Kev Tiv Thaiv Cov Khoom Ntawm GLP-1 Thiab Koom Tes Peptide Hormones hauv Neurodegenerative Disorders Part 4

20|DUAL GLP-1/GIP RECEPTORAGONISTS muaj kev tiv thaiv nyob rau hauv cov tsiaj txhu ntawm PARKINSON'S Disease

Hauv kev sib piv ncaj qha ntawm GLP-1 analogs, GIP analogs,oxyntomodulin, thiab DA1-JC, peb pom tias DA1-JC yog qhov zoo tshaj plaws tiv thaiv SH-SY5Y hlwb los ntawm kev ntxhov siab rotenone (Jalewa thiab ib., 2016).

Oxyntomodulin yog ib yam khoom tseem ceeb hauv endocrine uas tuaj yeem cuam tshuam rau kev tso tawm ntawm gastric acid thiab plab hnyuv motility, pab peb zom zaub mov. Txawm li cas los xij, kev tshawb fawb tshiab tau pom tias oxyntomodulin tuaj yeem muaj txiaj ntsig zoo rau peb lub cim xeeb.

Ua ntej, oxyntomodulin tuaj yeem txhawb kev sib txuas ntawm cov neurons thiab txhim kho kev kawm thiab kev nco. Cov kev tshawb fawb tau pom tias oxyntomodulin tuaj yeem ua rau kom tso tawm ntawm ib qho tseem ceeb neurotransmitter hu ua acetylcholine, uas ua lub luag haujlwm tseem ceeb hauv lub hlwb. Acetylcholine tuaj yeem txhawb kev sib txuas ntawm cov neurons thiab txhim kho kev ua kom muaj zog ntawm cov neurons, yog li txhim kho kev kawm thiab kev nco.

Qhov thib ob, oxyntomodulin tuaj yeem txhawb kev loj hlob thiab kho cov neurons. Cov kev tshawb fawb tau pom tias oxyntomodulin tuaj yeem nce qib ntawm kev loj hlob tseem ceeb hu ua BDNF, uas tseem ua lub luag haujlwm tseem ceeb hauv lub hlwb. BDNF tuaj yeem txhawb kev loj hlob thiab kho cov neurons thiab txhim kho kev sib txuas ntawm cov neurons, yog li txhim kho kev kawm thiab kev nco.

Thaum kawg, oxyntomodulin tuaj yeem txhawb kev pw tsaug zog thiab txhim kho cov txiaj ntsig ntawm kev nco ua ke. Cov kev tshawb fawb tau pom tias kev pw tsaug zog tseem ceeb heev rau kev sib koom ua ke ntawm kev nco, thiab oxyntomodulin tuaj yeem cuam tshuam kev pw tsaug zog. Oxyntomodulin tuaj yeem txo cov qib ntawm cov neurotransmitter hu ua histamine hauv lub hlwb, uas tuaj yeem ua rau tib neeg zoo siab thiab cuam tshuam rau kev pw tsaug zog. Los ntawm kev txo cov qib ntawm histamine, oxyntomodulin tuaj yeem txhawb kev pw tsaug zog thiab txhim kho cov txiaj ntsig ntawm kev nco ua ke.

Yog li, oxyntomodulin muaj txiaj ntsig zoo rau peb lub cim xeeb. Los ntawm kev txhawb nqa kev sib txuas thiab kev loj hlob ntawm cov neurons thiab txhim kho kev pw tsaug zog zoo, oxyntomodulin tuaj yeem pab peb txhim kho peb txoj kev kawm thiab kev nco. Nyob rau tib lub sijhawm, peb kuj yuav tsum tau ua tib zoo saib xyuas kev noj qab haus huv thiab kev ua neej kom txo tau qhov kev pheej hmoo ntawm cov kua qaub ntau dhau ntawm lub plab, yog li ua kom lub cev noj qab haus huv thiab lub hlwb. Nws tuaj yeem pom tias peb yuav tsum txhim kho peb lub cim xeeb, thiab Cistanche tuaj yeem txhim kho peb lub cim xeeb zoo vim tias Cistanche yog cov tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam, uas tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem paub ntxiv los txhim kho kev nco

Cov txiaj ntsig tau lees paub cov kev tshawb fawb yav dhau los uas pom tau tias GIP tuaj yeem sib koom ua ke ntxiv rau kev tiv thaiv los ntawm GLP-1 receptoractivation. DA1-JC tau qhia txog kev tiv thaiv hauv MPTP mousemodel ntawm Parkinson tus kab mob. Cov kev puas tsuaj ntawm lub cev muaj zog tau txo qis thiab synapses raug tiv thaiv los ntawm kev ntxhov siab. Dopamine neurons tau tiv thaiv los ntawm MPTP toxicity, ib yam nkaus.

