Kev Pom Zoo Tshiab Thiab Muaj Peev Xwm Kho Mob Lub Hom Phiaj Ntawm CB2 Cannabinoid Receptors hauv CNS Disorders Part 3
May 08, 2024
4.1.5. CB2R-ECS hauv Autism Spectrum Disorder (ASD)
Nrog rau kev nce qib tsis ntev los no hauv kev tshawb fawb cannabis thiab cannabinoid, nrog rau kev lees paub ntau ntxiv ntawm cov tshuaj cannabis, cannabinoids tau pom zoo hauv cov menyuam yaus xws li mob vwm, raws li tau tham hauv qab no, thiab hauv Autism spectrum disorder (ASD).
Epilepsy yog ib yam kab mob loj heev. Thaum lub sij hawm tag nrho cov kab mob no, cov neeg mob yuav tsis tau tsuas yog raug kev txom nyem lub cev thiab puas siab puas ntsws kev puas tsuaj, tab sis kuj ua rau mob loj heev rau kev nco. Txawm li cas los xij, peb yuav tsum saib qhov teeb meem no kom zoo thiab zoo.
Ua ntej, peb yuav tsum to taub tias dab tsi yog qaug dab peg. Yooj yim muab, qaug dab peg yog qhov txawv txav ntawm hluav taws xob hauv lub hlwb tshwm sim los ntawm cov neurons hauv lub hlwb poob lawv cov zaus ib txwm. Qhov no tuaj yeem ua rau muaj ntau yam tsos mob xws li tsis nco qab, convulsions, pom kev cuam tshuam, thiab lwm yam. Qhov tshwm sim ntawm kev qaug dab peg feem ntau cuam tshuam rau cov neeg mob lub neej thiab kev ua haujlwm, uas muaj kev cuam tshuam zoo rau lawv lub cim xeeb. Txawm li cas los xij, peb yuav tsum paub tias qhov no tsuas yog cuam tshuam ib ntus ntawm kev qaug dab peg ntawm lub hlwb ua haujlwm, thiab nws tsis tau txhais hais tias qaug dab peg yuav ua rau tsis nco qab mus tas li.
Qhov thib ob, peb yuav tsum nco ntsoov tias cov teeb meem nco hauv cov neeg mob qaug dab peg tuaj yeem txo tau. Qhov tseeb, qee cov tshuaj thiab lwm yam kev kho mob tuaj yeem pab tswj cov tsos mob, yog li pab cov neeg mob khaws lawv lub cim xeeb. Tsis tas li ntawd, cov neeg mob qaug dab peg kuj tuaj yeem siv ntau txoj hauv kev los tawm dag zog lawv lub hlwb thiab txhim kho lawv txoj kev nco. Piv txwv li, kawm tej yam tshiab, ua si nyeem ntawv, sau ntawv, thiab nco ua si, thiab lwm yam. Lub stimulation ntawm lub hlwb los ntawm cov kev ua ub no tuaj yeem txhawb kev sib txuas synaptic, yog li txhim kho kev nco.
Thaum kawg, peb yuav tsum pab cov neeg mob qaug dab peg ntsib lub neej zoo thiab muaj kev cia siab. Txawm hais tias qaug dab peg yuav muaj qee yam cuam tshuam rau lawv lub cim xeeb, nws tsis yog ib qho teeb meem uas lawv kov tsis tau. Ntau tus neeg mob qaug dab peg txuas ntxiv ua lub neej zoo, nrog rau kev ua haujlwm zoo thiab kev sib raug zoo. Peb yuav tsum txhawb lawv thiab qhia rau lawv paub tias lawv tuaj yeem ua tiav lawv txoj kev npau suav.
Piv txwv li, muaj kev sib raug zoo ntawm kev qaug dab peg thiab kev nco, tab sis qhov no tsis tau txhais hais tias kev qaug dab peg yuav ua rau koj tsis nco qab. Hloov chaw, peb yuav tsum nquag ua haujlwm txhawm rau txo cov tsos mob thiab txhim kho kev nco qab ntawm cov neeg mob qaug dab peg, yog li pab lawv kom dim ntawm tus kab mob thiab ua lub neej nquag, noj qab haus huv, thiab ua tiav lub neej. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.
Nyem paub ntxiv los txhim kho kev nco
ASD muaj qhov pib thaum yau thiab kev loj hlob mus ib txhis. Nws yog tus cwj pwm los ntawm kev tsis zoo ntawm kev sib raug zoo, kev tsis txaus ntawm kev sib txuas lus, nrog rau kev coj cwj pwm tsis zoo [111]. TheECS plays lub luag haujlwm tseem ceeb hauv ASD. Kev tshuaj xyuas lub luag haujlwm ntawm ECS hauv kev puas hlwb pom tias endocannabinoid signaling ua lub luag haujlwm tseem ceeb hauv ntau tus tib neeg kev noj qab haus huv thiab kab mob ntawm CNS [112].
Txawm li cas los xij, muaj cov ntaub ntawv tsawg, kev kho ua ntej thiab kev kho mob, ntawm lub luag haujlwm ntawm CB2Rs hauv ASD. CB2Rs kuj tau txheeb xyuas tias yog lub hom phiaj ua rau muaj kev puas hlwb hauv kev tshawb fawb ua ntej. Tseeb, nyob rau hauv peb cov kev tshawb fawb ua ntej, nyob rau hauv lub cerebellum ntawm BTBR T + tF / J, ib tug mousemodel ntawm ASD, peb qhia ib tug nce qib ntawm CB2A mRNA qhia, tab sis tsis yog ntawm theCB2BR, gene-transcript isoforms [15].
