Txhais Lus Pov Thawj Rau Lithium-induced Brain Plasticity Thiab Neuroprotection hauv Kev Kho Mob Ntawm Neuropsychiatric Disorders

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

Stefano Puglisi-Allegra1 ✉, Stefano Ruggieri1 thiab Francesco Fornai

Cov pov thawj ntxiv qhia tau hais tias lithium (Lit) ua tau zoo hauv neuropsychiatry, taw qhia rau cov txheej txheem sib tshooj uas tshwm sim hauv cov neeg sib txawv neuronal. Qhov tseeb, tib txoj hauv kev nyob ntawm seb lub voj voog ua haujlwm yuav poob rau hauv kev puas siab puas ntsws thiab / lossis kev puas siab puas ntsws, Lirestores ob qho tib si neurotransmission thiab lub paj hlwb nthuav tawm tias kev puas siab puas ntsws thiab paj hlwb sib koom ua haujlwm tsis zoo ntawm cov molecular thiab morphological mechanisms, uas tuaj yeem koom nrog cov hlwb sib txawv, Ntawm no ib qho kev piav qhia yog qhia txog kev kho mob /neuroprotectiveCov teebmeem ntawm Lit hauv cov kab mob neuropsychiatric sib txawv los qhia txog cov txheej txheem molecular uas Lit ua rau nws qhov kev xav-stabilizing cov teebmeem thiab qhov twg cov kev sib txuam nrog cov yas hauv cov hlwb sib txawv. Lit mus ob peb vas-stabilizing cov teebmeem yog tshwm sim nyob rau hauv raug kev puas siab puas ntsws bipolar (BD) yam ntxwv los ntawm ib tug cyclic chav kawm ntawm mania los yog hypomania ua raws li los ntawm kev nyuaj siab lub sij hawm, thaum nws ua tau zoo yog tsis muaj zog nyob rau hauv lub opposite qauv. Peb tsom ntawm no ntawm neural adaptations uas tej zaum yuav underlie psychostimulant-induced psychotic txoj kev loj hlob thiab dissect, los ntawm cov txheej txheem sensitization, uas nta tau qhia nyob rau hauv BD thiab lwm yam kev puas hlwb, nrog rau schizophrenia. Ntau lub luag haujlwm ntawm Li yog qhov tseem ceeb ntawm no los ua pov thawj nws cov tshuaj tshwj xeeb, uas tuaj yeem pab qhia meej txog nws cov txheej txheem ntawm kev ua. Cov no tuaj yeem ua ib qho kev qhia rau ntau lub tswv yim tshuaj. Peb tawm tswv yim tias qhov pib ntawm rhiab heev nyob rau hauv ib qho tshwj xeeb BD subtype tej zaum yuav kwv yees qhov kev kho mob ntawm Li. Cov qauv no tuaj yeem pab ua pov thawj hauv BD uas cov txheej txheem molecular cuam tshuam rau kev kho mob ntawm Lit.

Cistanche muaj cov nyhuv neuroprotective zoo heev

Taw qhia

Lithium (Li plus ) tseem yog "tus qauv kub" tus kws tshuaj tshuaj rau kev kho thiab tiv thaiv kev rov qab los ntawm ob hom I thiab hom II kev puas siab puas ntsws bipolar (BDs). Nws kuj tseem siv tau los tiv thaiv tus cwj pwm tua tus kheej thaum muaj kev nyuaj siab loj. Txawm hais tias nws muaj kev ua tau zoo, nyob rau xyoo dhau los, Li ntxiv tau tsawg dua thiab siv tsawg dua vim muaj tshuaj lom thiab xav tau kev saib xyuas cov ntshav qab zib kom nruj kom tswj tau cov koob tshuaj tiv thaiv kev nyab xeeb [1–5]. Txawm li cas los xij, lwm txoj hauv kev los tswj cov tshuaj qis tab sis muaj txiaj ntsig zoo Li ntxiv koob tshuaj tau tsim [6]. Dhau li ntawm nws cov kev ua tau zoo hauv kev kho thiab tiv thaiv cov tsos mob ntawm kev puas siab puas ntsws, Li ntxiv tsimneuroprotectivecuam ​​tshuam rau ntau yam ntawm cov neeg neuronal uas koom nrog hauv ob qho tib si kev coj cwj pwm thiab lub cev muaj zog ntsig txog circuitries.

Qhov tseeb, cov pov thawj nce ntxiv yog nyob rau hauv kev sib cav, qhia Li ntxiv rau kev ua tau zoo hauvneurodegenerativemob, taw qhia rau cov txheej txheem intracellular, uas tshwm sim nyob rau hauv cov neeg sib txawv neuronal. Qhov no yog cov ntaub ntawv ntawm Alzheimer's disease (AD), amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD), thiab Parkinson's disease (PD) [4, 7].

Kev paub txog cov txheej txheem no tuaj yeem ua rau pom qhov tshwm sim ntawm pathogenesis thiab neuropathology ntawm ntau yam kev puas siab puas ntsws thiab paj hlwb. Cov txheej txheem molecular ntawm kev txiav txim ntawm Li ntxiv koom nrog cov hom phiaj kws tshuaj, xws li cov cell nto receptors lossis kev hloov pauv ntawm cov neurotransmitters, cov tshuab xa xov thib ob, enzyme cascades, thiab cov khoom siv hloov pauv [1, 8].

Ntawm no yog ib qho kev piav qhia txog kev kho mob c/neuroprotectiveCov teebmeem ntawm Li ntxiv rau hauv cov kab mob neuropsychiatric sib txawv los qhia txog cov txheej txheem molecular uas Li ntxiv ua rau nws qhov kev xav-stabilizing teebmeem thiab seb qhov no cuam tshuam li cas nrogneurotiv thaivnyob rau hauv ntau lub hlwb circuitries. Qhov tseeb, kev hloov pauv ntawm tes zoo sib xws nyob ntawm seb qhov chaw twg tuaj yeem poob rau hauv kev puas siab puas ntsws thiab / lossis kev puas hlwb.

GENERAL VERVIEW ntawm MOLECULAR MECHANISMS ntawm LI ntxiv

Qee qhov cuam tshuam ntawm Li plus muaj feem cuam tshuam rau kev sib tw lub cev-tshuaj lom neeg rov qab nrog magnesium ion (Mg2 ntxiv) nyob rau hauv tshwj xeeb catalytic protein domains koom nrog hauv substrate phosphorylation. Cov ntaub ntawv pov thawj qhia tias Li ntxiv muaj peev xwm inhibit Mg2 ntxiv rau -dependent enzymes los ntawm kev hloov Mg2 ntxiv los ntawm nws qhov chaw sib txuas, yog li txo qis enzyme stability thiab kev ua haujlwm [9]. Yog li, pharmacological kev ua ntawm Li ntxiv feem ntau yog nyob ntawm qhov sib txuam Li ntxiv / Mg2 ntxiv piv [10]. Cov txheej txheem ntawm kev nqis tes ua no ntxiv rau ntau qhov chaw muag tshuaj ntawm Li ntxiv [11], nrog rau nws ntau lub hom phiaj.