Cov mob o nyob rau hauv lub hlwb induced los ntawm MPTP thiab BDNF qib hauv lub hlwb tau txhim kho (Cao li al., 2016; Ji, Xue, Lijun, et al., 2016). Txawm li cas los xij, hauv kev sib piv ncaj qha nrog ib leeg GIP thiab GLP-1 receptor agonists, DA1-JC tsis tau qhia txog kev txhim kho (Li, Liu, Li, & Holscher, 2016; Liu, Jalewa, thiab al., 2015). Peb mam li sim DA1-JC hauv 6-OHDA nas qauv ntawm Parkinson tus kab mob.

DA1-JC tau txhim kho kev ua haujlwm ntawm lub cev muaj zog, txawm li cas los xijdopamine neurons hauv SN raug tiv thaiv los ntawm toxicity mus rau qee qhov. Dopamine qib nyob rau hauv lub basal ganglia tau pom tias yuav kho tau zoo tom qab 6-OHDA kev kho mob tab sis tsis mus txog qib pom cov nas uas tsis muaj kab mob.

Cov theem ntawm glial-derived neurotrophic factor (GDNF), kev tiv thaiv kev loj hlob rau dopamine neurons (Airaksinen & Saarma, 2002), tau txhim kho los ntawm DA1-JC, ib yam nkaus. Tsis tas li ntawd, Aktand CREB thib ob tus xa xov tooj ntawm tes taw qhia uas cuam tshuam nrog kev ua haujlwm loj hlob tau raug txhim kho. Autophagy kuj tseem ua tau zoo los ntawm DA1-JC (Jalewa li al., 2017).

Hauv kev sib piv ncaj qha, DA3-CH tau zoo dua liraglutide hauv MPTP mousemodel ntawm Parkinson tus kab mob. DA3-CH tau zoo dua hauv kev sim ntsuas lub cev muaj zog thiab tiv thaiv dopamine neurons (Yuan li al., 2017). Hauv kev soj ntsuam tom qab, liraglutide, DA1-JC, DA4-JC, thiab DA5-CH tau muab piv nrog cov koob tshuaj sib npaug hauv MPTP qauv.

Qhov tseem ceeb, cov agonists dual DA4-JC thiab DA5-CH uas qhia txog kev hla ntawm BBB muab qhov zoo tshaj plaws neuroprotection. Hauv kev ntsuam xyuas lub cev muaj zog rotarod thiab kev ntsuam xyuas lub zog, DA5-CH yog qhov zoo tshaj plaws hauv kev txhim kho lub cev muaj zog.

Dopamine neurons hauv SN tau tiv thaiv zoo dua los ntawm DA5-CH thiabDA4-JC dua li lwm cov tshuaj peptide. Cov qib ntawm proinflammatory cytokines tau qis tshaj hauv cov tsiaj kho los ntawm DA5-CH, thiab cov qib ntawm GDNF hauv lub hlwb tau nce ntau tshaj DA4-JC. Synapse tiv thaiv tau siab tshaj los ntawm DA4-JC thiab DA5-CHtreatment, whereas DA1-JC thiab liraglutide tsis zoo heev (Daim duab 2) (Feng li al., 2018).

Hauv kev tshawb nrhiav tom qab, hauv kev sib piv ncaj qha ntawm DA5-CH thiab exendin-4, DA5 tau ua haujlwm zoo dua hauv MPTP tus qauv nas. Thaum kuaj cov koob tshuaj sib txawv, DA5-CH tau zoo hauv kev tiv thaiv lub hlwb ntawm cov koob tshuaj qis dua piv nrog exendin-4 (Zhang li al., 2020).

Thaum muab piv DA5-CH nrog liraglutide ntawm qhov sib npaug ntawm koob tshuaj tib yam Parkinson tus kab mob animalmodel, DA5-CH tau zoo dua hauv kev txo cov lipid peroxidation, txo cov apoptotic neurons hauv SN, thiab normalizing autophagy hauv cov SN thiab striatum. Qhov tseem ceeb, mitochondria tau tiv thaiv los ntawm mitophagy los ntawm kev txo qis Bax/Bcl-2 piv (Zhang li al., 2020).