Kev tswj xyuas ntawm ASD ua rau cov menyuam yaus autistic tau pom tias cov noob qhia rau CNR2 tab sis tsis yog CNR1 tau tswj hwm nyob rau hauv peripheral ntshav mononuclear hlwb (PBMCs). Cov txiaj ntsig tau qhia tias CNR2 noob qhia tau ntau dua hauv cov tib neeg uas muaj ASD piv rau kev tswj hwm. Tsis tas li ntawd, thegene qhia rau ib qho ntawm cov enzymes lub luag haujlwm rau kev sib txuas ntawm endocannabinoidanandamide (NAPE-PLD) tau qis dua rau cov neeg uas muaj ASD.
Qhov no tuaj yeem ua rau muaj kev nce ntxiv hauv CB2Rs uas tshwm sim los ntawm kev txo qis hauv AEA synthesis, uas tej zaum qhia tau tias txo qis ECS suab hauv ASD [113]. Txawm hais tias muaj ntau qhov sib txuas thiab cov khoom sib txuas ntawm ECS rau ASDs, tsis muaj cov khoom siv biomarkers. Lwm tus tau ntseeg ntau ntxiv tias kev kho mob cannabis tuaj yeem ua rau cannabis-teb biomarkers thiab ECS tuaj yeem hloov pauv hauv ASDs. Txawm li cas los xij, peb qhov kev tshawb nrhiav siv BTBR T + tF / J thiab lwm cov qauv nas preclinical cia siab rau tus cwj pwm ntawm kev hloov pauv tus cwj pwm [15].
Muaj qhov tsis txaus ntseeg ntawm cov kev tshawb fawb yooj yim thiab kev kho mob, txawm hais tias peb cov kev tshawb fawb yav dhau los tuaj yeem txhawb kev txhim kho cannabinoids tsom rau ECS cov khoom. Muaj kev txhawb nqa rau qhov kev pom, raws li ECS cov khoom muab CB2R neuro-immunomodulatory lub hom phiaj rau ASDs [114].
Nws yog ib qho tseem ceeb uas yuav tsum tau soj ntsuam ntau qhov yooj yim thiab kev soj ntsuam, thiab kev sim ua kom daws tau qhov etiology ntawm ASDs, uas tsis yog tsuas yog muaj ntau yam kev pheej hmoo tab sis kuj tseem cuam tshuam txog kev loj hlob ntawm ib puag ncig hauv utero. Nrog rau kev paub ntau ntxiv ntawm kev hloov pauv ntawm ECS hauv ASDs, qhov pib nyem ntawm ASD cov tsos mob yuav tsum tau sim kom paub tseeb tias kev siv cov cannabis thiab cannabinoids modulating ECS hauv ASDs.
4.1.6. CB2R-ECS hauv Kev Noj Qab Haus Huv
Nws paub zoo tias ECS modulates qab los noj mov-ib lub hauv paus rau adjunctive cannabinoidsuse los tiv thaiv AIDs cachexia-thiab tswj cov metabolism hauv qabzib hauv pancreas thiab siab. "Diabesity" yog hais txog kev sib raug zoo ntawm ntshav qab zib thiab rog.
Txawm tias nws xav tias ua rau tus kab mob metabolic no yog kev ua neej tsis zoo, kev mob ntshav qab zib yog ib feem cuam tshuam nrog ECS teeb liab hauv adiposity thiab metabolism. Qhov no qhia tau hais tias qhov dysregulation ntawm lub plab ECS thiab hloov pauv qib ntawm PCBs cuam tshuam nrog kev rog thiab metabolic syndrome.Lub luag haujlwm ntawm lub cev ntawm ECS hauv plab hnyuv (GIT), adipogenesis, thiablipogenesis muab kev sib txuas ntxiv hauv kev ua haujlwm tsis zoo ntawm ECS nrog kev rog. , metabolicsyndrome, thiab lwm yam kev cuam tshuam nyob rau hauv lub periphery.
Kev noj zaub mov tsis zoo tshaj plaws yog anorexia nervosa (AN) thiab bulimia nervosa (BN), qhia txog kev noj zaub mov txawv txav uas feem ntau ua rau muaj kev txwv tsis pub noj zaub mov hnyav nrog rau ntu ntawm kev noj zaub mov thiab ntuav, tsis muaj kev hloov pauv ntawm lub cev hnyav hauv BN thiab poob ntawm lub cev hnyav. IB [111].
Cov hypothalamic eCBs tau pom tias yuav hloov tus cwj pwm noj mov hauv cov tsiaj thiab tib neeg, yog li qhia txog lub luag haujlwm ntawm ECS hauv pathophysiology ntawm kev noj zaub mov tsis zoo [115,116]. Hauv kev tshawb fawb tau ua rau 20 tus poj niam nrog AN, 23 tus poj niam nrog BN, thiab 26 tus poj niam noj qab haus huv, qib ntawm CB1R thiab CB2R qhia tau raug tshuaj xyuas. Kev tshawb nrhiav pom tsis muaj qhov sib txawv ntawm CB2R mRNA qib hauv cov ntshav ntawm AN thiab BN cov neeg mob thaum piv rau kev tswj hwm, tsis muaj qhov sib txawv ntawm ob pawg [117,118].
Sofar, tsuas muaj ib txoj kev tshawb fawb txog tib neeg caj ces los txheeb xyuas seb CNR2gene puas cuam tshuam nrog kev noj zaub mov tsis zoo [119]. Tag nrho ntawm 204 tus neeg uas muaj kev noj zaub mov tsis zoo (94 AN thiab 111 BN) thiab 1876 cov neeg ua haujlwm noj qab haus huv Nyij Pooj tau koom nrog hauv txoj kev tshawb no.
