Neuroprotective Thiab Immunomodulatory Action Ntawm Endocannabinoid System Hauv Neuroinflamation

Yog xav paub ntxiv:ali.ma@wecistanche.com

Paub meej: Endocannabinoids (CBs) yog lipid-raws li retrograde tub txib nrog ib tug luv luv ib nrab-lub neej uas yog tsim endogenously thiab, raws li khi rau thawj cannabinoid receptors CB1/2, kho ntau yam mechanisms ntawm intercellular kev sib txuas lus nyob rau hauv lub cev. Endocannabinoid signaling muaj feem cuam tshuam rau hauv lub hlwb kev loj hlob, tsim kev nco, kev kawm, mus ob peb vas, ntxhov siab vim, kev nyuaj siab, noj tus cwj pwm, analgesia, thiab yeeb tshuaj. Tam sim no nws tau lees paub tias cov kab ke endocannabinoid mediates tsis yog kev sib txuas lus hauv neuronal nkaus xwb tab sis tseem tswj hwm kev sib tham ntawm cov neurons, glia, thiab lub cev tiv thaiv kab mob, thiab yog li sawv cev rau tus neeg ua si tseem ceeb hauv kev sib txuas neuroimmune. Generation ntawm thawj endocannabinoids yog nrog los ntawm kev tsim tawm ntawm lawv cov congeners, N-acylethanolamines (NAEs), uas ua ke nrog N-acvlneurotransmitters, lipoamino acids, thiab thawj fatty acid amides suav nrog nthuav dav endocannabinoid / kawg vanilloid signaling systems. Feem ntau ntawm cov tebchaw no tsis khi CB, 2, tab sis teeb liab los ntawm ntau txoj hauv kev uas cuam tshuam nrog kev hloov pauv hloov pauv muaj peev xwm cation channel subfamily V tus tswv cuab 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)- thiab non-cannabinoid G-protein coupled receptors. (GPRs) los kho cov tshuaj tiv thaiv kab mob, immunomodulatory thiab neuroprotective kev ua ub no. Nyob rau hauv vivo tiam ntawm cannabinoid tebchaw yog tshwm sim los ntawm physiological thiab pathological stimuli thiab, tshwj xeeb tshaj yog nyob rau hauv lub hlwb, mediates zoo tswj ntawm synaptic zog, neuroprotection, thiab kev daws teeb meem ntawmneuroinflamation. Ntawm no, peb tshuaj xyuas lub luag haujlwm ntawm endocannabinoid system nyob rau hauv cov txheej txheem neuroprotective thiab nws cov peev xwm kho mob rau kev kho mob.neuroinflamationthiab txuam nrog synaptopathy.

Ntsiab lus: endocannabinoids; N-acylethanolamines;neuroinflamation; glutamate-mediated excitotoxicity; kab mob neurodegenerative; synaptic plasticity

Qhov tseem ceeb

•Retrograde endocannabinoid signaling muab ib tug mechanism uas neurons ua tau

ceev ceev tswj lub zog ntawm lawv cov synaptic inputs.

•Stimulation ntawm postsynaptic neurotransmitter receptors thiab sustained Ca2 ntxiv influx yog ib tug muaj zog tshwm sim rau zus tau tej cov endocannabinoids (eCBs) thiab lawv congeners.

•Neuroinflammation thiab alterations nyob rau hauv endocannabinoid signaling yog implicated nyob rau hauv ntau yam neurological ntshawv siab.

• Cov neeg ua haujlwm-dependent ntawm glutamate thiab eCBs los ntawm synapses tswj microglial attraction, tso tawm ntawm pro-inflammatory thiab pro-survival yam, thiab txhais synapse stability nyob rau hauv o thiab excitotoxicity.

•Lub pharmacological inhibition ntawm eCB degradation exerts ib tug tseem ceeb tshwm sim nyob rau hauv cov chaw raug mob, qhov twg cov neeg kho kom haum xeeb yog nquag tsim de novo.

•Lub endocannabinoid system mediates kev sib txuas lus nyob rau hauv lub tripartite synapse thaum lub sij hawm kev loj hlob thiab kev daws teeb meem ntawmneuroinflamation. 

