78, 78-kDa qabzib tswj cov protein; GSK-3 , glycogen synthase kinase 3 ; HDAC, histone deacetylase; HSP, kub poob protein; IGF, kev loj hlob zoo li insulin; IKK, inhibitor kappa B kinase; IR, insulin tsis kam; IRE-1, inositol-yuav tsum tau enzyme 1; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; LTD, kev nyuaj siab ntev; LTP, kev txhim kho mus ntev; MAPK, mitogen-activated kinase; Mash1, mammalian achaete-scute homologue 1; MPTP, 1-methyl-4-phenyl-1,2,3,{49}}tetrahydropyridine; mTOR, mammalian phiaj ntawm rapamycin; ND, kab mob neurodegenerative; NLRP3, recombinant NLR Tsev Neeg, pyrin domain uas muaj protein ntau 3; NMDA, N-methyl-D-aspartate; NSCs, neural qia hlwb; NF-κB, nuclear transcription factor-κB; PD, Parkinson tus kab mob; PERK, PKR-zoo li ER kinase; PGC1a, peroxisome proliferator-activated receptor c coactivator 1a; PI3K, phosphoinositide-3 kinase; p-JNK, phospho-Jun N-terminal kinase; PKA, protein kinase A; PSD95, postsynaptic density protein-95; PKR, protein kinase R; ROS, reactive oxygen hom; RR, txheeb ze txaus ntshai; SIRT1, NAD-dependent protein deacetylase sirtuin 1; UPR, unfolded protein teb; 3xTgAD, triple transgenic AD.
Kev lees paub
Txoj haujlwm no tau txais kev txhawb nqa los ntawm National Natural Science Fund ntawm Tuam Tshoj (81970687, 81670732 belongs rau Guixia Wang; 81900726 belongs rau Xue Zhao); qhov nyiaj pab los ntawm Engineering Research Center ntawm Kev Ntsuas Tus Kheej thiab Kev Kho Mob ntawm Jilin Province Science thiab Technology Department Project (20170623005TC); qhov nyiaj pab los ntawm Kev Txhim Kho thiab Kev Hloov Kho Commission Innovation Project (2017C019); cov nyiaj pab los ntawm Department Science thiab Technology Department ntawm Jilin xeev (20190901006JC belongs rau Guixia Wang; 20210101439JC belongs rau Xue Zhao); cov nyiaj pab los ntawm Kev Tshawb Fawb Cov Nyiaj Txiag ntawm Thawj Tsev Kho Mob ntawm Jilin University (2021-zl-01 koom nrog Xue Zhao) thiab cov nyiaj pab los ntawm Jilin Medical and Health Talent Project (JLSWSRCZX2021-081) belongs rau Xue Zhao ).
Qhia tawm
Cov neeg sau ntawv tshaj tawm tsis muaj qhov tsis sib haum xeeb ntawm kev txaus siab hauv txoj haujlwm no.
Cov ntaub ntawv
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