Anonymous CNR2 polymorphism tau pom tias txuas rau AN thiab BN. TheR allele muaj ntau ntau nyob rau hauv cov neeg uas muaj kev noj zaub mov tsis zoo dua li kev tswj hwm, raws li kev tshawb pom. Tsis tas li ntawd, tsis muaj qhov hloov pauv ntawm allele zaus ntawm cov neeg mob nrog AN thiab BN thaum lawv sib cais. Cov kev tshawb fawb qhia txog qhov sib txuas ntawm CB2Rs thiab kev noj zaub mov tsis zoo thaum noj ua ke, tab sis xav tau kev tshawb fawb ntxiv los txheeb xyuas cov kev tshawb pom no.
4.2. Lub luag haujlwm muaj peev xwm ntawm CB2Rs hauv Neurologic thiab Neurodegenerative Disorders
4.2.1. CB2R-ECS hauv Alzheimer's Disease (AD)
Vim yog lub luag haujlwm tiv thaiv neuroprotective ntawm CB2Rs hauv CNS cov teeb meem nrog neuroinflammatory biomarkers, tau muaj kev txaus siab thiab tsom mus rau lub peev xwm ntawm kev tsom mus rau CB2Rs hauv Alzheimer's disease (AD) hauv ntau hom tsiaj ntawm AD. AD yog tus cwj pwm los ntawm qhov txawv txav ntawm -amyloid (A) nyob rau hauv senile plaques nyob rau hauv lub hlwb, uas ua rau lub hlwb tsis zoo, nco tsis tau, thiab kev coj cwj pwm hloov vim neurodegeneration thiab o [120].
Cov kev tshawb fawb pom tau tias ECBs tau pom tias txo qis A-induced microglia activation thiab neuroinflamation [121-123]. Tsis ntev los no, CB2Rs tau ntxim nyiam nyob rau hauv kev tshawb nrhiav AD vim tias lawv cov lus qhia hauv lub cev tiv thaiv kab mob thiab lawv cov lus qhia tau zoo thaum mob. Cov kev tshawb fawb pom tias muaj kev nthuav qhia ntau ntxiv ntawm CB2Rs hauv cov ntaub so ntswg hauv hlwb hauv cov neeg mob AD thiab cov qauv nas qhia cov kab mob sib txawv ntawm amyloid precursor protein (APP) [121,124,125].
Cov kev tshawb fawb yav dhau los pom tias kev tshem tawm cov noob caj noob ces ntawm CB2Rs nce Iba1 staining thiab exacerbated soluble A42 thiab cov quav hniav tso [126], qhia tias CB2Rs ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv amyloidplaque pathology hauv AD [127]. Hauv cov nas, kev tswj hwm ntawm JWH-133 txhim kho kev paub tsis meej, inhibited neuroinflammation thiab oxidative stress, txo tau hyperphosphorylation, induced vasodilation [128,129], thiab txhim kho cov piam thaj, qhia tias CB2R agonists tuaj yeem siv los ua nootropics [130].
Ib txoj kev tshawb fawb tsis ntev los no ntsuas lub luag haujlwm ntawm AEAanalog-N-linoleyltyrosine (NITyr) hauv APP/PS1 nas ua raws li tus qauv AD qhia tias NITyr tiv thaiv cov neurons tiv thaiv kev raug mob, uas feem ntau yog kho los ntawm CB2Rs [131].Interestingly Rivas-Santisteban li al. [132] pom tau tias CB2R ua kom bluntedNMDA receptor-mediated signaling hauv thawj hippocampal neurons los ntawm APPSw / Indmice qauv ntawm AD, qhia txog lub luag haujlwm ntawm CB2Rs hauv AD pathogenesis. Tsis tas li ntawd, hauv ADmodel nas, CB2R ua kom los ntawm JWH-015 tau pom los txhim kho cov khoom tshiab paub txog thaum tseem tswj hwm microglia-mediated neuroinflammation thiab dendritic complexity nyob rau hauv ib cheeb tsam tshwj xeeb (Li et al., 2019) [133] .
Parenteral kev tswj hwm ntawm 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6- yl) carbonyl) piperidine (MDA7), anovel selective CB2R agonist, inhibited qhov ua kom cov microglial hlwb thiab astrocytes, txo cov theem ntawm kev qhia ntawm CB2R, txhim kho qhov clearance ntawm A, thiab txhim kho kev paub thiab nco nyob rau hauv nas AD qauv [134,135].In ntau yam hauv vitro thiab hauv vivo AD qauv, CB2R ua kom txo qis cov theem ntawm cov tshuaj tiv thaiv neurotoxic thiab pro-inflammatory mediators uas tsim los ntawm reactive astrocytes thiab microglial hlwb, stimulated microglial proliferation thiab migration, thiab txo A qib [136-138].
Txawm hais tias lub cev loj ntawm cov pov thawj rau kev koom tes ntawm CB2Rs hauv kev txo thiab ua tiav A hauv tus qauv nas ntawm AD, nws nyuaj rau txiav txim siab txog kev kho tus nqi ntawm cov tshuaj cannabis hauv AD [139]. Qee cov ntaub ntawv qhia tau hais tias cov nas nrog CB2R tsis muaj peev xwm pom tau tias txo qis hauv cov hlwb microglial thiab macrophages, txo qis ntawm lub hlwb pro-inflammatory cytokines, txo qis ntawm solubleA 40/42, thiab txhim kho kev txawj ntse thiab kev kawm tsis txaus [121]. Hauv ob peb qhov kev tshawb fawb soj ntsuam, muaj cov lus ceeb toom tsis sib xws ntawm lub peev xwm ntawm CB2R ligand hauv AD, thiab kev tshawb fawb ntxiv yuav tsum tau txiav txim siab lub luag haujlwm ntawm CB2Rs hauv tib neeg thiab tsiaj cov qauv ntawm AD.