Kev sib tw khi ntawm Li ntxiv thiab Mg2 ntxiv rau ntawm qhov chaw enzyme substrate modulates cov haujlwm ntawm ntau cov enzymes hauv txoj hauv kev hauv lub cev koom nrog cov teebmeem biochemical, uas cuam tshuam rau ob qho tib si rau neuropsychiatric thiabneurodegenerativekev txiav txim. Cov no suav nrog inositol monophosphatase (IMPase), Akt/ -arrestin-2, thiab glycogen synthase kinase-3 (GSK-3 ). Muaj

Daim duab 1 Daim duab qhia ntxaws txog cov txheej txheem molecular zoo ntawm lithium ntawm lub hom phiaj ntawm tes. Lithium inhibits lub voj voog PI, uas yog qhib tom qab stimulation ntawm G-coupled neurotransmitter receptors (GPCRs). PLC mediates lub hydrolysis ntawm phosphatidylinositol 4, 5-bisphosphate (PIP2) mus rau lwm tus tub txib diacylglycerol (DAG) thiab inositol trisphosphate (IP3), uas nyob rau hauv lem qhib downstream signaling txoj kev, nrog rau cov protein kinase C (PKC), thiab IP3 receptor (IP3R) / ER kev nyuaj siab / unfolded protein teb (UPR). Hauv kev nthuav dav, lithium inhibits (a) reuptake ntawm inositol (I), nrog rau IMPase thiab IPPase (b), uas ua rau tag nrho cov depletion ntawm IP3 (c). Nyob rau hauv txoj kev no, lithium tiv thaiv autophagy impairment thiab apoptosis uas raug khi rau IP3R-txog ER kev ntxhov siab, loj Ca2 ntxiv rau kev tso tawm ntawm ER, txawv txav UPR, nrog rau kev sib xyaw ntawm misfolded / unfolded proteins thiab puas mitochondria (d). Kev txawv txav UPR muaj, piv txwv li, ntawm kev tswj hwm ntawm TRAF / JNK thiab XBP1, uas txhawb nqa cov xwm txheej apoptotic thaum ua rau tsis zoo autophagy. Nyob rau tib lub sijhawm, los ntawm inhibition ntawm PKC thiab GSK3 (e), lithium inhibits qhov muaj peev xwm ua rau muaj kev cuam tshuam rau hauv qab ntawm txoj kev no. Cov no muaj xws li (f) oxidative kev nyuaj siab vim tsub zuj zuj ntawm reactive oxygen hom (ROS) leaked los ntawm puas mitochondria thiab downregulation ntawm lub nuclear factor erythroid 2 (NFE2)-txog yam 2 (NRF2), uas, dhau li ntawm nws cov teebmeem antioxidant, kuj muaj feem xyuam. mus rau mitophagy thiab mitochondrial-genesis; (g) impaired transcription ntawm neurotrophic,neuroprotective, thiab antioxidant genes, xws li BDNF, VEFG, Bcl-2, thiab NRF2, uas yog hloov dua siab tshiab los ntawm lithium ntawm ob qho tib si GSK3 inhibition thiab ua kom cov CREB transcription factor tso downstream ntawm GPCRs; (h) zus tau tej cov pro-inflammatory cytokines hauv qab ua kom lub STAT/interferon-gamma (INF)/nuclear factor kappa-light-chain enhancer ntawm activated B hlwb (NF-k) txoj kev; thiab (i) tsub zuj zuj ntawm hyperphosphorylated tau, uas yog khi rau cytoskeletal alterations thiab autophagy impairment.

two closely related forms of GSK-3 are termed alpha (GSK-3α) and beta (GSK-3β), which are equivalently inhibited by Li+ [12]. Li+ inhibits GSK-3 by competing with Mg2+ for an essential binding site [13]. In addition to Mg2+ competition, Li+ inhibits GSK-3β activity by increasing its phosphorylation [14]. Li+ also decreases GSK-3β levels by inhibiting its transcription [15]. It is worth noting that, of all the kinases, GSK-3 influences the largest number of substrates [16]. Thus, Li+ has been estimated to act at several hundreds of GSK3-dependent substrates through the modulation of a number of GSK-3-dependent pathways. Since Li+ affects other Mg2+-dependent proteins, the occurrence of >3000 tib neeg cov proteins tau kwv yees tias tuaj yeem cuam tshuam los ntawm Li ntxiv [17]. Qhov no muaj peev xwm ua rau ntau ntau ntawm cov molecules, txhua tus muaj qhov cuam tshuam rau kev ua haujlwm, ua rau Li ntxiv rau cov tshuaj muaj zog thiab cov cuab yeej muaj txiaj ntsig hauv kev tshawb fawb soj ntsuam thiab kev tshawb fawb.

Lub sijhawm xyoo dhau los, cov pov thawj tau muab qhia tias Li ntxiv inhibits ntau cov phosphatase los ntawm kev ua tus tsis sib tw thiab tsis sib tw inhibitor. Txawm hais tias cov txheej txheem ntawm Li plus -induced phosphatase inhibition tseem tsis tau nthuav tawm tag nrho [18, 19], uncompetitive inhibition of IMPase thiab inositol polyphosphate 1-}phosphatase (IPPase) tau tsis ntev los no tau hais tawm [19, 20]. Inhibition ntawm IMPase thiab IPPase ua rau txo qis inositol triphosphate (IP3) qib, uas nyob rau hauv lem modulate ntau intracellular txoj kev paub tias muaj feem xyuam rau ob leeg neuropsychiatric thiab degenerative mob, xws li autophagy [1].

Ntau tus neurotransmitters suav nrog dopamine (DA), norepinephrine, thiab serotonin ua los ntawm G protein-coupled receptors. Yog li, cov teebmeem ntawm Li ntxiv rau ntawm lub voj voog inositol tuaj yeem hloov mus rau hauv kev hloov pauv receptor kev ua haujlwm tom qab kev txhawb nqa monoamine, uas ua rau muaj kev cuam tshuam cov neurotransmitter zoo, yog li inducing synaptic stabilization [10].

Zoo kawg li, Li ntxiv kuj txhawb nqa cov noob qhia nrog rau lub hlwb-derived neurotrophic factor (BDNF) thiab vascular endothelial.

Growth factor (VEGF). Qib qis ntawm BDNF thaum muaj kev nyuaj siab, thiab cov theem manic hauv cov neeg mob bipolar [21], tau tshaj tawm tias yuav rov qab los ntawm Li ntxiv kev kho mob. Nyob rau hauv txoj kab nrog qhov no, Li ntxiv thiab BDNF plasma qib yog sib cuam tshuam [22]. Li ntxiv kuj tseem tswj cov txheej txheem inflammatory blunting lub pro-inflammatory teb. Hauv kev nthuav dav, nws txo qis lipopolysaccharide-induced inflammation hauv glial hlwb [23] thiab txo qhov tsim ntawm interleukin -1 beta thiab qog necrosis factor-alpha. Lub peev xwm ntawm Li ntxiv rau kev hloov pauv kev mob tshwm sim yog cuam tshuam rau nws cov tshuaj pharmacological vim tias cov txheej txheem inflammatory ua lub luag haujlwm tseem ceeb hauv ob qho tib si.neurodegenerationthiab kev xav tsis zoo [24, 25].

Li ntxiv rau lub hom phiaj unfolded protein teb (UPR) hais txog cov xwm txheej, xws li endoplasmic reticulum (ER) kev nyuaj siab, excitotoxicity, thiab autophagy dysfunction nyob rau hauv lub synapses los yog nyob rau hauv lub cell lub cev. Qhov no yuav tsum induce neuroplasticity, uas cuam tshuam rau tus cwj pwm thiab lub cev muaj zog, los ntawm kev sib tshooj mechanisms hauv ntau lub hlwb (Fig. 1).

UPR activation induces autophagy [26, 27], uas tiv thaiv ER kev nyuaj siab los ntawm degradation ntawm protein aggregates thiab organelles, nrog rau puas mitochondria, nuclear membrane, thiab ER. Ntxiv mus, Li ntxiv cawm autophagy tsis ua haujlwm, uas feem ntau tau tshaj tawm hauvneurodegenerativeCov kab mob xws li PD, AD, tauopathies, ALS, thiab Huntington's disease [7, 12, 25, 28–42]. Ib yam li ntawd, autophagy feem ntau tau tshaj tawm tias muaj kev cuam tshuam hauv ntau yam kev puas siab puas ntsws.

Autophagy yog phylogenetically conserved eukaryotic cell-clearing system uas plays lub luag hauj lwm seminal hauv cell homeostasis [36]. Nws yog qhov txawv rau hauv macro-autophagy, micro-autophagy, thiab chaperone-mediated autophagy, uas txhua tus txhawb nqa lysosome-dependent substrate degradation [37]. Autophagy tuaj yeem raug ntxias los ntawm ntau qhov cascades, ntawm cov uas tswj hwm los ntawm cov hom tsiaj tsiaj ntawm rapamycin complex1 (mTORC1) ua lub luag haujlwm tseem ceeb. Lub mTOR complex sawv cev rau ib tug downstream substrate ntawm phosphoinositide-3 kinase/phosphatase thiab tensin homolog/Akt txoj kev.