Hauv kev tshawb nrhiav tom qab, kev sim DA5-CH qhov sib piv tsis ncaj nrog exendin-4 hauv 6-OHDA nas qauv ntawm Parkinson tus kab mob, Da5-CH muaj zog ntau dua hauv kev ua kom lub cev muaj zog , nce dopamine qib hauv striatum, txo qhov poob ntawm dopamine neurons hauv SN pars compacta, txo cov kab mob chronicinflammation thiab qib ntawm pro-inflammatory cytokines hauv lub hlwb, txhim kho mitogenesis thiab autophagy, normalizing insulin signaling thiab txo cov nqi ntawm -synuclein (Zhang et ib., 2021).

Raws li exendin-4 twb tau pom tias muaj txiaj ntsig zoo rau kev tiv thaiv kab mob hauv cov neeg mob nrog Parkinson tus kab mob (Cheong li al., 2020), cov txiaj ntsig tau txhawb nqa thiab qhia tias DA5-CH yuav ua tau zoo dua hauv tsev kho mob.

FIGURE 2 Ib qho kev sib piv ncaj qha ntawm peb tus agonists dual thiab liraglutide hauv MPTP nas tus qauv ntawm tus kab mob Parkinson (PD). (a) Motorperformance nyob rau hauv lub rotarod xeem.
Lub dual agonists DA4-JC thiab DA5-CH uas tuaj yeem nkag mus rau BBB zoo tshaj plaws yog qhov ua tau zoo tshaj plaws. *P < .05 piv nrog tswj; #P < .05 piv nrog MPTP pawg; $P < .05 piv nrog liraglutide + MPTP pawg. %P < .05 piv nrog DA-JC1+ MPTP pawg, %P < .05 piv nrog DA1-JC + MPTP pab pawg. (b): Kev ntsuas lub zog tuav tau pom zoo ib yam. *P < .05 piv nrog tswj; #P < .05 piv nrog MPTP pawg; $P < .05 piv rau liraglutide + MPTP pawg. %P < .05 piv nrog DA1-JC + MPTPgroup. (c) Kev tiv thaiv ntawm dopamine neurons hauv substantria nigra (SN). Quantification ntawm TH-positive neurons hauv SN qhia tau hais tias cov dualagonists DA4-JC thiab DA5-CH tau rov ua haujlwm zoo tshaj plaws. *P < .05 piv nrog rau pawg tswj; #P < .05 piv rau MPTP pawg; $P < .05 piv nrog pab pawg Liraglutide; $P < .05 piv rau liraglutide pawg; %P < .05 piv nrog DA-JC1 pawg; %P < .05 piv nrog DA-JC1 pawg.

Qhia yog cov duab sawv cev, nplai bar=200 μm. (d) Western blot kom muaj nuj nqis ntawm pro-inflammatory cytokines thiab qhov loj hlob ntawm glial cell-derived neurotrophic factor (GDNF) hauv lub hlwb. (a,b) Tag nrho cov peptides sim txo cov pro-inflammatory cytokines.(c) DA4-JC yog qhov zoo tshaj plaws hauv normalizing GDNF qhia hauv lub hlwb. Hloov los ntawm (Feng li al., 2018).

21|DUAL GLP-1/GIP RECEPTORAGONISTS yog kev tiv thaiv INALZHEIMER'S DISEASE ANIMAL MODELS

Hauv kev tshawb fawb ua ntej, DA3-CH tau qhia txog cov teebmeem neuroprotective hauv APP/PS1 nas qauv ntawm Alzheimer's disease. DA3-CH txhim kho kev kawm thiab nco txog cov dej tshawb nrhiav dej num thiab txo cov amyloidplaque load hauv lub hlwb. Endoplasmic reticulum stress thiab autophagybiomarker qib tau txhim kho los ntawm DA3-CH, ib yam nkaus (Panagakiet al., 2018).

Hauv kev sib piv ncaj qha ntawm liraglutide thiab DA4-JC, ob lub agonist yog qhov zoo tshaj plaws hauv kev txhim kho kev nco thiab kev muaj peev xwm mus sij hawm ntev ntawm synaptic plasticity hauv hippocampus ntawm APP/PS1 nas. Tsis tas li ntawd, DA4-JC muaj peev xwm ntau dua hauv kev txo cov plaque qib amyloid. Cov kab mob rhiab heev raws li pom hauv microgliaactivation thiab qib ntawm cov cytokines pro-inflammatory cytokines tau txo qis dua los ntawm DA4-JC (Daim duab 3) (Maskery et al., 2020).

DA5-CH kuj tau qhia txog kev tiv thaiv zoo hauv APP/PS1 mousemodel. DA5-CH tau txhim kho kev ua haujlwm thiab kev nco qab thiab txo qis amyloid plaque thiab phosphorylated tau protein ntau hauv lub hlwb. Hauv cov ntaub ntawv electrophysiology, DA5-CH muaj peev xwm thim rov qab qhov cuam tshuam ntawm synaptic plasticity (LTP) hauv hippocampus.