4.2.2. CB2R-ECS hauv Parkinson's Disease (PD)
Cov kev tshawb fawb yav dhau los tau qhia txog kev hloov pauv hauv ECS tshwj xeeb nrog kev sib cuam tshuam ntawm dopaminergic system thiab eCBs hauv basal ganglia cuam tshuam nrog kev txav mus los, ib qho ntawm cov cim ntawm Parkinson's disease (PD). PD yog ib qho kev txav tsis zoo uas tshwm sim los ntawm kev degeneration ntawm dopaminergic neurons, uas ua rau lub cev muaj zog tsis ua haujlwm [140,141].
Kab mob kev loj hlob yog tus cwj pwm los ntawm kev mob los ntawm kev ua kom microglia [142] thiab nce hauv cytokines [143,144]. Cov ntaub ntawv pov thawj pom tau tias muaj peev xwm muaj zog rau ECS los muab kev tiv thaiv kev tiv thaiv kab mob tiv thaiv kab mob orchronic neurodegenerative mob [145–149]. CB2R qib tau nce siab hauv cov qauv tsiaj ntawm PD thiab kev tshawb fawb tom qab ntawm cov neeg mob PD, thiab qhov kev nce ntxiv no cuam tshuam nrog kev nce hauv microglial activation, qhia txog lub luag haujlwm ntawm CB2Rs hauv PD [61,150]. Cov kev tshawb fawb pom tau hais tias tsis muaj kev tswj hwm ntawm CB2Rs hauv substantia nigraand hippocampus peb lub lis piam tom qab 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) txhaj rau hauv nas. nrog MPTP-induced Parkinsonian syndrome.
Tsis tas li ntawd, AM1241, cov kev xaiv CB2R agonist, tau pom tias yuav rov tsim DA neurons tom qab neurotoxiceffect ntawm MPTP kev kho mob [145]. Tsis tas li ntawd, cov nas uas tsis muaj CB2R tau pom tias muaj kev txhim kho ntawm cov hlwb microglial thiab kev puas tsuaj ntau dua ntawm tyrosine hydroxylase (TH) - muaj cov paj hlwb nigral hauv cov qauv tsiaj ntawm PD [150], uas txhawb nqa lub luag haujlwm neuroprotective ntawm CB2Rs.In tsiaj qauv ntawm PD, ∆9-THCV, CB2R agonist, txo lub cev muaj zog inhibition los ntawm 6-hydroxydopamine (6-OHDA) thiab poob ntawm TH-positive neurons tshwm sim los ntawm 6-OHDA qhov mob hauv lub substantia nigra tom qab kev tswj hwm mob hnyav thiab mob ntev, feem. Txawm li cas los xij, CB2Rs tau tswj tsis tau zoo hauv cov nas 'substantia nigra teb rau 6-OHDA.
Los ntawm qhov sib txawv, qhov substantia nigra ntawm cov nas uas tau txhaj tshuaj nrog lipopolysaccharide (LPS) tau nthuav tawm kev tswj hwm ntau dua ntawm CB2Rs. Cov kws sau ntawv qhia tias ∆9-THCV ua rau kev khaws cia ntawm TH-positive neurons, tej zaum los ntawm kev koom tes ntawm CB2Rs [151]. Hauv lwm txoj kev tshawb fawb, qhov kev tiv thaiv ntawm JWH-015 tawm tsam MPTP-induced nigrostriatal degeneration thiab kev tawm tsam ntawm microglial activation / infiltration los ntawm kev ua kom CB2Rs [152] cuam tshuam. Tsis tas li ntawd, cov ntaub ntawv qhia tau hais tias BCP txo oxidative kev nyuaj siab thiab neuroinflammation, thaiv gliosis thiab pro-inflammatory cytokine tso tawm, thiab txo qis nigrostriatal degeneration nyob rau hauv ib tug rotenone (ROT)-induced tsiaj qauv ntawm PD [153].
Zoo li cov kev tshawb fawb ua ntej, cov kev tshawb fawb soj ntsuam tau qhia tias qhov kev qhia ntawm CB2Rs hauv cov hlwb sib txawv tau tswj hwm hauv cov neeg mob PD. Ib txoj kev tshawb fawb pom tau tias CB2Rs tau nce siab hauv cov hlwb microglial tau txais thiab ua haujlwm ntawm qhov chaw mob hauv cov neeg mob PD ntawm cov neeg mob piv rau kev tswj hwm [150]. Hauv lwm txoj kev tshawb fawb, cov kws sau ntawv tau pom tias CB2R nyob hauv TH-muaj cov neurons hauv substantia nigra ntawm qib qis hauv cov neeg mob PD piv rau kev tswj hwm [154]. Yog li, CB2Rs tej zaum yuav yog lub hom phiaj kws kho mob tau zoo rau kev txo cov tsos mob ntawm Parkinsonian thiab ua kom cov kab mob qeeb qeeb hauv Parkinson tus kab mob.
