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

1 Tshooj ntawm Neurosurgery, Department of Neuroscience, Uppsala University, 75124Uppsala, Sweden;

dfsgustafsson@gmail.com

2 Department of Clinical Neuroscience, Rehabilitation Medicine, Uppsala University, 75124 Uppsala, Sweden;

andrea.klang@akademiska.se

3 Department of Clinical Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden; sebastian.thams@ki.se 4 Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden *Cov Lus Qhia: elham.rostami@neuro.u.se

Abstract: Kev mob hlwb raug mob yog ib qho ua rau muaj kev tuag thiab kev tuag nyob hauv lub ntiaj teb uas tsis muaj kev kho mob tam sim no. Lub luag haujlwm ntawm BDNF hauv kev kho neural thiab rov tsim dua tshiab tau tsim tau zoo thiab tseem yog qhov tseem ceeb ntawm TBI kev tshawb fawb. Ntawm no, peb tshuaj xyuas cov qauv tsiaj sim ntsuas BDNF qhia tom qab raug mob nrog rau kev tshawb fawb soj ntsuam hauv tib neeg nrog rau lub luag haujlwm ntawm BDNF polymorphism hauv TBI. Muaj qhov sib txawv loj hauv kev sim teeb tsa thiab yog li cov txiaj ntsig nrog cov kev hloov pauv hauv cheeb tsam thiab ntu ntu ntawm BDNF qhia. Ntau qhov kev tshawb fawb kuj tau soj ntsuam cov kev cuam tshuam sib txawv los cuam tshuam rau BDNF qhia tom qab raug mob. Cov kev tshawb fawb soj ntsuam qhia txog qhov tseem ceeb ntawm BDNF polymorphism hauv qhov tshwm sim thiab qhia txog lub luag haujlwm tiv thaiv ntawm BDNF polymorphism tom qab raug mob. Xav txog qhov muaj peev xwm cuam tshuam rau BDNF txoj hauv kev nrog cov khoom muaj, peb sib tham txog cov kev tshawb fawb yav tom ntej uas siv cov nas transgenic nrog rau iPSC txhawm rau nkag siab txog cov txheej txheem hauv qab ntawm BDNF polymorphism hauv TBI thiab tsim kho cov tshuaj pharmacological.

Cov lus tseem ceeb: BDNF; neurotrophins; neurotrophic yam; mob hlwb raug mob; neuroregeneration; neuroprotection; hlwb; neurons

Cistanche muaj cov nyhuv neuroprotective zoo heev

1. Taw qhia

Kev puas tsuajhlwbKev raug mob (TBI) yog qhov ua rau tuag thoob ntiaj teb, thiab hauv cov tub ntxhais hluas hnub nyoog qis dua 35 xyoo, qhov kev tuag yog 3.5 npaug ntawm kev mob qog noj ntshav thiab mob plawv ua ke [1]. TBI yog ib qho mob hnyav nrog qhov kev raug mob thawj zaug ua rau cov xwm txheej thib ob uas tuaj yeem ua tiav ntau teev, hli, thiab ntau xyoo. Cov xwm txheej no tuaj yeem ua rau muaj teeb meem xws li ischemia, lub zog tsis ua haujlwm, thiab ua rau mob, lossis muaj txiaj ntsig zoo xws li kev nthuav tawm ntau ntxiv.neurotrophinsthiab loj hlob yam uas txhawb nqa neuronal ciaj sia taus thiab plasticity.

Neurotrophins, tshwj xeebhlwb-derivedneurotrophic factor (BDNF), tau raug txheeb xyuas los ua lub luag haujlwm tseem ceeb hauv cov xwm txheej cellular uas tshwm sim hauv cov txheej txheem rov qab los ntawm TBI, xws li neuronal survival, axonal sprouting, thiab synaptogenesis [2]. Vim yog lub luag haujlwm tseem ceeb ntawm BDNF, nws qhov kev cuam tshuam tau raug tshawb fawb dav hauv kev sim TBI qauv thiab kev tshawb fawb tib neeg [3]. Nws kuj tau pom tias BDNF polymorphism cuam tshuam qhov tshwm sim tom qab TBI, tab sis lub hauv paus txheej txheem tsis tau nkag siab tag nrho. Raws li peb yuav tshawb hauv tsab xov xwm no, kuj tseem muaj qhov sib txawv ntawm cov txiaj ntsig los ntawm kev sim ua qauv kawm BDNF qhia txog lub sijhawm tom qab raug mob, anatomical localization, thiab cov txiaj ntsig. Hauv qhov kev tshuaj xyuas no, peb tsom los npog cov kev tshawb pom hauv kev sim TBI tshawb xyuas BDNF thiab tib neeg cov kev tshawb fawb tshawb fawb txog cov txiaj ntsig ntawm BDNF polymorphism txhawm rau txheeb xyuas cov kev paub tseem ceeb rau kev tshawb fawb yav tom ntej.