Taw qhia

Neuroinflamationyog dav suav hais tias yog o ntawm lub hauv paus paj hlwb (CNS) uas muaj lub hlwb thiab qaum qaum. Cov txheej txheem inflammatory yog tsav los ntawm kev tso tawm ntawm pro-inflammatory mediators xws li cytokines, prostaglandins, thiab reactive oxygen thiab nitrogen hom los ntawm activated endothelial thiab glial hlwb nrog ntxiv infiltration ntawm peripheral inflammatory hlwb mus rau hauv lub CNS. Raws li qhov tshwm sim,neuroinflamationtuaj yeem ua rau edema, cov ntaub so ntswg puas, thiab poob ntawm cov haujlwm neuronal nrog rau nrawm thiab ua rau kev paub tsis meej thiab cov kab mob neurodegenerative. Feem ntau ua rau mob ntevneuroinflamationsuav nrog cov tshuaj lom neeg metabolites, muaj teeb meem rau tus kheej cov protein thaum lub sijhawm autoimmunity, kev laus, kab mob thiab kab mob, nrog rau kev puas hlwb, thiab kev raug mob ntawm tus txha caj qaum. Lub endocannabinoid system (ECS), muaj xws li cannabinoid receptors CB1 thiab CB2, lawv loj endogenous ligands 2-arachidonylglycerol (2-AG) thiab arachidonoylethanolamide (AEA los yog anandamide), thiab lawv synthesizing thiab degrading enzymes, plays lub luag haujlwm tseem ceeb hauv cov lus teb hauv qhov tseeb rauneuroinflamation, mob hlwb, thiab kab mob neurodegenerative [1–3].

Nyem rau cistanche deserticola ma rau neuroprotection

Cov kab ke no tam sim no tau nthuav dav nrog ligands uas tsis qhia txog kev sib raug zoo rau CB1 / 2 tab sis tso saib cov haujlwm cannabimimetic thiab tuaj yeem hloov kho cov kev ua ntawm eCBs tseeb. N-acylethanolamine's generated li AEA congeners ua ke nrog lipoaminoacids thiab acyl conjugates ntawm neurotransmitters tawm lawv cov kev ua ub no los ntawm kev sib txawv receptors xws li peroxisome proliferator-activated receptor (PPAR)- [4], transient receptor muaj peev xwm cation channel subfamily V tus tswv cuab 1 (TRPV1) thiab Tsis-cannabinoid G-protein coupled receptors (GPRs). Cov tebchaw no nrog rau qhov tseeb eCBs, lawv lub hom phiaj molecular, tag nrho cov kev sib cuam tshuam, thiab cov metabolism hauv endocannabinoidome muaj lub luag haujlwm tseem ceeb hauv cov lus teb hauv homeostatic rau cov tsis muaj zog endogenous thiab exogenous stimuli. Muaj ntau lub hom phiaj thiab txoj hauv kev rau ligand synthesis thiab degradation nyob rau hauv endocannabinoidome enables complex scanning ntawm cellular xeev thiab tso cai rau ib tug nruj tswj teb rau cov kev hloov cuam tshuam. Ntawm qhov kev txaus siab tshwj xeeb yog kev koom tes ntawm cov kab ke no hauv cov lus teb muaj kev tiv thaiv tiv thaiv kab mob thiab cov txheej txheem neurodegenerative hauv lub hlwb raws li cov phiaj xwm kev tswj hwm ntawm cov kab ke no muaj peev xwm kho tau siab. Hauv kev tshuaj xyuas no, peb muab cov ntsiab lus ntawm kev tiv thaiv kev tiv thaiv kab mob thiab kev tiv thaiv kev muaj peev xwm ntawm endocannabinoidome thaum lub sijhawmneuroinflamation. 

Cov lus xaus

Neuroinflamationyog tshwm sim thiab / los yog nrog los ntawm infiltration ntawm lub cev tiv thaiv kab mob los ntawm lub BBB thiab tso tawm ntawm ib tug ntau yam ntawm pro-inflammatory cytokines thiab lwm yam molecules uas muaj peev xwm neurotoxic. Cov kev hloov pauv no ua ke nrog glutamate receptor-mediated neurotoxicity thiab cov txheej txheem neurodegenerative underlie lub pathogenesis ntawm ob peb neuropathologies, ntawm lawv, yogAlzheimer tus kab mob, amyotrophic lateral sclerosis, mob stroke, ntau yam sclerosis, thiab Parkinson tus kab mob. Kev kis kab mob thiab kab mob, kev raug mob, thiab kab mob autoimmune cuam tshuam rau kev ncaj ncees ntawm BBB thiab pom zoo rau kev hloov pauv ntawm cov kab mob mus rauneuroinflamation. Kev tu lossis kho kom rov zoo ntawm cov kev xaiv permeability ntawm cov ntshav-hlwb barrier yog ib qho ntawm cov tswv yim kho mob nyob rau hauv cov kab mob inflammatory los tiv thaiv kab mob kis mus rau CNS.