Tsis tas li ntawd, DA5-CH normalized insulin signaling thiab PI3K thiab AKT secondmessenger signaling (Cao et al., 2018). Tus qauv icv streptozotocin (STZ) nas qauv ntawm insulin desensitization nyob rau hauv lub hlwb yog suav hais tias yog tus qauv ntawm tus kab mob Alzheimer's (Lester-Coll li al., 2006; Moloney et al., 2010; Steen et al., 2005; Talbot et al. ., 2012).

Txhim kho qib ntawm GLP-1 tau zoo hauv kev thim rov qab insulin desensitization hauv tus qauv no (Knezovic li al., 2018). Thaum kuaj DA4-JC hauv tus qauv thestreptozotocin, kev kho tshuaj kho tau txhim kho kev nco thiab txo qis ntawm phosphorylated tau hauv lub hlwb. DA4-JCalso txo ​​cov kab mob rhiab heev.

Apoptosis thiab mitophagy raug txo los ntawm DA4-JC thiab cov teeb liab insulin tau hloov pauv raws li pom los ntawm kev txo qis ntawm phosphor-IRS1Ser1101 qib thiab nce qib phospho-AktSer473 hauv lub hlwb (Shi li al., 2017). Hauv kev tshawb nrhiav cais, DA5-CH tau pom cov txiaj ntsig zoo neuroprotective hauv tus qauv nas streptozotocin. Tau phosphorylation hauv lub hlwb raug txo qis, cov cim qhia tshuaj insulin yog normalized thiab cov cim o raug txo.

Hauv EEG cov ntaub ntawv, streptozotocin icv txhaj tshuaj txo qhov kev sib dhos thiab kev kho mob nrog DA5-CH thim rov qab qhov kev puas tsuaj no (Li et al., 2020).Raws li liraglutide twb tau qhia txog kev tiv thaiv hauv Phase IIclinical sim hauv cov neeg mob Alzheimer's disease, cov txiaj ntsig tau tshaj tawm hauv qab no qhia tias DA4-JC thiab DA5-CH tuaj yeem muaj cov txiaj ntsig zoo dua ua rau txo qis kev kis kab mob.

FIGURE 3 Sib piv cov teebmeem ntawm dual agonist DA4-JC nrog cov liraglutide ib sab ntawm APP/PS1 qauv ntawm Alzheimer'sdisease (AD). (a) Tau txais lub sijhawm rau kev cob qhia dej tshawb nrhiav. Ob tus agonist txhim kho lub sijhawm kawm zoo dua liraglutide. (b) Tshawb nrhiav qhov feem pua ​​​​ntawm lub hom phiaj quadrant ua luam dej lub sijhawm. Hauv qhov kev ntsuam xyuas rov qab no, DA4-JC yog qhov zoo tshaj plaws hauv kev nco qab thiab nco qab tshaj liraglutide.

Sampleswimming lem yog qhia hauv qab no. (c) Kev ntsuas ntawm beta-amyloid plaque loads hauv neocortex. DA4-JC tau ua haujlwm zoo dua hauv kev txo cov theamyloid load piv nrog liraglutide cov qauv micrographs qhia: A=WT; B=APP/PS1 Sal; C=APP/PS1 lira; D=APP/PS1 DA4-JC.Scale bar=50 μm. (d) Qhov ntau ntawm pro-inflammatory cytokines nyob rau hauv lub hlwb. DA4-JC tau zoo dua los txo cov kab mob chronicinflammation. *P < .05; Cov qhab nia raug qhia. Hloov los ntawm (Maskery et al., 2020).

22|DUAL GLP-1/GIP RECEPTORAGONISTS yog tiv thaiv nyob rau hauv STROKEAND EPILEPSY tsiaj qauv

Peb tau sim dual agonist DA1-JC hauv MCAO ratreperfusion qauv thiab muab piv nrog GLP-1 analog Val(8)-GLP-1(glu-PAL). Cov pab pawg kho tshuaj tau pom tias txo cov qhab nia ntawm kev ua haujlwm tsis zoo ntawm lub paj hlwb, lub paj hlwb infarction loj, thiab feem pua ​​​​ntawm apoptotic neurons hauv lub hlwb.

Tsis tas li ntawd, theem ntawm mitophagymarker Bax thiab cov cim o ntawm iNOS raug txo qis, thaum qib ntawm mitogenesis marker Bcl-2 tau nce ntau. DA1-JC tau txais txiaj ntsig zoo hauv kev tiv thaiv kev tiv thaiv neurodegeneration dua li Val(8)-GLP-1(glu-PAL), raws li kev ntsuas kev ua haujlwm tsis zoo ntawm lub paj hlwb, lub paj hlwb infarction loj, thiab kev qhia ntawm Bcl-2 tau txhim kho. , qhov feem pua ​​​​ntawm apoptotic neuronsand qib ntawm Bax thiab iNOS tau qis dua hauv DA1-JC pawg (Han li al., 2016).