Kev ua kom 5′ AMP-activated protein kinase thiab inhibition ntawm GSK3- [8, 41] yog lwm txoj hauv kev paub zoo tswj kev pib autophagy.

Dhau li ntawm degrading oxidized / misfolded proteins thiab puas organelles, autophagy modulates tseem ceeb cell functions xws li los ntawm lub neural raj thiab synapse kev loj hlob mus rau neurotransmitter tso tawm thiab synaptic plasticity, raws li zoo raws li neuroinflammation thiab tiv thaiv kab mob [4, 43].

Txawm hais tias Li ntxiv inhibits GSK-3 , uas txo cov autophagy ntawm mTOR ua kom, cov nyhuv ntawm Li ntxiv muaj nyob rau hauv mTOR- ywj siab autophagy activation txij li Li ntxiv rau inhibits IMPase [7, 44]. Nyob rau hauv txoj kab nrog qhov no, inositol depletion muaj qhov tsis zoo rau lub siab [1, 42], thaum nyob hauv tauopathies Li ntxiv tuaj yeem ua lub luag haujlwm tiv thaiv dual los ntawm inhibiting GSK-3 [45], ua kom muaj zog autophagy- ywj siab.neuroprotectivecuam ​​tshuam thiab tiv thaiv tau tsub zuj zuj los ntawm autophagy activation ([46], Fig. 1).

Autophagy activation yuav tsum tshem tawm cov kev puas tsuaj mitochondria (mitophagy), thiab los ntawm kev sib koom ua ke ntawm mitochondrial-genesis, qhov no ua rau kom mitochondrial turnover, uas txhim kho mitochondrial muaj nuj nqi. Li ntxiv -induced mitochondrion thiab mitophagy tshwm sim ob leeg hauv cov hlwb endothelial [47] thiab tshwj xeeb hauv ntau hom neuronal [27, 34].

Xws li ib tug nyhuv, uas yog overtly tseem ceeb heev nyob rau hauvneurodegeneration, kuj tseem siv tau rau cov kev xav tsis zoo txij li kev ua haujlwm mitochondrial tsis ua haujlwm tau tshaj tawm hauv cov neeg mob bipolar [48, 49].

Yog li, txawm tias xav txog kev kho mob muaj zog ntawm kev puas siab puas ntsws, nws zoo li tias autophagy yuav siv sij hawm nruab nrab ntawm nws cov tshuaj tiv thaiv thiab tshuaj tiv thaiv kev nyuaj siab. Qhov no tsis yog qhov xav tsis thoob thaum txiav txim siab tias ntau cov tshuaj autophagy-inducing, uas yog nyob rau ntawm daim ntawv lo nrog rau lwm cov tshuaj kho mob, muaj cov teebmeem rau lub siab (piv txwv li, valproate, rapamycin, [46]). Ib yam li ntawd, qhov ua tau zoo ntawm kev xav tsis zoo ntawm ntau yam tshuaj psychotropic tej zaum yuav cuam tshuam rau cov teebmeem autophagy-inducing [50–52].

LITHUM INNEURODEGENERATIVETHIAB PsychiatRIC

cistanche tubolosa cov txiaj ntsig: tiv thaiv neurons

PHEM

NeurodegenerativeCov kab mob: AD thiab PD thiab ALS / FTD

Ib lub cev loj hlob ntawm cov pov thawj taw qhia rau lubneuroprotectivecov teebmeem ntawm Li plus. Cov ncauj lus nrog BD tswj hwm nrog Li ntev ntev ntxiv muaj qhov pheej hmoo tsawg dua los tsim kev puas siab puas ntsws suav nrog AD [53, 54]. Ib txoj kev tshawb fawb meta-analysis [55] qhia tau tias Li ntxiv rau kev kho mob tseem ceeb txo qis kev txawj ntse poob qis dua li piv nrog cov placebo, yog li qhia tau tias Li ntxiv yuav muaj txiaj ntsig zoo hauv kev txhawb kev paub.

kev ua tau zoo hauv cov kev kawm uas muaj kev paub tsis meej me ntsis (MCI) thiab AD.

Li ntxiv tuaj yeem ua ntawm ntau cov kauj ruam hauv biochemical cascades koom nrog qhov pib thiab kev loj hlob ntawm AD (Fig. 1). Piv txwv li, GSK-3 inhibition tuaj yeem cuam tshuam cov pathological nce enzyme kev ua haujlwm tshwm sim hauv cov neeg mob cuam tshuam los ntawm MCI thiab AD [56]. GSK-3 koom nrog hauv amyloidogenesis thiab tau phosphorylation, uas nyob rau theem preclinical yog inhibited los ntawm Li ntxiv rau kev tswj hwm [57]. Ntxiv dua thiab, Li ntxiv rau-induced autophagy tuaj yeem tiv thaiv kev tiv thaiv autophagy, uas xav tau hauv cov neeg mob AD vim tias muaj kev nce ntxiv hauv mTOR kev ua haujlwm thaum lub sijhawm tus kab mob [35, 58]. Ntxiv mus, Li ntxiv txhawb cov synthesis thiab tso tawm ntawm cov teeb meem neurotrophic, tshwj xeeb tshaj yog BDNF thiab VEGF uas muaj ntau ntxiv tiv thaiv neurons tiv thaiv neurotoxic insults, stimulates hippocampal neurogenesis, thiab nce synaptic plasticity [2]. Tseeb tiag, BDNF polymorphisms tau tshaj tawm rau nruab nrab A-txog kev paub txog kev poob qis hauv preclinical AD [59], thiab BDNF txo A hauv lub hlwb [60]. Txawm li cas los xij, ib nrab-lub neej luv luv thiab tsis muaj peev xwm hla cov ntshav-hlwb teeb meem cuam tshuam cov peev txheej kho mob ntawm BDNF [61].

Qhov kev txwv no tau kov yeej los ntawm cov khoom me me xws li BDNF mimetic compounds uas muaj peev xwm tiv thaiv thawj cov neurons los ntawm A -induced toxicity thiab txhawb synaptogenesis [62]. Ntxiv mus, Li plus muaj peev xwm ua tau zoo qhib txoj hauv kev molecular nce BDNF synthesis [10] Nws yog ib qho tsim nyog sau cia tias tsiaj qauv ua lub luag haujlwm tseem ceeb hauv kev tshawb fawb AD kuj txhawb nqa kev tshawb fawb soj ntsuam hauv cov neeg mob los ntsuas Li ntxiv rau kev ua tau zoo ntawm qhov sib txawv A thiab tau pathology [ 63] ib.

ALS yog tus kab mob neuron lub cev muaj zog, koom nrog pab pawg ntawm cov kab mob neurological uas xaiv cuam tshuam rau lub cev muaj zog neurons tswj kev yeem leeg nqaij ntawm lub cev. ALS tuaj yeem raug faib ua tsev neeg lossis tsis sib xws, nyob ntawm seb puas muaj tsev neeg keeb kwm ntawm tus kabmob. Txawm hais tias tsis muaj kev pom zoo ntawm tsev neeg txhais tau tias, ntau cov noob raug suav hais tias ua rau tus kab mob.

Kev txhim kho cov tsos mob ntawm lub cev muaj zog los ntawm Li ntxiv tau tshaj tawm nyob rau ob xyoo dhau los. Yog li, hauv kev sim tshuaj, Li ntxiv kev kho mob rau 15 lub hlis tau pom tias muaj kev nyab xeeb thiab cuam tshuam nrog kev qeeb qeeb ntawm cov kab mob thiab kev tuag [28]. Kev tiv thaiv neuroprotection tseem ceeb nrog rau kev mob qeeb qeeb thiab nce lub neej ncua tau pom hauv G93A murine qauv [28]. Nws yuav tsum tau taw qhia tias ob peb ALS genetic murine qauv tau tsim [64]. Txawm hais tias muaj txiaj ntsig loj hauv kev tshawb fawb preclinical, lawv yog ib feem ntawm tus neeg sawv cev ntawm pathology thiab kev ua tau zoo ntawm lithium hauv cov qauv no tsim nyog yuav tsum tau tshawb xyuas ntxiv [65].