4.2.3. CB2R-ECS hauv Huntington's Disease
Huntington's disease (HD) yog kab mob neurodegenerative tshwm sim los ntawm kev nthuav dav ntawm CAG triplet rov ua dua (cytosine-adenine-guanine) hauv cov noob encoding protein Huningtin (Htt), uas ua rau kev paub tsis meej thiab kev txav txav tsis zoo (chorea) [1,155 ]. Tam sim no, tsis muaj kev kho mob zoo rau HD, thiab qhov xav tau rau cov hom phiaj kho mob tshiab tau nce ntxiv [1]. Vim hais tias ECS muaj ntau nyob rau hauv lub basal ganglia, qhov ua kom los yog inhibition ntawm ECS signaling txoj kev yuav muaj kev cuam tshuam loj rau cov lus teb ntawm lub cev muaj zog [156], thiab CB2R tau tshwm sim los ua lub hom phiaj kho tshiab rau kev kho thiab kev kuaj mob ntxov ntawm HD [157]. Nyob rau hauv lub transgenic R6/2, CAG rov ntev Huntingtonchorea nas qauv, CB2R qhia tau hais tias yuav tsum tau nce nyob rau hauv lub hippocampus, hlwb, striatum, thiab cerebellum [158].
Cov kev tshawb fawb tseem pom tau tias cov nas tsis muaj CB2Rs tau nkag siab ntau dua rau malonate dua li pawg tswj hwm. Tsis tas li ntawd, CB2R-cov nas uas tsis muaj peev xwm nthuav tawm qhov pib txhim kho ntawm lub cev muaj zog thiab nce qhov hnyav [159,160]. Kev nthuav qhia ntawm CB2R tau nce hauv striatal microglia hauv cov qauv hloov pauv ntawm HD thiab cov neeg mob. Tsis tas li ntawd, cov genetic ablation ntawm CB2R exacerbated HD, thiab kev tswj hwm ntawm CB2R-xaiv agonists txo cov striatal neurodegeneration los ntawm microglialactivation [161]. Ua ke, CB2Rs tej zaum yuav yog lub hom phiaj, thiab cov tebchaw uas xaiv qhib CB2R yuav raug siv los ua tus neeg sawv cev kho mob hauv kev kho HD.
4.2.4 ib. CB2R-ECS hauv Ntau Yam Sclerosis
Ntau tus kab mob sclerosis (MS) yog ib qho kab mob autoimmune uas tshwm sim los ntawm o, neurodegeneration, thiab demyelination ntawm neurons uas tsis muaj kev kho mob zoo [162], thiab kev tshawb fawb tau pom lub luag haujlwm ntawm CB2Rs hauv cov mob inflammatory uas cuam tshuam nrog MS [157,163].Microglial activation tau txuas rau CB2 overexpression nyob rau hauv ib qho kev sim autoimmuneencephalomyelitis (EAE) tsiaj qauv ntawm MS [164]. HU-308, CB2R-xaiv agonist, kuj txo qis EAE cov tsos mob, axonal poob, thiab microglial activation thaum tswj qhov ncauj [165]. O-1966, tus CB2R agonist, kuj tau pom tias txo qis kev tiv thaiv kab mob hauv lub cev, txo qis ntawm tes dawb dov thiab adhesion rau cerebral microvessels, thiab txhim kho kev ua haujlwm ntawm lub paj hlwb tom qab kev thuam ntawm EAE kev nce qib [166].
Kev tshawb fawb ntxiv tau ua los ntawm EAE cov qauv tsiaj pom tau tias BCP cuam tshuam rau microglial hlwb, CD4+ thiab CD8+ T lymphocytes, thiab cytokines, txo qis axonaldemyelination thiab modulates Th1 / Treg tiv thaiv kab mob los ntawm kev ua kom CB2Rs [167] . Maresz et al. [164] kuj tau tshaj tawm tias CB2R qhia los ntawm encephalitogenic T hlwb txo cov EAE-txuas nrog o. Tsis tas li ntawd, thaum lub sij hawm EAE, CB2R-tsis muaj T hlwb hauv CNS tau pom tias txo qis apoptosis, nce kev loj hlob, thiab nce kev tsim cov kab mob cytokines, ua rau mob hnyav heev.Theiler murine encephalomyelitis virus-induced demyelinating kab mob (TMEV- IDD), uas ua rau muaj kev cuam tshuam. lub hauv paus neuronal demyelination uas tshwm sim hauv MS, yog lwm tus qauv ntawm MS [168]. Hauv TMEV-IDD nas, CB1R thiab CB2R agonists tau pom cov txiaj ntsig kho mob tau zoo los ntawm kev siv tshuaj tiv thaiv kab mob thiab tiv thaiv kab mob [169,170], uas yog lwm cov pov thawj rau lub luag haujlwm ntawm CB2Rs hauv MS. Postmortem thiab kev tshawb fawb soj ntsuam kuj qhia txog kev koom tes ntawm CB2Rs hauv MS. Ib qho kev koom tes ntawm CB2R rs35761398 (Q63R) polymorphism thiab MS tau pom nyob rau hauv ib txoj kev tshawb fawb ua rau tag nrho 100 IranianMS cov neeg mob thiab 100 noj qab haus huv tswj [171].
Cov ntaub ntawv pov thawj qhia tias cov neeg mob MS tau pom qhov tseem ceeb CB2 qhia hauv B hlwb, tab sis tsis nyob hauv T lossis NK hlwb [172]. Yiangouet al. [173] qhia txog qib siab ntawm microglial hlwb hauv tib neeg postmortem spinal cordspecimens. Cov ntaub ntawv pov thawj tau qhia tias T lymphocytes, astrocytes, thiab ob qho tib si perivascular andreactive microglial hlwb kuj tau pom los qhia CB2Rs hauv cov ntaub so ntswg hauv hlwb los ntawm MS pub [174]. Cov kev tshawb pom no qhia tias CB2Rs ua si ib qho kev tiv thaiv neuroprotective hauv MS pathology, thiab tsom CB2Rs tuaj yeem pab hauv kev tswj cov tsos mob thiab teeb meem neurologic hauv MS cov neeg mob.