1.1. Lub hlwb-Derived Neurotrophic Factor (BDNF)

BDNF yog qhov ntau tshajneurotrophinhauvhlwb[4,5], ua lub luag haujlwm tseem ceeb hauv kev ciaj sia, kev sib txawv, synaptic plasticity, thiab axonal outgrowth ntawm peripheral thiab central neurons thoob plaws hauv neeg laus [2,4,6]. BDNF mediates nws cov txiaj ntsig los ntawm kev sib raug zoo siab tyrosine kinase receptor (TrkB) [7]. Ib qho kev qhia ntau ntxiv ntawm TrkB mRNA tau kuaj pom nyob rau hauv qhov chaw ntawm kev raug mob tom qab raug mob qaum qaum thiab TBI [8,9]. BDNF kuj khi rau lub lauj kaub-neurotrophin receptor p75NTR, tus tswv cuab ntawm cov qog necrosis factor receptor (TNFR) tsev neeg [10]. Lub p75NTR receptor tau raug qhia kom muaj lub luag haujlwm dual ob qho tib si ua tus pabcuam ntawm Trk-mediated neuronal ciaj sia taus thiab ua tus tswj hwm ntawm neuronal cell tuag los ntawm kev pib ntawm apoptosis. Raws li, ib qho ntawm qhov tsis zoo ntawm kev kho mob siv BDNF analogs tau hais tias lawv kuj cuam tshuam rau p75NTR receptors mediating apoptosis. Yog li, ib qho tshuaj TrkB xaiv lossis p75NTR inhibitor yuav muaj txiaj ntsig zoo dua.

1.2 TSI BDNF Val66met Polymorphism

BDNF ib leeg nucleotide polymorphism (SNP) hauv rs6265 ua rau muaj kev hloov pauv tsis zoo, Val66Met (196G/A), uas ua rau muaj qhov tsis zoo hauv kev ua haujlwm-dependent secretion ntawm BDNF [11]. Kev hloov pauv ntawm Val66Met tshwm sim li ntawm 30 feem pua ​​​​ntawm cov pej xeem hauv Teb Chaws Asmeskas (tau ntsib cov neeg nqa khoom / ntsib ntxiv ). Thaum txhais, BDNF molecule muaj peb yam tseem ceeb: lub teeb liab peptide, prodomain, thiab kev ua haujlwm BDNF molecule, txhua yam ua haujlwm ntawm cov receptors sib txawv. Mature BDNF khi rau TrkB receptors thiab txhawb nqa lub sijhawm ntev (LTP), cell ciaj sia taus, thiab tsim dendrite; whereas proBDNF khi rau p75NTR thiab ua kom muaj kev nyuaj siab ntev (LTD), apoptosis, thiab txo cov dendritic complexity. Qhov no dual mechanism ua haujlwm antagonistically thiab tswj cov neuroplasticity. Qhov kev hloov pauv ntawm Val66Met ua rau muaj kev sib sau ntawm metBDNF hauv lub soma thaum valBDNF accumulates nyob rau hauv punctuate vesicles hauv dendrites. Neurons tsis tuaj yeem zais metBDNF hauv cov lus teb rau cov haujlwm uas ua rau muaj qhov tsis zoo ntawm plasticity hauv cov neeg nqa khoom.