Kev noj tshuaj txhua hnub ntawm Li plus, ua rau cov ntshav plasma xws li {{0}}.4 txog 0.8 mM, ncua kev kis kab mob hauv ib pawg me ntawm cov neeg mob ALS [28]. Qhov no tau raug lees paub ntxiv nyob rau hauv kev tshawb fawb stratified ntawm ALS cov neeg mob nqa UNC13A variant qhov twg Li ntxiv rau ob npaug rau lub sijhawm muaj sia nyob [29], thaum nyob rau hauv cov neeg ALS ntau ntau cov kev tiv thaiv ntawm Li ntxiv yog qhov sib cav. Yog li, nws yog qhov tseeb tias Li ntxiv cuam tshuam li cas rau ntau lub hom phiaj, tag nrho cov uas yuav ua rau muaj kev txhim kho ntawm ALS, xws li autophagy uas cuam tshuam nrog Li ntxiv rau inhibitory kev txiav txim ntawm GSK- 3 thiab IP3 turnover los yog kev tawm tsam ntawm glial cell activation. nyob rau hauv lub cev [4]

Li ntxiv induces autophagy los tiv thaiv ER kev nyuaj siab thiab hloov UPR thiab cawm autophagy tsis ua hauj lwm tshwm sim nyob rau hauv ob qho tib si ALS / FTD thiab BD [7, 28, 34, 35, 49, 66–72]. Qhov tseem ceeb, UPR cov cim (p-eIF2a, GRP78, GRP94, XBP1, thiab CHOP) tau pom tias kwv yees Li ntxiv rau kev teb rau cov neeg mob bipolar [70].

Li ntxiv -xws li kev puas siab puas ntsws, xws li BD, kev nyuaj siab, thiab kev ntxhov siab, feem ntau yuav ua ntej ALS / FTD, thiab cov neeg mob uas muaj kev puas siab puas ntsws uas tau txais kev kho mob Li ntxiv li qub tau txo qis ntawm ALS thiab dementia [73].

Cov pov thawj no qhia ib zaug ntxiv tiasneurodegenerativeCov kab mob thiab cov kab mob cuam tshuam tuaj yeem sib koom cov txheej txheem neural uas Li ntxiv ua raws li kev kho mob, pom zoo tias cov txheej txheem no yog qhov tseem ceeb hauv etiology.

Li ntxiv rau kev ua tau zoo hauv PD tau kawm tsis zoo thiab cov txiaj ntsig tau qhia tias nws tsim nyog tau txais kev sim tshuaj kho mob kom paub tseeb tias muaj kev tiv thaiv neuroprotection raws li tau hais los ntawm cov qauv kev sim.

Nyob rau hauv ib tug parkin mutant transgenic nas, tsawg koob tshuaj Li ntxiv tiv thaiv lub cev muaj zog tsis zoo li dopaminergic striatal degeneration, parkin-induced striatal astrogliosis, thiab microglial activation. Cov txiaj ntsig no txuas ntxiv siv tau Li ntxiv raws li kev kho muaj peev xwm rau PD [74]. Thaum xub thawj siab ib muag, qhov no tej zaum yuav tsis txawv vim Li ntxiv los ntawm impeding rhiab heev uas tsim los ntawm DA [75] yuav tsum tau attenuate lub efficiency ntawm lub sij hawm ntev L-DOPA teb, uas sawv cev rau ib feem tseem ceeb ntawm L-DOPA cov tsos mob tshwm sim. Yog li, asymptomatic cuam tshuam ntawm Li ntxiv nrog PD tuaj yeem zais cov kab mob-hloov cov txiaj ntsig uas tsim los ntawm Li ntxiv rau kev ua haujlwm ntawm autophagy-dependent tsis tu ncua degenerative cov kauj ruam [7, 69].

Alpha-synuclein, ib tug loj substrate ntawm autophagy, accumulates nyob rau hauv Lewy lub cev, uas yog feem ntau pom nyob rau hauv spared dopaminergic neurons ntawm lub substantia nigra pars compacta [76], thiab nyob rau hauv extra-nigral neuronal pejxeem [77].

Ntxiv mus, genetic ablation ntawm Atg7 tshwj xeeb hauv DA neurons tag nrho rov tsim dua PD pathology, suav nrog kev tsim ntawm alpha-synuclein-stained Lewy lub cev. Cov ntaub ntawv pov thawj uas taw qhia rau lub luag haujlwm tseem ceeb ntawm autophagy hauv DA-txog kev tsis sib haum xeeb [78] thiab Li ntxiv raws li kev kho muaj peev xwm rau PD tau muab [4].

Psychiatric Disorders: BD, Kev Nyuaj Siab Loj (MDD), thiab schizophrenia

Li ntxiv tau raug tshaj tawm tsis tu ncua kom ua tau zoo los txo qhov kev pheej hmoo ntawm kev tua tus kheej ob leeg hauv cov neeg mob unipolar thiab bipolar [83], tej zaum ua rau GABA [67] los hloov kev aggression thiab impulsivity [84–86] ntawm autophagy [87] .

Li ntxiv tsis zoo rau tus mob schizophrenia, raws li sau tseg los ntawm cov ntaub ntawv los ntawm ntau xyoo dhau los (saib [86] rau kev tshuaj xyuas). Txawm li cas los xij, Li plus tau koom nrog cov tshuaj tiv thaiv kab mob tshwj xeeb txhawm rau txo qee qhov kev mob tshwm sim, qhov no tsis txhais tau tias muaj txiaj ntsig ntawm Li ntxiv los kho tus mob schizophrenia [88, 89]. Qhov no yuav zoo li tsis xav txog txij li tus mob schizophrenia thiab BD qhia qee qhov kev ua haujlwm thiab cov tsos mob. Qhov tseeb, qhov tsis sib xws hauv kev kho mob tau lees paub qhov uas tau hais los ntawm Emil Kraepelin uas xyoo 1899 txawv "dementia praecox" (tseem hu ua schizophrenia) los ntawm "manic-depressive," "manic-depressive insanity," thiab manic-depressive disorder, tam sim no. . Xws li qhov sib txawv tam sim no tau khaws cia txawm tias qee qhov kev xav tsis sib haum xeeb [90].

Peb tsis xav nrog qhov teeb meem nosographic; peb xav hais tias yuav ua li cas qhov tsis sib xws ntawm Li ntxiv rau hauv cov kab mob no tuaj yeem vam khom cov txheej txheem molecular uas ua haujlwm hauv tus mob schizophrenia piv nrog BDs, vim muaj cov hom phiaj molecular.

Qhov no yog qhov tseem ceeb tshaj plaws txij li tus mob schizophrenia thiab BD qhia qee qhov kev hloov pauv ntawm tus cwj pwm thiab kev hloov pauv ntawm cov neurotransmitter (xws li DA thiab glutamate). Ntxiv mus, kev sib txheeb ntawm caj ces thiab cov noob caj noob ces ntawm cov kab mob no tau pom [91–93].

Qhov zoo sib xws no qhia tias cov kab mob no muaj qee qhov sib tshooj hauv lawv cov txheej txheem molecular. Txawm li cas los xij, qhov tseeb yooj yim uas Li ntxiv tsis zoo lossis tsis ua haujlwm zoo hauv schizophrenia xav kom tshawb xyuas seb Li plus -dependent lossis Li plus - ywj pheej molecular txoj hauv kev muaj nyob hauv BDs piv nrog schizophrenia, feem [94, 95].

Vim li cas Li Plus thiaj li muaj txiaj ntsig zoo hauv BD thiab muaj cov txiaj ntsig tsis zoo yog tias muaj, hauv schizophrenia? Peb yuav sib tham txog qhov sib txawv no los ntawm kev taw qhia txog kev caij tsheb kauj vab ntawm BD nyob rau hauv qhov sib piv nrog rau kev nce qib ntawm tus mob schizophrenia.