Hauv pilocarpine-induced epileptogenesis nas qauv, DA3-CH txo qhov ua kom cov microglia thiab astrocytes thiab tso tawm ntawm cov pro-inflammatory cytokines hauv lub hlwb.

Tsis tas li ntawd, DA3-CH txo cov qib ntawm mitochondrialpro-apoptotic protein Bax thaum nce qib ntawm theanti-apoptotic protein Bcl-2. DA3-CH tiv thaiv cov neurons los ntawm neurotoxicity nyob rau hauv hippocampus cheeb tsam CA1 raws li kev soj ntsuam los ntawm quantification ntawm neuronal tooj.

Cov kev tshawb pom no nyob rau hauv ob qho qauv sib txawv ntawm cov kab mob neurodegenerative ua rau pom tias muaj dualGLP-1/GIP agonists muaj cov khoom siv tshuaj tiv thaiv kab mob uas qhia tias cov tshuaj no tuaj yeem tiv thaiv kev kho mob.

23|TEEB MEEM

Muaj cov pov thawj zoo preclinical uas GLP-1 thiab GIP receptoragonists yog neuroprotective nyob rau hauv ntau yam ntawm neurodegenerativedisorders.

Kev soj ntsuam tias lawv txo qis cov lus teb mob ntev, normalize insulin thiab lwm yam kev loj hlob ntawm cov cim qhia, txhim kho kev siv lub zog, thiab tiv thaiv mitochondria tuaj yeem piav qhia vim li cas cov tshuaj no muaj kev tiv thaiv hauv ntau hom kab mob neurodegenerative uas txhua tus qhia cov kab mob no.

Dual GLP-1/GIP receptor agonists tuaj yeem ua haujlwm tau zoo dua li ib leeg receptor agonists thiab muaj peev xwm hla BBB yog qhov tseem ceeb uas txiav txim siab lawv lub zog.

Thawj qhov tshwm sim los ntawm kev kuaj mob hauv cov neeg mob Alzheimer's disease lossis Parkinson's diseasetesting GLP-1 receptor agonists qhia meej txog kev tiv thaiv thiab yog ib qho pov thawj ntawm lub tswv yim tias qhov kev tshawb fawb no siv tau.

Cov tshuaj kho kom zoo uas tau tsim los kho cov kab mob CNS thiab tuaj yeem hla BBB ntawm tus nqi zoo dua li GLP-1 receptor agonists uas tau tsim kho kom nyob twj ywm hauv cov hlab ntsha ntev ntev los kho hom 2 mob ntshav qab zib mellitus tau cog lus tias yuav kho tau zoo dua rau Alzheimer's disease. los yog tus kab mob Parkinson.

Dual receptoragonists uas tau tsim los hla BBB yog tam sim no cov neeg sib tw zoo tshaj plaws rau kev kho tshiab rau cov kab mob neurodegenerative.

23.1|Nomenclature ntawm lub hom phiaj thiab ligands

Cov hom phiaj tseem ceeb ntawm cov protein thiab ligands hauv tsab xov xwm no yog qhov sib txuas sib txuas rau cov khoom nkag hauv IUPHAR / BPS Phau Ntawv Qhia rau PHARMACOLOGY http://www.guidetopharmacology.org thiab tau khaws cia mus tas li nyob rau hauv Phau Ntawv Qhia Txog Tshuaj Kho Mob 2019/20 (Alexander, Christopoulos, thiab al. 2019; Alexander, Fabbro, et al., 2019; Alexander, Mathie, et al., 2019).

Kev tsis sib haum xeeb ntawm kev txaus siab

Tus kws sau ntawv yog tus tsim muaj npe rau ntawm daim ntawv patents thiab daim ntawv thov patent uas npog kev siv GLP-1, GIP, thiab dual GLP-1/GIP receptor agonists astreatments rau neurodegenerative ntshawv siab. Cov patents yog muaj los ntawm Ulster University thiab Lancaster University, UK. Nws yog CSO ntawm lub tuam txhab Kariya Pharmaceuticals.

DAIM NTAWV THOV KEV PAB CUAM

Qhov no yog kev tshuaj xyuas thiab tag nrho cov ntaub ntawv suav nrog hauv daim ntawv no tau tshaj tawm rau lwm qhov.

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