cistanche tshuaj ntsuab

2. BDNF Polymorphism hauv Tib Neeg Kev Kawm

Qhov feem ntau kawm polymorphism ntawm BDNF nyob rau hauv tib neeg yog rs6265 (Val66Met), nyob rau hauv kev sib raug zoo rau ib txwm kev txawj ntse muaj nuj nqi, cuam tshuam rau kev puas siab puas ntsws, neurodegenerative, thiab neuro in-flammatory kab mob, thiab traumatic.hlwbraug mob [11–15]. Qhov no kuj tau tshwm sim hauv TBI [16,17], txawm hais tias ntxiv SNPs xws li rs71244 [18,19], rs1519480, rs7124442 [20], thiab rs1153659 [21] tau raug txheeb xyuas kom cuam tshuam qhov tshwm sim tom qab.hlwbraug mob. SNP rs6265 ntawm BDNF ua rau kev hloov pauv ntawm valine rau methionine thiab qhov tshwm sim ntawm heterozygote lossis homozygote cov neeg nqa khoom ntawm methionine yog nyob ib ncig ntawm 30 feem pua ​​​​ntawm cov pej xeem hauv Tebchaws Meskas [22], tab sis txawv thoob ntiaj teb [23]. Feem ntau cov kev tshawb fawb piv ho- mozygote valine-carriers (Met-) rau heterozygote thiab homozygote methionine-carriers (Met plus ). Ib pawg neeg tsawg ntawm kev tshawb fawb muaj peb pawg [17,24,25], sib cais heterozygote ntsib ntxiv los ntawm homozygote met plus .

Ntawm cov tib neeg noj qab haus huv (txhais tau tias muaj hnub nyoog 36 y), cov neeg nqa khoom ntawm met-allele tau mob hnyav zuj zus nrog kev ntsuas n-rov qab ua haujlwm nco, nrog rau kev ua haujlwm hippocampal txawv txav los ntawm kev ua haujlwm MRI (fMRI), piv rau Met- [11 ]. Cov txiaj ntsig zoo sib xws tau pom nyob rau hauv lwm txoj kev tshawb fawb nrog cov tib neeg noj qab haus huv (txhais tau tias muaj hnub nyoog 30 y), kuj ntsuas lub cim xeeb thiab kev ua haujlwm ntawm hippocampus nrog fMRI thaum lub sijhawm kuaj [26]. Cov neeg nqa khoom tau ntsib muaj 25 feem pua ​​​​tsawg ua kom cov cheeb tsam hippocampal thiab kev ua haujlwm tsis zoo ntawm kev lees paub cov ntaub ntawv "tshiab" thiab " qub". Interestingly, muaj cov cim qhia tias ua tus neeg nqa khoom tuaj yeem muaj txiaj ntsig zoo thaum laus. Scottish Mental Survey 1947 suav nrog kev tshuaj ntsuam genetic tsom xam thiab kev soj ntsuam mus sij hawm ntev thiab qhia tau hais tias cov neeg sib ntsib tau zoo dua khaws cov kev txawj hais lus tsis zoo thaum muaj hnub nyoog laus dua (txhais tau tias muaj hnub nyoog 79) [15], qhia tias cov neeg sib ntsib tuaj yeem txuag kev paub. ua haujlwm zoo dua li kev sib ntsib-, thaum laus. Cov txiaj ntsig kuj tau pom nyob rau hauv kev pheej hmoo ntawm kev tsim Alzheimer's kab mob ntawm cov neeg tsis yog TBI, qhov kev pheej hmoo siab dua rau Val-homozygotes tom qab hauv lub neej tab sis qhov rov qab ntawm cov neeg hluas [14]. Qhov no yog ua raws li txoj kev xav ntawm kev sib ntsib ntxiv rau qhov muaj txiaj ntsig zoo rau kev khaws cia ntawm kev paub txog kev ua haujlwm ntawm lub hnub nyoog laus.