Kev sib cuam tshuam ntawm qhov tseeb ECB thiab ligands uas tam sim no koom nrog nthuav dav ECS tso cai rau kev txiav txim siab txhua lub hom phiaj molecular rau kev kho mob.neuroinflamation-txoj kev neuropathologies. Kev cuam tshuam ntawm PCB congeners nrog enzymatic degradation lossis endocannabinoid signaling qhia lawv lub luag haujlwm hauv kev kho cov haujlwm ntawm thawj eCBs. Lub 'entourage effect' ntawm cov uas tsis yog-cannabinoid tsim tawm 2-acylglycerols, NAEs, thiab N-acylneurotransmitters tuaj yeem ua tus tswj hwm kev ua haujlwm zoo ntawm cannabinoid. Cov neeg nyob hauv microglia thiab astrocytes tau nruj ua ke rau kev ua haujlwm ntawm cov neeg sib txuas lus sib txuas thiab muaj kev koom tes nrog kev mob inflammatory, kev hloov pauv kev ciaj sia, thiab kev daws teeb meem ntawm neuroinflammation. Cov hlwb no txhawb kev muaj sia nyob neuronal, synaptogenesis, qaum induction, thiab illumination thiab tiv thaiv cov neurons los ntawm cov tshuaj lom metabolites.

Lub contri-Int. J. Mol. Sci. 2021, 22, 5431 23 ntawm 35 nyees khawm ntawm eCB teeb liab rau hauv kev ua haujlwm sib txuas ntawm neurons, astrocytes, thiab microglia, qhia tias nyob rau hauv txoj kab nrog lub tswv yim ntawm tripartite synapses, microglial hlwb yog sib npaug koom nrog hauv kev sib txuas lus. Ua kom muaj zog thaum lub cev tiv thaiv kab mob, microglial hlwb pab txhawb rau kev daws teeb meem ntawmneuroinflamation; Txawm li cas los xij, kev ua kom ntev ntev ntawm microglia ua rau muaj kev puas tsuaj rau cov neurons thiab pab txhawb kev txhim kho ntawm synaptopathy hauv ntau yam kab mob neurodegenerative. Cov Cheebtsam ntawm ECS ua lub luag haujlwm tseem ceeb hauv kev ua haujlwm ntawm cov hlwb no thaum lub sijhawm ua rau mob, txo qis kev tsim cov cytokines pro-inflammatory, thiab kho cov neuroprotection tiv thaiv glutamate-receptor mediated excitotoxicity, ischemia, thiab oxidative stress. Ib txwm ua haujlwm synaptic nrog rau pathological overstimulation ntawm postsynaptic neurotransmitter receptors yog lub zog ua rau kev tsim cov eCBs thiab non-cannabinoid NAEs. Glutamate-induced endocannabinoids [78] cov phooj ywg los ntawm cov synapses nquag thiab cov chaw raug mob tuaj yeem nyiam cov neeg nyob hauv microglial hlwb [76,79].

Tight structural thiab functional kev koom tes ntawm synaptic hu, astrocytes, thiab microglia enables ib tug heev dynamic teb rau synaptic txheej xwm. Retrograde endocannabinoid signaling yog cuam tshuam rau ntau hom kev luv- thiab ntev-ntev synaptic plasticity. Cov lipid mediators mus txog qhov chaw presynaptic ntawm tib yam lossis lwm yam kev sib txuas lus sib txuas thiab los ntawm kev khi rau CB1/2 inhibit synaptic vesicle fusion thiab neurotransmitter tso tawm. Qhov no yog li cas synaptic hu dynamically tune lawv lub zog thiab muaj peev xwm potentiate / depress lub teb nyob ntawm seb tam sim no inputs. Tso tawm eCBs muaj qhov txwv tsis pub ua haujlwm vim yog lub neej luv luv thiab qhov sib txawv ntawm CB receptor qhia ntawm cov hlwb nyob ze.

Yog li, qhov concentration gradient ntawm eCBs yog tsim rau ntawm qhov chaw ntawm lawv cov synthesis. Qhov no ua rau pharmacological inhibition ntawm eCB degradation feem ntau siv tau zoo hauv cov chaw raug mob, qhov chaw uas lawv nquag ua. Cov tshiab, xaiv cov inhibitors ntawm FAAH thiab MAGL uas muaj kev nyab xeeb zoo tuaj yeem dhau los ua cov neeg ua haujlwm yav tom ntej nrog kev tiv thaiv nociceptive, anxiolytic, thiab tiv thaiv kev ua haujlwm thiab kev ua haujlwm. Tag nrho cov kev sib cuam tshuam thiab cov metabolism hauv endogenous ligands ntawm CB1/2, TRPV1, GPR55, thiab GPR18 yog tam sim no koom ua ke rau hauv "endocannabinoidome", uas yog nquag koom tes rau hauv cov lus teb rau qhov mob thiab neuroinflammation. Lub polymodality ntawm no system muab ib tug dav teb rau txoj kev loj hlob ntawm heev npaum neuroprotective neeg ua hauj lwm rau kev kho mob ntawm inflammation-associated synaptopathy.