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias txoj hauv kev molecular uas cuam tshuam rau qhov tshwm sim rhiab heev yog qhov tseem ceeb hauv schizophrenia, BD, nrog rau cov teebmeem ntawm kev puas siab puas ntsws ntawm kev tsim txom psychostimulants. Qhov tseeb, kev caij tsheb kauj vab ntawm BD tuaj yeem yog qhov tseem ceeb hauv cov qauv tshwj xeeb ntawm kev nkag siab, uas tshwm sim hauv qhov tsis sib xws, sib piv nrog cov kev kawm nce qib, uas txwv tsis pub muaj tus mob schizophrenia.

Li ntxiv muaj txiaj ntsig zoo hauv kev tawm tsam lossis ncua kev puas siab puas ntsws-induced rhiab heev [96] los ntawm kev ua ntawm qee qhov kev sib koom ua ke los ntawm schizophrenia thiab BD.

Txawm hais tias ob qho tib si kev tsis sib haum xeeb sib koom cov txheej txheem rhiab heev, tsuas yog BD yog rhiab rau Li ntxiv, uas tseem nyob hauv kev tshawb nrhiav kev piav qhia.

Peb xav hais tias cov txheej txheem rhiab heev muaj nyob rau hauv ob qho tib si kab mob txawm hais tias lub sij hawm kawm ntawm xws li ib tug rhiab heev diverges, uas piav txog qhov sib txawv tshwm sim ntawm ib tug zoo xws li pharmacological manipulation.

Kev hnov ​​​​mob yog ib qho txheej txheem los ntawm kev rov ua kom tsis sib haum xeeb rau qhov kev txhawb nqa, xws li kev ntxhov siab, kev raug mob, lossis kev puas siab puas ntsws, ua rau kev coj tus cwj pwm zoo dua rau qhov tshwm sim tom ntej [97–99].

Lub xub ntiag ntawm kev coj cwj pwm coj cwj pwm nyob rau hauv cov neeg mob nrog BD tau raug npaj los piav qhia txog kev rov qab los thiab kev loj hlob ntawm tus cwj pwm tsis zoo [97, 100].

Cov teebmeem ntawm psychostimulants muaj feem xyuam rau kev kawm cov txheej txheem molecular uas ua haujlwm hauv cov txheej txheem rhiab heev, uas tshwm sim hauv kev puas siab puas ntsws thiab koom nrog schizophrenia thiab BD. Qhov tseeb, thaum psychostimulants raug tsim txom tsis tu ncua, cov tsos mob ntawm kev puas siab puas ntsws lossis manic tuaj yeem tshwm sim, uas ntxiv ua pov thawj rau kev sib tshooj ntawm cov txheej txheem molecular ua haujlwm hauv cov teeb meem no.

Yog li ntawd, peb tsom ntawm no rau cov teebmeem ntawm psychostimulants ntawm neural adaptations hauv qab kev siv yeeb tshuaj thiab kev loj hlob ntawm kev puas siab puas ntsws, los qhia txog, los ntawm cov txheej txheem rhiab heev, uas cov yam ntxwv sib koom los yog tsis ntawm schizophrenia thiab BD.

Li plus, dopamine-related rensitization, thiab cell-clearing systems

Amphetamine (AMPH) rov ua dua kev tswj hwm ua rau kev coj tus cwj pwm rhiab heev uas qhia txog tus qauv manic zoo li preclinical [101-103]. Kev txhais lus siv tau ntawm kev nkag siab rau kev xav txog kev puas siab puas ntsws kev ntxhov siab [97, 104-106] kuj tau txais kev txhawb nqa los ntawm kev sib tshooj ntawm lawv cov teebmeem neural, tshwj xeeb tshaj yog ntawm kev sib kis ntawm dopaminergic. Qhov no kuj tseem yuav piav qhia vim li cas AMPH ua rau cov tsos mob manic hauv ob qho tib si noj qab haus huv pab dawb thiab BD cov ntsiab lus [107].

Cov yeeb yaj kiab ntev hauv cov qauv ua ntej ua rau tus cwj pwm hloov pauv thiab txo qis -catenin qib hauv prefrontal cortex, amygdala, thiab dorsal striatum. Raws li, GSK-3 qib kev ua haujlwm hauv cov cheeb tsam no tau nce [108]. Li ntxiv rau kev kho mob cawm -catenin qib thiab thaiv cov yeeb yaj kiab vim raug mob [108]. Cov txiaj ntsig no zoo ib yam nrog Li ntxiv rau -induced GSK-3 inhibition thiab hauv qab no nce qib -catenin. Txawm li cas los xij, cov txiaj ntsig sib piv qhia tau nce -catenin ntau ntau hauv cov nucleus accumbens uas sib piv cov lus qhia ntawm kev ua yeeb yaj kiab, ob qho xwm txheej raug cawm los ntawm Li ntxiv rau kev tswj hwm [109, 110], yog li ua qhov xwm txheej uas Li ntxiv cov teebmeem tshwm sim tsis sib xws.

Qhov muaj peev xwm koom tes ntawm neurotransmitters tau tawm tswv yim los piav qhia qhov sib txawv no thiab lub luag haujlwm ntawm neural networks, uas cuam tshuam txog kev cuam tshuam ntawm lub paj hlwb tuaj yeem cuam tshuam rau lawv sib txawv [109].

Methamphetamine (METH), nrog rau lwm yam kev puas siab puas ntsws, feem ntau tsim kev puas siab puas ntsws nrog cov tsos mob zoo ib yam li cov neeg mob schizophrenia. Cov txiaj ntsig zoo li no ua rau METH siv / ua phem rau feem ntau suav tias yog tus qauv sim ntawm tus mob schizophrenia. High pre-synaptic DA synthesis thiab tso tawm yog peculiar rau schizophrenia [111–113]; Ib yam li ntawd, cov teebmeem psychostimulant ntawm METH vam khom DA synthesis thiab loj DA tso tawm nyob rau hauv limbic thiab dorsal striatal thaj chaw, nrog rau qhov txawv txav ntawm postsynaptic DA receptors (DARs), feem ntau yog D1 subtype (D1Rs) [114, 115]. Ntawm qhov tod tes, cov neeg mob schizophrenic yog oversensitive thiab overresponsive rau AMPHs [98, 111]. METH dysregulates ib tug xov tooj ntawm susceptibility noob rau schizophrenia, xws li DISC1, NRG1 / ErbB4, thiab CRMP2, uas yog paub tias yuav koom nyob rau hauv cov kev cai ntawm presynaptic DA tso tawm los yog postsynaptic D1R-txog cascades. Qhov tsim nyog, lawv txhua tus sib koom ua ke ntawm mTOR signaling, yog li qhov txawv txav ntawm D1Rs activates significantly mTOR, uas inhibits autophagy machinery [116]. Qhov no qhia tau hais tias hloov mTOR thiab txoj kev tsis zoo autophagy sawv cev rau ib qho chaw nruab nrab ntawm

psychostimulant-induced neuroplasticity thiab schizophrenia. METH cuam tshuam rau ubiquitin-proteasome system (UPS) kev ua haujlwm,