2.1. BDNF Polymorphism thiab Cov txiaj ntsig tom qab Mild thiab Moderate TBI

Cov nyhuv ntawm BDNFval66met polymorphism ntawm qhov kev paub ntxov ntxov tom qab mob me me TBI (mTBI) tau raug soj ntsuam hauv ob qhov kev tshawb fawb sib txawv thiab pom qhov tshwm sim tsis zoo rau cov neeg nqa khoom. Ntawm kev ua raws li subacute (ib lub hlis) tom qab mTBI, ob qho tib si Met plus controls thiab Met plus TBI-pab pawg muaj lub sij hawm rov qab qeeb dua nyob rau hauv ob qho tib si lub sij hawm cov tshuaj tiv thaiv yooj yim (SRTRT - lub sij hawm yooj yim cov tshuaj tiv thaiv) thiab cov ntaub ntawv ceev ceev ( ntsuas nrog Gordon Nruam Kev Xeem Ua Haujlwm-CPT) piv rau Met-cov neeg mob thiab kev tswj hwm [17]. Qhov no cuam tshuam rau lwm txoj kev tshawb fawb uas cov neeg koom tau raug sim hauv tsib lub hauv paus kev paub: kev mloog, kev nco, lus, visuospatial, thiab kev ua haujlwm, tam sim ntawd tom qab rov zoo thiab tom qab rau lub hlis [27]. Zuag qhia tag nrho, Met- muaj qhov ua tau zoo dua neurocognitive, tsis muaj qhov sib txawv tseem ceeb ntawm ob lub sijhawm. Txawm li cas los xij, cov neeg nqa khoom sib ntsib tau ua qhov tsis zoo ntawm qhov kev ntsuam xyuas nco ntawm rau lub hlis, qhia tias muaj kev puas tsuaj ntawm qee qhov kev paub txog kev ua haujlwm.

Txawm li cas los xij, nyob rau hauv kev ua raws li cov tub rog qub tub rog tom qab mTBI nyob rau hauv lub sij hawm ntev (txhais tau tias 4.5 xyoo), ntsuas kev nco thiab kev ua haujlwm, pawg Met plus nrog TBI tau txais txiaj ntsig zoo dua li lawv pawg tswj hwm, qhov Met- muaj qhov sib txawv. qhov tshwm sim [28]. Qhov no tuaj yeem qhia tau tias qhov muaj nyob ntawm Met plus SNP ua rau lub hauv paus qis ntawm kev txawj ntse tab sis muaj kev tiv thaiv zoo ntawm kev paub tom qab TBI.

Qhov kev pheej hmoo rauneurodegenerationTom qab TBI tau tham thiab tshuaj xyuas hauv kev tshawb fawb sib txawv [29]. Mob hnyav TBI tau cuam tshuam nrog kev pheej hmoo siab dua rauneurodegenerationtab sis nyob rau hauv kaum xyoo dhau los, qhov txuas no kuj tau thov rau me me TBI [30,31]. Txhawm rau nrhiav pom cov tsos mob thaum ntxov ntawm kev dementia, qhov ntim ntawm Hippocampus tau soj ntsuam nrog MRI hauv cov tib neeg uas muaj keeb kwm ntawm mTBI piv rau kev tswj hwm, cuam tshuam nrog ntau BDNF SNPs. Rs1153659 me me allele tau cuam tshuam rau qhov kev pheej hmoo siab dua ntawm kev txo qis hippocampal ntim tom qab mTBI piv rau kev tswj tab sis tsis muaj qhov sib txawv rau rs6265 [21].

Hauv kev tshawb fawb soj ntsuam cov txiaj ntsig ntawm cov npe hauv cov neeg ncaws pob hauv rau lub hlis ntawm remyelination soj ntsuam los ntawm diffusion tensor imaging (DTI), nws tau pom tias cov neeg nqa khoom tau pom muaj qhov cuam tshuam tsawg dua piv rau Val homozygote players [32]. Qhov no yuav piav qhia txog ib feem ntawm cov kab mob hauv qab no hauv cov txiaj ntsig ua haujlwm tsis zoo tom qab rov ua dua mTBI hauv cov neeg ncaws pob. Tej zaum yuav muaj qhov sib txawv ntawm poj niam txiv neej raws li qhia los ntawm Larson-Depuis li al. qhov twg cov poj niam ncaws pob nrog keeb kwm ntawm concussion muaj ib tug zoo olfactory muaj nuj nqi yog hais tias lawv tau ntsib-carriers piv rau Val-homozygotes [25]. Olfactory muaj nuj nqi tau npaj los ua ib qho kev qhia muaj peev xwm ntawm cov qauv thiab kev ua haujlwm raug mob tom qab kev raug mob, nrog rau cov qauv ntawm lub cev.hlwbpaub tias muaj peev xwm rov tsim dua thiab raug rau BDNF.