4.2.5 ib. CB2R-ECS hauv Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) yog ib yam kab mob degenerative cuam tshuam rau cortex, lub hlwb qia, thiab tus txha caj qaum lub cev muaj zog neurons. Qhov tsis zoo ntawm ob qho tib si sab sauv thiab qis lub cev muaj zog neurons yog qhov tseem ceeb ntawm kev kis kab mob [121,175]. Kev koom tes ntawm CB2Rs hauv ALS tau pom los ntawm cov kev tshawb fawb sib txawv. Kev txo qis hauv motorneuron degeneration thiab kev khaws cia ntawm lub cev muaj zog hauv ALS tau pom tom qab kev xaiv ua haujlwm ntawm CB2Rs hauv cov tsiaj [176-178]. TDP-43 transgenic nas thiab postmortem cov kev tshawb fawb pom tau tias muaj kev tswj hwm ntawm CB2Rs hauv cov kab mob activatedmicroglia [173,179]. Cov kev tshawb fawb kuj tau pom tias lub sijhawm muaj sia nyob tom qab ALS pib tau nce los ntawm 56% tom qab kev tswj hwm ntawm CB2R agonist AM1241, pib muaj cov tsos mob tshwm sim [176]. Tsis tas li ntawd, Kim et al. [177] tau tshaj tawm qhov txo qis ntawm cov tsos mob ntawm tus kab mob tshwm sim thaum AM1241 tau muab tshuaj tom qab qhov pib ntawm cov cim hauv anALS nas qauv (hSOD1(G93A) transgenic nas. , ib qho kev sim ua qauv ntawm ALS, tau pom qhov nce ntxiv ntawm CB2Rs [180].Tag nrho cov pov thawj no qhia tias CB2R ua lub luag haujlwm hauv kev tiv thaiv kev loj hlob ntawm ALS.Yog li ntawd, CB2Rs yuav raug suav hais tias yog lub hom phiaj zoo rau kev kho mob hauv ALS.
4.2.6. CB2R-ECS hauv Epilepsy
Epilepsy yog ib yam kab mob uas tshwm sim hauv lub paj hlwb, cuam tshuam ntau dua 70 lab tus tib neeg thoob ntiaj teb. Cov tshuaj tiv thaiv kab mob vwm uas muaj tam sim no tsis tuaj yeem tswj hwm tus mob vwm hauv feem ntau ntawm cov neeg mob [181], thiab yog li yuav tsum muaj cov phiaj xwm kho mob tshiab rau cov tshuaj tiv thaiv kab mob vwm. Muaj pov thawj ntawm lub luag haujlwm ntawm ECS inepilepsy [182,183], thiab cov kev tshawb fawb pom tias CBD tau ua haujlwm zoo hauv kev kho mob epileptics hauv preclinical [184] thiab kev tshawb fawb soj ntsuam [185,186]. Lub luag haujlwm ntawm CB2Rs hauv kev mob vwm tau raug sau tseg hauv lwm cov kev tshawb fawb [33,187]. Ib txoj kev tshawb fawb tau pom tias cov selectiveCB2R antagonist AM630 inhibited ib tug palmitoyl ethanolamide (PEA)-induced nce nyob rau hauv lub latency ntawm qaug dab peg pib thiab txo lub sij hawm ntawm qaug dab peg nyob rau hauv ib tug mob pentylenetetrazol (PTZ) nas qaug dab peg qauv [188]. Tsis tas li ntawd, kev tswj hwm ntawm BCP tau pom los txhim kho kev qaug dab peg hauv tus qauv nas [189]. Txawm hais tias muaj pov thawj qhia txog lub luag haujlwm ntawm CB2Rs hauv kev tswj kev qaug dab peg hauv cov tsiaj, ob peb txoj kev tshawb fawb pom muaj kev sib koom ua ke ntawm kev ua kom CB2Rs thiab tswj kev qaug dab peg. Hauv kev tshawb fawb siv HU-308, CB2R xaiv agonist, HU-308 tsis tau qhia txog kev tiv thaiv kab mob, thiab AM630 tau nce qaug dab peg [190]. Ntxiv mus, CB2R agonist AM1241 nce qaug dab peg hauv PTZmodel [191], thiab AM630 thiab SR144528 tuaj yeem ua rau qaug dab peg [190]. Kev tshawb fawb siv cov tshuaj genetically manipulated nas tau qhia tias CB2R knockout nas qhia txog kev txhim kho depileptic susceptibility, thiab kev txo qis hauv CB2R kev ua haujlwm tau cuam tshuam nrog kev nce ntxiv [192]. Ua ke, cov ntaub ntawv pov thawj txhawb nqa kev koom tes ntawm CB2Rs hauv pathophysiology ntawm qaug dab peg. Kev nthuav qhia ntawm CB2Rs nyob rau hauv lub hlwb thaum lub sij hawm ntau yam kab mob xeev xws li qaug dab peg ua rau lawv ib tug tseem ceeb lub hom phiaj rau neuroprotection, thiab li no CB2Rs yuav ua tau raws li ib tug ua tau lub hom phiaj rau kev kho mob vwm.