uas feem ntau nyob ntawm DA [117–122]. Proteasome

Fig. 2 Lithium, amphetamine-related sensitization, thiab cell-clearing systems. Lithium inhibits IMPase thiab IPPase, nrog rau PKC thiab GSK3, uas tau ua rau qis qis ntawm dopamine GPCRs. Qhov no ua rau txo qis ntau lawm thiab phospho-tau / misfolded proteins thiab kev cawm ntawm cell-clearing systems, uas yog impaired los ntawm mTOR hyperactivation tso downstream ntawm D1 DA receptors thiab / los yog los ntawm ntau yam txawv txav ntawm phospho-tau. Nyob rau tib lub sijhawm, lithium disassembles GSK3- - ua kom cov proteins -ARR thiab PP2A los ntawm cov complex lawv tsim nrog GPCRs / AKT lub sijhawm no tsom rau lawv rau kev degradation los ntawm cov cell-clearing systems. Nyob rau hauv txoj kev no, lithium kho dopamine imbalances uas tshwm sim tom qab psychostimulant kom tau txais / kev tswj hwm, thiab kev ua kom tsis zoo ntawm GPCRs thiab lwm yam kev taw qhia hauv qab regulates DA presynaptic tso tawm thiab receptors thiab postsynaptic DARs. Kev ua kom DAD2 receptor subtype (D2Rs) pab txhawb rau kev qhia ntawm DA-dependent METH-vim kev coj tus cwj pwm hloov pauv los ntawm kev teeb tsa ua ke ntawm -arrestin 2 (-arr2), AKT, thiab protein phosphatase-2A (PP2A) , uas Li ntxiv yog ib qho ncaj qha inhibitor ntawm GSK-3 thiab tseem inhibits GSK-3 kev ua haujlwm hauv lub cell los ntawm kev tsis ncaj ncees uas cuam tshuam nrog kev ua kom Akt. Li ntxiv rau 'kev muaj peev xwm cuam tshuam -arr2-mediated Akt/GSK- 3 signaling contributing to suppressing the behaviour effect of enhanced DA transmission (Fig. 2, [123–127]).

D2Rs qhib lub teeb liab ua ke ntawm -arr2, Akt, thiab PP2A, uas ua rau GSK-3 [123–126, 128, 129] thiab txhawb nqa DA- nyob ntawm tus cwj pwm hloov pauv los ntawm METH. Li ntxiv antagonizes DA-txog kev coj cwj pwm rhiab heev los ntawm inhibition ntawm GSK-3 (Fig. 2, [123–127]). Tag nrho cov khoom ntawm cov complex uas ua rau GSK3, suav nrog -arr2, AKT, thiab PP2A, yog UPS substrates, uas nws inhibition, zoo ib yam li METH thiab DA, activates GSK-3, thaum, Raws li lub cev ntawm cov pov thawj peb xav tias qhov tshwm sim ntawm rhiab heev nyob rau hauv ib tug subtype ntawm BD tej zaum yuav muaj feem xyuam rau cov kev kho mob tshwm sim ntawm Li ntxiv nyob rau hauv tib heev BD phenotype. Qhov no tuaj yeem tso cai rau kev txiav txim siab uas cov txheej txheem molecular cuam tshuam rau kev kho cov teebmeem ntawm lithium hauv BD.

Li ntxiv yog qhov tsis muaj txiaj ntsig zoo hauv BD1 piv rau theem hypomanic uas ua rau hom 2 tsis meej (BD2). Txawm hais tias qhov muaj txiaj ntsig zoo ntawm qhov sib txawv ntawm BD1 thiab BD2 tsis yog sib koom ua ke [132], nws sawv cev rau lub ntsiab lus tseem ceeb rau kev nkag siab txog kev ua ntawm Li ntxiv, nrog rau blunted Li ntxiv rau kev ua tau zoo ntawm BD kev nyuaj siab piv nrog mania.

Cov ntaub ntawv pov thawj rau Li ntxiv rau kev kho tau zoo hauv BD1 qhia meej meej tias nws qhov kev ua tau zoo txuas nrog rau qhov tshwj xeeb ntawm qhov tsis sib xws, uas yog cyclicity. Qhov tseeb, nws yog qhov tsim nyog los txiav txim siab tias thaum lub sijhawm uas mania nce siab ("mania nce"), raws li tau hais los ntawm kev coj tus cwj pwm, Li ntxiv muaj ntau dua "kev sib raug zoo" [133] rau cov xwm txheej neural spurring "manic sawv."

Cov xwm txheej cuam tshuam hauv qhov kev sib raug zoo no yuav tsum tau nrhiav nyob rau hauv "dynamic" xwm txheej ntawm cov tshuab uas muaj ntau lub tshuab molecular yuav "raug hluav taws" mus txog qhov kawg. Qhov tseeb, tus mob "evolves" zuj zus mus rau tag nrho cov lus qhia ntawm manic theem (Fig. 3). Cov yam ntxwv molecular ntawm qhov "dynamic" mob no yog tus neeg sib tw loj los nthuav tawm cov txheej txheem uas tso cai rau lithium kom ua tau zoo tshaj plaws nyob rau theem ntawm BD1.

Raws li tau hais los saum toj no, kev xav tau yog tsav los ntawm txoj hauv kev molecular txuas rau DA kis tau tus mob, uas muaj lub luag haujlwm tseem ceeb hauv BD [134]. Lub hlwb DA thaum lub sijhawm "mania nce" yog qhov ua tau zoo thiab ua rau muaj kev nkag siab zoo, raws li qhia meej los ntawm kev coj cwj pwm, neural, thiab cov pov thawj tshuaj ([134], rau kev tshuaj xyuas).

Qhov tseem ceeb, rhiab heev tshwm sim nyob rau hauv ntau yam kab mob. Yog li, raws li pom tseeb los ntawm kev hloov pauv tus cwj pwm, hauv BD1 lub ncov ntawm mania tau mus txog rau lub sijhawm ntawm lub limtiam. Psychostimulant-induced sensitization poob rau hauv qhov zoo sib xws (txawm tias luv dua) lub qhov rais ntawm lub cev. Hauv schizophrenia, cov txheej txheem, tseem hu ua endogenous sensitization [135], txhim kho lub sijhawm ntev.

cistanche phelypaes

Nyob rau hauv txhua tus kab mob, ob theem tuaj yeem paub qhov txawv thaum lub sijhawm kev loj hlob: ib qho ua rau muaj kev hloov pauv hauv neural kev ua haujlwm mus txog qhov "peak," thaum lwm qhov ua rau muaj kev hloov kho tsis tu ncua thaum lub ncov dhau lawm. Qhov tseeb, hauv BD, lub mania theem rov qab mus rau qhov kev hloov kho uas ua rau lub sijhawm tom ntej (euthymia lossis kev nyuaj siab). Molecular mechanisms feem ntau sib tshooj hauv peb kab mob no; Txawm li cas los xij, txij li thaum lawv tshwm sim raws li lub sijhawm sib txawv, lawv muaj peev xwm koom nrog ntau txoj hauv kev thiab tshwj xeeb molecular. Qhov kev vam meej sib txawv no tuaj yeem piav qhia txog kev ua tau zoo ntawm Li ntxiv raws li lub sijhawm lub sijhawm thaum nws raug tswj hwm.

Nyob rau sab nraud, cia peb xav txog luv luv tias thaum lub sijhawm manic dhau ntawm qee txoj hauv kev molecular koom nrog "mania nce" kuj koom nrog rau theem ntawm kev nyuaj siab [126], tejzaum nws yuav cuam tshuam qhov kev hloov pauv hloov pauv los ntawm cov txheej txheem rov qab. Qhov no tuaj yeem dhau qhov kev hloov kho uas xav tau, yog li tsim qhov tshwm sim, uas yog qhov "tawm tsam" ntawm mania. Nws tuaj yeem xav tias Li ntxiv rau qhov kev ua ntawm cov kev no antagonizes kev nyuaj siab mus ob peb vas; Txawm li cas los xij, cov khoom siv roj ntsha uas Li ntxiv khi tsis muaj ntau txaus kom tso cai rau stochastic Li ntxiv rau khi kom txaus nyob rau lub sijhawm luv luv. Qhov no yuav tsis tso cai rau Li ntxiv kom nthuav tawm nws cov tshuaj pharmacological. Qhov kev pom no tau txais kev txhawb nqa los ntawm cov pov thawj preclinical qhia tias AMPH tshem tawm tom qab kev tswj hwm rov ua rau muaj kev nyuaj siab zoo li tus cwj pwm [99, 136]. Txawm li cas los xij, Li ntxiv tuaj yeem tswj hwm qhov kev nyuaj siab ntxhov siab los ntawm kev ntsuas cov txheej txheem neural hauv qab kev txhawb siab, uas tau tswj hwm los ntawm DA kev sib kis [106, 134, 137].