Kev paub txog qhov tshwm sim tom qab TBI yog multifactorial. Hnub nyoog thiab poj niam txiv neej cuam tshuam rau qhov tshwm sim [18,19,33] thiab qhov hnyav thiab homhlwbkev raug mob yuav cuam tshuam txog kev paub. Tsis tas li ntawd, kev puas siab puas ntsws tuaj yeem ua rau muaj kev cuam tshuam rau kev paub txog kev ua haujlwm. Post-traumatic stress disorder (PTSD) tau dhau los sib tham ntau ntxiv raws li qhov tshwm sim ntawm TBI [34], uas rov qab tuaj yeem cuam tshuam rau kev txawj ntse. Ib txoj kev tshawb fawb qhia txog kev nce ntxiv ntawm PTSD ntawm Met ntxiv rau cov neeg mob nrog mTBI [24]. Lwm qhov kev puas siab puas ntsws uas tuaj yeem cuam tshuam nrog kev paub yog kev nyuaj siab, uas rov qab tuaj yeem yog qhov tshwm sim ntawm TBI [35]. Tau ntsib nrog cov tub ntxhais kawm tau tshaj tawm qhov tshwm sim ntau dua ntawm cov tsos mob kev nyuaj siab tom qab tus kheej tshaj tawm mTBI piv rau Met- cov tub ntxhais kawm uas muaj keeb kwm ntawm mTBI [36,37]. Qhov sib txawv tau tshaj tawm ntawm cov tub ntxhais kawm poj niam.

Cov poj niam txiv neej sib txawv ntsig txog kev nyuaj siab thiab kev ntxhov siab txog cov tsos mob tau hais ntxiv hauv kev tshawb fawb uas ua raws li cov tsos mob hauv ib pawg neeg mob ib thiab rau lub lis piam tom qab mTBI [36]. Txoj kev tshawb no ntsuas qhov sib txawv BDNF polymorphism thiab pom tias cov txiv neej nrog t-allele, ib qho polymorphism sib txawv los ntawm val66met, muaj kev pheej hmoo siab dua rau kev nyuaj siab tom qab rau lub lis piam, thaum qhov no tsis yog rau cov poj niam. Cov neeg mob uas muaj keeb kwm ntawm me me mus rau nruab nrab TBI thiab kev mob kev nyuaj siab tau teb txawv rau Citalopram, nyob ntawm BDNF rs6265, qhov twg cov neeg teb zoo tshaj plaws yog val-homozygotes [38].

cov txiaj ntsig cistanche

2.2. BDNF Polymorphism thiab Outcome hauv Severe TBI

Tsuas yog ib txoj kev tshawb nrhiav tuaj yeem txheeb xyuas qhov cuam tshuam ntawm BDNFval66met polymorphism ntawm kev rov zoo thaum ntxov tom qab hnyav TBI [39]. Bagnato et al. soj ntsuam kev paub txog kev ua haujlwm ntawm 53 tus neeg mob hauv lub xeev vegetative tom qab hnyav TBI siv Rancho Levels of Cognitive Function Scale. Qhov kev sim tau ua nyob rau ntawm 1-, 3-, 6-, thiab 12- hli tom qab raug mob, thiab tsis muaj qhov sib txawv ntawm cov neeg nqa khoom piv rau Met-.