4.2.7 ib. CB2R-ECS hauv Traumatic Brain Injury
Traumatic hlwb raug mob (TBI) yog tshwm sim los ntawm ib tug neeg kho tshuab raug mob ntawm lub hlwb uas tshwm sim nyob rau hauv lub tsim ntawm hematoma uas thaum kawg ua rau lub sij hawm ntev teeb meem thiab tuag [193]. Cov ntaub ntawv pov thawj qhia txog kev koom tes ntawm CB2Rs hauv kev hloov kho pathophysiology ntawm TBI. Cov kev tshawb fawb siv CB2R agonist, O-1966, hauv nas nrog TBI tau qhia tias kev tswj hwm ntawm O-1966 txo qis kev cuam tshuam ntawm cov ntshav-hlwb barrier thiab neuronaldegeneration [194], thiab induced mob neuroprotective teebmeem [195] , txhawb nqa lub luag haujlwm ntawm CB2Rs hauv kev tswj hwm TBI. Kuj tseem muaj cov ntaub ntawv qhia txog kev nce ntxiv ntawm CB2Rs hauv nas nrog TBI cuam tshuam nrog edema neurologic deficits. Nyob rau hauv txoj kev tshawb no, cov kws sau ntawv pom muaj kev sib raug zoo ntawm qhov kev qhia ntawm CB2Rs thiab TBI [59].Nyob rau hauv lwm txoj kev tshawb fawb tsom rau kev ntsuam xyuas qhov muaj feem cuam tshuam ntawm CB2R agonists, HU-910thiab HU-914, hauv pathophysiology ntawm TBI hauv nas, Magid et al. [196] pom tau tias muaj kev tiv thaiv kab mob neuroprotection thiab kev kho mob neurobehavioral rov qab. Nyob rau hauv ib txoj kev tshawb no tsis ntev los no, tus selectiveCB2R agonist, JWH133, tiv thaiv cov teeb meem dawb raug mob los ntawm PERK signaling nyob rau hauv ib tug nas qauv ntawm kev raug mob hlwb [197].
5. Cov lus xaus thiab cov kev xav kho yav tom ntej
Kev debunking ntawm cov dab neeg hais tias CB2Rs tsuas yog pom nyob rau hauv "periphery" thiab qhov tsis muaj kev cuam tshuam ntawm cov receptors no ua rau muaj kev txaus siab rau kev soj ntsuam ntawm cov receptors no ua lub hom phiaj kho mob hauv neuropsychiatric thiab neurodegenerative ntshawv siab. Tam sim no, peb tsis tuaj yeem txaus siab rau qee qhov kev kho mob zoo rau feem ntau ntawm cov kab mob no, thiab yog li kev tshawb fawb ntxiv tau lees paub rau cov hom phiaj kho mob tshiab uas siv cov tswv yim tshiab, suav nrog kev txawj ntse (AI), uas yuav ua rau muaj kev kwv yees zoo dua thiab cov txiaj ntsig kho mob nrog cov kev cuam tshuam tsawg kawg nkaus.
Kev tawg sai ntawm kev tshawb fawb cannabinoid kuj tseem tuaj yeem hloov pauv thaj chaw tam sim no los ntawm kev siv hauv vitro thiab hauv vivo thev naus laus zis uas yuav txhim kho peb txoj kev nkag siab txog lub luag haujlwm ntawm CBRs hauv neuropsychiatric thiab neurodegenerative mob. Txawm hais tias qhov kev vam meej tsis ntev los no, qhov kev tshem tawm ntawm FAAH inhibitor thaum lub sij hawm soj ntsuam kev sim thiab cov kev tsis zoo tshwm sim los ntawm kev tiv thaiv kev rog rog CB1R antagonist tau ua rau muaj kev ceev faj txog kev kho mob. Nws yog kev txhawb siab tias kev sim tshuaj tsom rau CB2R, thiab kev pom zoo los ntawm Foodand Drug Administration (FDA) ntawm nabiximols rau kev qaug dab peg, tab tom tig lub hom phiaj ntawm CB2R-ECS rau hauv lub tswv yim tshuaj kho mob.
Cov kev tshawb pom suav nrog hauv qhov kev tshuaj xyuas no tau pom tias CB2Rs tau qhia ntau heev hauv cov kab mob neuropsychiatric thiab neurodegenerative mob, thiab cov kev xaiv CB2R ligands tau cog lus los ntawm kev tswj cov tsos mob ntawm cov kab mob no. Cov kev tshawb fawb ntxiv yuav tsum tau ntsuas qhov kev koom tes ntawm CB2Rs hauv cov teeb meem no siv tag nrho cov cuab yeej uas muaj los kawm txog CB2Rs thiab lawv cov ligands xaiv hauv cov qauv tsiaj nrog rau hauv kev sim tshuaj. Cov kev tshawb fawb yav tom ntej yuav tsum suav nrog kev txhais lus thiab kev kho mob thiab hauv vivo thiab hauv vitro qauv qhia txog tib neeg CB2Rs. Tsis tas li ntawd, kev soj ntsuam xyuas kom zoo ntawm cov kev mob tshwm sim cuam tshuam nrog kev kho mob ntev ntawm CB2R ligands yuav muab kev nkag siab ntxiv rau lub luag haujlwm ntawm CB2Rs hauv kev tswj cov neurophysiological thiab kev coj cwj pwm ua haujlwm.Cov kev tshawb fawb loj hlob hauv eCBome, kev cuam tshuam hauv nws txoj cai, hloov pauv ntawm eCBs, thiab kev tshawb pom. ntawm cov noob caj noob ces polymorphisms muab lub hom phiaj rau kev kho mob kev cuam tshuam hauv neuropsychiatric thiab neurodegenerative mob. Qhov tseeb, qhov ntom ntom ntawm eCB receptors thiab qib ntawm eCBs tau pom tias ua tau biomarkers hauv neuropsychiatric mob.