Qhov kev vam meej no coj mus rau lub siab ntawm ib kab lus ntawm ib tus kws tshaj lij ntawm BD, Athanasios Koukopoulos, "Mania yog qhov hluav taws kub thiab kev nyuaj siab nws cov tshauv" [138, 139]. Qhov no ua rau kev txiav txim siab txog qhov tseem ceeb ntawm Li ntxiv rau kev ua, uas yog lub peev xwm, thaum lub sijhawm mania dhau lawm (kho), kom tswj tau qhov kev ua haujlwm sib npaug uas ua rau "stabilization."

Nws yog ib qho tseem ceeb uas yuav tau txiav txim siab tias qhov kev kho mob tau zoo (txawm tias feem pua ​​​​ntawm cov neeg mob tseem ceeb) muaj feem cuam tshuam hauv BD1, feem ntau ntawm kev puas siab puas ntsws rhiab heev, txawm hais tias nws tsis tshua muaj tshwm sim nyob rau hauv rooj plaub ntawm tus mob schizophrenia thaum nws qhov kev ua tau zoo tsawg tsawg hauv kev caij tsheb kauj vab thiab nyob rau hauv cov xwm txheej ceev. BD 2.

Qhov sib txawv loj hauv kev nkag siab ntawm cov kab mob no yog nyob ntawm lub sijhawm kawm thiab kev siv zog (qhov hnyav) ntawm kev hloov pauv biochemistry, tshuaj rhiab heev, thiab kev cuam tshuam tus cwj pwm. Qhov sib txawv tshaj plaws hauv lub sijhawm kawm tshwm sim ntawm BD1 thiab

schizophrenia nrog rau ntawm maj mam vs ceev-cycling BD1, thaum lub feem ntau cuam tshuam qhov sib txawv ntawm cov tsos mob ntawm manic phenotype yog nyob nruab nrab ntawm BD1 thiab BD2 los yog "mixed" xeev [140].

Qhov tseem ceeb, kev nce ntxiv hauv DA kis tau tus mob tom qab muaj kev sib tw AMPH raug pom nyob rau hauv cov neeg mob uas muaj tus mob schizophrenia piv nrog cov kev tswj kev noj qab haus huv. Cov teebmeem no tau tshwm sim nyob rau hauv cov neeg mob thaum pib ntawm tus kab mob thiab cov uas tsis tau yav tas los raug rau neuroleptics los yog nyob rau hauv cov neeg mob uas muaj ib tug mob exacerbation, tab sis tsis nyob rau hauv ib tug remission theem [111]. Cov pov thawj no qhia tau hais tias DA hyperactivity muaj nyob rau hauv tus neeg mob schizophrenic thaum pib ntawm cov tsos mob, nyob rau hauv cov theem rov qab, thiab, tejzaum nws, thaum lub sij hawm prodromal.

Qhov no qhia tau tias cim Li ntxiv rau kev ua tau zoo hauv BD1 yog vim muaj kev ua kom DA loj heev, tom qab rhiab heev, thiab cov txheej txheem molecular uas tau qhib kom deb dhau los piv nrog rau lwm yam kev mob. Cov molecular substrates tau qhib los ntawm DA overload tuaj yeem muab Li ntxiv rau qhov tsim nyog "hooking" uas yuav ua rau muaj kev tswj hwm zoo thiab, dhau los, kev kho tau zoo.

Kev sib tham, kev txwv, thiab kev txiav txim siab

Hauv cov ntawv sau tam sim no, peb tau tsom mus rau cov txiaj ntsig kho mob ntawm Li ntxiv los qhia txog cov txheej txheem ntawm kev ua haujlwm hauv cov kab mob neuropsychiatric sib txawv. Cov txheej txheem no muab cov ntaub ntawv tseem ceeb los pab kom nkag siab txog etiology ntawm kev tsis sib haum xeeb uas lawv koom nrog thiab taw qhia txog kev txhim kho kho tau. Li ntxiv rau kev hloov pauv ntau txoj hauv kev biochemical hauv lub hlwb koom nrog hauv neuroplasticity thiab neuroprotection.

Li plusneuroprotectiveQhov kev txiav txim tso siab rau qhov kev hloov pauv ntawm ntau txoj hauv kev hauv nruab nrog cev koom nrog hauv ER kev ntxhov siab, kev ua haujlwm mitochondrial, Ca2 ntxiv rau toxicity, UPR, thiab autophagy. Cov teebmeem ntawm cov tshuab autophagy tseem yog cov txheej txheem molecular tseem ceeb los piav qhia txog kev tiv thaiv ntawm Li ntxiv rauneurodegenerativecov kab mob, uas qhia tau hais tias Li ntxiv li cas siv cov tshuab molecular zoo sib xws los hloov cov kev sib txawv ntawm cov kab mob sib txawv uas yog sib txawv.

Xws li tshuab molecular tej zaum yuav muaj ib tugneuroprotectivethiab neurotrophic ua rau AD thiab lwm yam degenerative dementias. Qhov tseeb, upregulation ntawm GSK-3 kev ua, uas yog inhibited los ntawm Li ntxiv ,

tshwm sim hauv AD.

Kev ua tsis tiav ntawm autophagy-dependent tuav ntawm misfolded proteins impeds lub clearance ntawm cov substrates uas accumulates nyob rau hauv lub cell. Yog li ntawd, ib tug ntau pathogenesis hauv qabneurodegenerativeCov kev mob tshwm sim tau txuas nrog autophagy inhibition vim yog kev ua kom mTOR. Cov txheej txheem feem ntau koom nrog Li ntxiv rau kev tiv thaiv cov teebmeem hauvneurodegenerativeALS/FTD kab mob raws li qhia los ntawm kev txhim kho tseem ceeb ntawm lub cev muaj zog ua haujlwm los ntawm kev kho nrog Li ntxiv rau ob xyoo dhau los hauv kev tshawb fawb soj ntsuam thiab preclinical.

Li ntxiv cov cuab yeej los hloov kho autophagy muaj peev xwm kho cov tswv yim rau kev kho mob neuropsychiatric mob thiab hais txog kev sib tshuam sib txuas ntawm autophagy,neurodegenerativekev tsis sib haum xeeb, thiab lub siab stabilization (kev ua haujlwm antimanic). Remarkably, cov txheej xwm molecular nyob rau hauv kev loj hlob ntawm mania kev txhawj xeeb neuroplastic mechanisms cuam tshuam nyob rau hauv neurotransmission thiab mechanisms ntawmneurodegeneration.

Sensitization yog cov txheej txheem neuroplastic uas yog qhov tseem ceeb hauv cov kab mob ntawm cov kab mob tseem ceeb, txawm tias qhov sib txawv me ntsis hauv cov txheej txheem rhiab heev ntawm cov kab mob no yuav pab txheeb xyuas tias vim li cas qee tus ntawm lawv rhiab heev rau Li ntxiv, uas yog cov ntaub ntawv ntawm BD1. Kev hnov ​​​​mob los ntawm psychostimulants yog tsav los ntawm txoj hauv kev molecular txuas rau DA kis tau tus mob thiab taw qhia rau ntau lub tswv yim koom nrog hauv psychopathology, feem ntau tseem ceeb heev hauvneurodegenerativetsis meej pem.

Li ntxiv, raws li nws feem ntau lees paub, muaj ntau lub zog, hauv kev nkag siab tias nws cuam tshuam rau txoj hauv kev sib txawv molecular. Nyob rau hauv cov ntaub ntawv ntawm manic theem ntawm BD1, ntau txoj hauv kev thiab cov txheej txheem sib txawv uas Li ntxiv rau kev ua haujlwm tuaj yeem ua rau muaj ntau txoj haujlwm txhawb nqa nws txoj haujlwm (Daim duab 1).

Thaum lub sij hawm "mania nce", rhiab heev ntawm theem intracellular recruits ib tug xov tooj ntawm molecular txoj kev uas yog matched los ntawm tib tus naj npawb ntawm substrates khi Li ntxiv.

cistanche noj qab haus huv pab: tiv thaiv Parkinson cov kab mob

Cov txheej txheem sensitization tsim los ntawm dysregulation ntawm ntau yam DAR subtypes, feem ntau yog D1, D2, thiab D3, ntawm presynaptic thiab / los yog postsynaptic qib [126], nrog rau kev koom tes ntawm DA transporter. Nws yuav tsum tau nco ntsoov tias, txawm hais tias cov mesoaccumbens thiab striatal txoj kev muaj kev cuam tshuam loj heev, cov qauv cortical uas tswj cov cheeb tsam subcortical hauv kev sib xyaw ua ke muaj lub luag haujlwm tseem ceeb. Yog li, vim qhov kev xav, monoaminergic systems nyob rau hauv medial prefrontal cortex undergo receptor lossis metabolic adaptations uas tsis yog sib piv los ntawm cov uas ua nyob rau hauv subcortical thaj chaw [105, 106, 132, 141–143]. Yog li, txoj hauv kev molecular cuam tshuam hauv kev hloov pauv hauv kev sib koom tes yuav muaj peev xwm muab cov substrates ntxiv rau Li ntxiv rau kev ua tau zoo.

Qhov tseem ceeb, qee qhov kev tsis sib haum xeeb ntawm Li ntxiv rau cov qib molecular thiab / lossis cov kab ke hauv lub cev tuaj yeem pom ib qho kev ua haujlwm ib txhij ntawm cov kab ke sib txawv lossis cov kab ke [14, 144].

Qhov tshwj xeeb kho tau zoo ntawm Li ntxiv rau hauv mania kuj tseem tuaj yeem ua rau muaj peev xwm ntawm cov ion los ua rau ntau txoj hauv kev molecular thiab cov yam ntxwv tswj cov neurotransmission [145], neuroplasticity, thiab neuroprotection. Nws tuaj yeem xav tias qhov kev hloov pauv hloov pauv hauv "mania nce" coj mus rau hauv cov xwm txheej molecular uas Li ntxiv rau kev tawm tsam kev tawm tsam ntawm lub xeev khov kho (homeostasis). Qhov tsim nyog, Li ntxiv tau pom tias yog "txaus" los ntawm lub hlwb neurons ntawm BD cov neeg mob thiab tsis yog los ntawm cov neeg noj qab haus huv [133], ua kom pom qhov "kev sib raug zoo" ntawm ion rau kev ua haujlwm tsis zoo ntawm neural molecular substrates. Qhov kev sib raug zoo no tseem tuaj yeem hloov kho los ntawm cov yam ntxwv ntawm caj ces uas pom tseeb cuam tshuam rau tus neeg sib txawv hauv kev kho mob zoo. Hauv kev sib tw ceev ceev, cov tsos mob ntawm ob lub xeev nyob rau lub sijhawm luv luv txiav tawm qhov kev sib tw uas ua rau muaj kev nce qib ntawm BD1. Nws yog qhov txaus siab rau kev xav tias qhov ua tau zoo ntawm Li ntxiv rau hauv cov kab mob no yog vim tsis muaj kev sib tw thiab lub sijhawm ntev dua thiab kev hloov pauv biochemical hnyav dua. Qhov no sib piv nrog qhov tshwm sim hauv BD1, thiab nws yuav tsum tiv thaiv kom tsis txhob muaj qhov cuam tshuam loj heev los ntawm kev sib txuas los ntawm Li ntxiv rau nws txoj kev kho mob zoo. Ntau lub luag haujlwm ntawm Li ntxiv ua pov thawj nws qhov tshwj xeeb kws tshuaj, uas tuaj yeem pab qhia meej txog nws cov txheej txheem ntawm kev ua. Li ntxiv kev nqis tes ua tuaj yeem ua cov lus qhia rau ntau lub tswv yim tshuaj thiab txhim kho kev txhim kho ntawm txoj kev kho kom zoo dua.

Peb qhov kev pom tsis yog tsis muaj kev txwv. Peb tau txiav txim siab txog cov txheej txheem molecular uas muaj rau ntau tus kabmob uas qhia txog lawv lub luag haujlwm hauvneurodegenerationthiab neuroprotection, hais txog autophagy machinery raws li ib qho tseem ceeb mechanism rau neural regulation thiab dysregulation nyob rau hauv ob qho tib sineurodegenerativethiab kev puas siab puas ntsws. Ib qho kev txwv muaj peev xwm muaj nyob rau hauv qhov tsis muaj kev tshuaj xyuas tob txog yuav ua li cas tag nrho cov txheej txheem no ua rauneurodegeneration, nyob rau hauv sib txawv neuronal pej xeem nyob rau hauv txawv lub hlwb. Qhov tseeb, kev hloov pauv ntawm lub hlwb ntse tshwm sim hauv cov kab mob neurodegenerative zoo li hauv schizophrenia thiab BD [146].

cistanche tubolosa cov txiaj ntsig: neuroprotection

Lwm qhov kev txwv, uas tau txheeb xyuas nyob rau hauv cov ntawv nyeem dhau los, yog qhov tsis muaj kev tshuaj xyuas ntau ntawm cov neeg sib txawv ntawm tes nrog rau ntau yam kev sib cuam tshuam ntawm neural tes hauj lwm nrog rau cov neurons thiab glia [147, 148] Cov no suav nrog kev tsom xam tshwj xeeb ntawm cov neurons tuav nyob rau hauv lub hlwb tshwj xeeb. yog ib feem ntawm cov kev sib txuas lus nyuaj uas nws cov kev sib txuas tuaj yeem nyiam lossis ua kom tsis zooneurodegenerativeCov txheej txheem [131] Xws li qhov tsis muaj kev sib txawv ntawm kev tsom xam yuav yog qhov tseem ceeb thaum xa mus rau cov txheej txheem rhiab heev uas yuav siv sij hawm nruab nrab ntawm qhov xwm txheej tau muab los ntawm no. Qhov tseeb, lub hom phiaj thiab tej zaum nyob rau hauv txoj kev tsis ncaj ncees, peb tau tsom mus rau DA kev kis tus kab mob dysregulation, uas tau coj los qhia txog ntau hom DARs uas nws qhov kev hloov pauv tuaj yeem tsim cov teebmeem sib txawv nyob ntawm seb lawv puas yog presynaptic lossis postsynaptic. Ntxiv mus, dopaminergic neurons tau txais kev sib txuas los ntawm ntau cov neurons nyob rau hauv reciprocal DA cortical-subcortical tes hauj lwm, nrog sib txawv neurotransmitters thiab neuromodulators, uas nyob rau hauv lem yuav modulate neurodegenerative dab. Cov no tsuas yog cov piv txwv uas qhia yuav ua li cas nkag siab txog cov txheej txheem hais txog ntawm no; Kev xav dav dav yuav tsum muaj nyob rau hauv tib neeg thiab cov qauv ua ntej kom ncav cuag cov txiaj ntsig kev txhais lus.

Qhov tseeb, cov duab kos duab thiab kev tshuaj ntsuam xyuas molecular yuav pab txhawb kev tshawb pom ntawm molecular thiab neurobehavioral biomarkers. Los ntawm qhov kev xav no, Li ntxiv ua pov thawj qhov cuab yeej tshwj xeeb rau kev nkag siab txog cov txheej txheem pathogenic thiab tsim kho cov kev kho mob zoo.

Ntawm qhov kev pheej hmoo ntawm qhov tshwm sim ntau dhau "conservative," peb rov lees paub qhov txawv ntawm Li ntxiv rau ob qho tib si ua tus kws kho mob thiab ua ib qho cuab yeej tshwj xeeb hauv kev tshawb fawb neuroscience. Qhov no yog tsim nyog ntawm nws lub peev xwm los txhawb nqa, tib lub sijhawm, neurotransmission thiab neuroprotection. Cov khoom no kuj nthuav tawm tias kev puas siab puas ntsws thiab kev puas siab puas ntsws muaj feem cuam tshuam rau cov txheej txheem molecular uas muaj peev xwm ua kom muaj kev sib npaug ntawm kev kho mob thiab cov xwm txheej hloov kho.