Nrog rau cov pov thawj nce ntxiv uas CB2Rs koom nrog hauv lub hlwb, lub luag haujlwm ua haujlwm ntawm CB2R neuro-immune axis hauv pathophysiologicalsignaling hauv kev txhim kho kev puas siab puas ntsws warrants ntxiv kev tshawb nrhiav. Nws kuj tseem ceeb heev uas qhov kev txiav txim siab ntawm cov qauv siv lead ua ntawm CB1R thiab CB2R nthuav tawm yin-yang kev sib raug zoo thiab kev ua haujlwm ntawm CB2R antagonism piv rau CB1R agonism [43,133,198]. Qhov no qhia txog lwm qhov chaw uas CB1R thiab CB2R zoo li yuav ua haujlwm ntawm nws tus kheej thiab / lossis kev koom tes, thiab qhov ntawd yuav tau txais txiaj ntsig los ntawm kev txhim kho cov ntawv thov kev kho mob tseem ceeb. Muaj cov kev txwv thiab kev txhawj xeeb txog kev siv CB2Rmedication rau cov kab mob neurological, vim tias lawv tau nthuav tawm ntau nyob rau hauv peripheryand tej zaum yuav muaj kev phiv rau peripheral, thaum lawv yuav pab tau rau hauv CNS mob txuam nrog neuroinflammation.
Nws yuav tsum tau hais ntxiv tias qhov ncaj qha kws tshuaj lossis geneticmanipulation ntawm ECS yuav ua rau muaj kev cuam tshuam txawv dua li cov uas ua los ntawm phytocannabinoids. Tsis tas li ntawd, kev tshawb fawb soj ntsuam ntau lub tebchaw hauv cannabis, nrog rau terpenes thiab flavonoids, yuav ntxiv rau peb txoj kev nkag siab ntawm lub ntuj eCBomein neuropsychiatric thiab neurodegenerative ntshawv siab thiab pab txhawb rau biomarkers tshiab thiab kho cov neeg ua haujlwm.
Tus Sau Kev Pabcuam: BGK tau tshawb nrhiav cov ntaub ntawv thiab sau thawj thiab cov ntawv sau tom qab ntawm cov ntawv sau. ESO saib xyuas thiab kho cov ntawv sau. HI thiab YH tau pab hauv kev tshawb nrhiav cov ntaub ntawv thiab sau cov ntawv sau. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Kev Pab Nyiaj: University of Yamanashi thiab Tokyo Metropolitan Institute of Medical Science txhawb kev ua haujlwm thiab kev sib koom tes tshawb fawb los ntawm Dr. Ishiguro thiab Dr. Horiuchi. Kev tshawb fawb hauv Dr. Onaivi pawg nrog rau Dr. Berhanu Kibret tau txais kev txhawb nqa los ntawm NIAAA-NIH nyiaj pab AA027909, William Paterson University, thiab Dean ntawm CoSH, Dr. Venkat Sharma. Cov nyiaj CoSH txhawb cov tub ntxhais kawm thiab cov chaw kuaj tsiaj.
Institutional Review Board Statement: Tsis siv tau.
Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.
Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.
Kev tsis sib haum xeeb ntawm kev txaus siab: Cov kws sau ntawv tshaj tawm tias tsis muaj qhov tsis sib haum xeeb ntawm kev txaus siab.
Cov ntawv luv
6-OHDA, 6-hydroxydopamine; AC, adenylyl cyclase; AD, Alzheimer's kab mob; AEA, anandamide; AI, kev txawj ntse; ALS, Amyotrophic lateral sclerosis; AN, anorexia nervosa; APP, amyloid precursor protein; ASD, autism spectrum teeb meem; A, -amyloid; BCP, -caryophyllene; BN, bulimia nervosa; CB1R, cannabinoid hom 1 receptor; CB2R, cannabinoid hom 2 receptor; CBD, cannabidiol; CMS, kev nyuaj siab me me; CNS, central paj hlwb; CPP, conditioned qhov chaw nyiam; D1Rs, dopamine hom 1 receptors; EAE, autoimmune encephalomyelitis; eCBome, endocannabinoidome; eCBs, endocannabinoids; ECS, endocannabinoid system; ERK, 1/2extracellularsignal-regulated kinase; FDA, zaub mov thiab tshuaj noj; GIT, kab mob plab; GPCRs, G-protein coupled receptors; HD, Huntington tus kab mob; JNK, Jun N-terminal protein kinase; Kir, inwardly rectifying potassium tam sim no; LPS, lipopolysaccharide; MAPK, mitogen-activated proteinkinase; MDA7, 1-((3-benzyl-3-methyl{20}},3-dihydro-1-benzofuran-6-}yl) carbonyl) piperidine; MPTP,1-methyl-4-phenyl{26}},2,3,{29}}tetrahydropyridine; MS, ntau yam sclerosis; NAc, nucleus accumbens; NITyr, N-linoleyltyrosine; NMDA, N-methyl-D-aspartate; PD, Parkinson tus kab mob; PEA, palmitoylethanolamide; PI3K, phosphoinositide 3-kinase; PPI, pre-pulse inhibition; PTZ, pentylenetetrazol; ROT, rotenone; TBI, mob hlwb raug mob; TH, tyrosine hydroxylase; TMEV- IDD, Theiler murineencephalomyelitis virus-induced demyelinating disease; VTA, ventral tegmental cheeb tsam; ∆9-THC, Delta-9-tetrahydrocannabinol.
Cov ntaub ntawv
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