Muaj qee qhov kev tshawb fawb txog cov txiaj ntsig mus ntev tom qab hnyav, nkag mushlwbKev raug mob hauv Asmeskas Nyab Laj cov qub tub rog uas qhov kev sib raug zoo ntawm BDNF polymorphism thiab cov txiaj ntsig kev paub tau raug kawm [16,20,40]. Kev ua raws li cov kev tshawb fawb no yog 40 xyoo tom qab TB I. Ob ntawm cov no tau kawm txog qhov cuam tshuam ntawm BDNF polymorphism ntawm IQ thiab kev ua haujlwm hauv cov qub tub rog nrog kev nkag mus rau TBI hauv prefrontal cortex (PFC). Ob leeg pom tau txais kev paub txog kev ua haujlwm hauv kev sib ntsib nrog TBI piv rau cov neeg tsis sib ntsib [16,40]. Hauv kev tshawb fawb thib peb, tag nrho cov kev raug mob nkag mus tau suav nrog tsis nyiam PFC [20]. Hauv txoj kev tshawb no, tsis muaj qhov sib txawv tseem ceeb ntawm cov pab pawg rau SNP rs6265 tab sis ob qho tib si BDNF SNP's tau muaj txiaj ntsig zoo rau IQ, rs1519480, thiab rs7124442. Qhov no yuav qhia tau tias muaj kev tiv thaiv ntawm BDNF polymorphism tom qab raug mob thiab tej zaum yuav muaj kev sib koom ua ke nrog cov cheeb tsam sib txawv.

Peb txoj kev tshawb fawb tau siv cov txiaj ntsig ntawm noob caj noob ces raws li "kev pheej hmoo" BDNF SNPs (rs6265 thiab rs 7124442) [18,19,33], hloov kho rau hnub nyoog, los ntsuas cov txiaj ntsig thoob ntiaj teb thiab kev tuag tom qab TBI hnyav. Ob qhov kev tshawb fawb pom tias kev tuag tsawg dua thaum xyoo thawj (8-365 d) tom qab TBI ntawm cov neeg yau (<45 and=""><48 y)="" with="" the="" low="" gene="" risk="" score="" (ie="" met-="" and="" rs7124442="" t-homozygote),="" whilst="" the="" older="" population="" with="" low="" gene="" risk="" score="" had="" higher="" mortality="" [18,33].="" the="" third="" study="" had="" similar="" results="" where="" lower="" age="" had="" a="" higher="" rate="" of="" survival="" at="" six="" months="" with="" a="" low="" gene="" risk="" score,="" though="" these="" results="" were="" to="" some="" extent="" influenced="" by="" levels="" of="" csf="" cortisol="" as="" well="">

2.3. BDNF Qib hauv CSF thiab Plasma tom qab TBI

Peb qhov kev tshawb fawb tuaj yeem txheeb xyuas qhov twg BDNF qib tau ntsuas hauv ntshav thiab / lossis CSF. Simon et al. txheeb xyuas cov theem ntawm BDNF hauv ntshav thaum nkag mus rau ICU, ntawm qhov nruab nrab ntawm 6.4 teev tom qab tuaj txog hauv tsev kho mob tom qab mob hnyav TBI hauv 120 tus txiv neej (Glasgow Coma Scale (GCS) 3-8). Tsis muaj kev sib raug zoo ntawm BDNF plasma qib thiab qhov tshwm sim luv luv (ICU tuag vs. ICU tso tawm) lossis ntawm kev sib caishlwbkev raug mob rau ntau yam kev raug mob [41]. Hauv 12 cov menyuam yaus uas muaj TBI hnyav ntawm BDNF hauv CSF thiab ntshav ntshav ntawm 2 thiab 24 teev tom qab raug mob, tsis muaj kev cuam tshuam nrog Glasgow Outcome Scale (GOS) thaum tso tawm [42], txawm hais tias muaj lub siab siab ntawm BDNF tom qab lub taub hau. raug mob hauv txhua yam. Lwm txoj kev tshawb fawb suav nrog 315 cov neeg mob uas muaj TBI hnyav tau pom muaj kev sib raug zoo ntawm qib BDNF hauv CSF cuam tshuam rau qib cortisol hauv CSF thaum thawj lub lim tiam tom qab raug mob, thiab 6- lub hli tuag [19]. Ib yam li ntawd, CSF qib siab ntawm BDNF niaj hnub ua piv txwv thawj lub lim tiam tom qab raug mob, tau cuam tshuam nrog kev tuag ntau ntxiv (8–365 d tom qab raug mob), thaum qhov mob hnyav ({14}}-7 d) tau txuam nrog cov ntshav qis. qib BDNF [33].

Cov kev tshawb fawb ntawm cov nyhuv ntawm BDNF val66met polymorphism sib txawv ntawm cov txiaj ntsig ntsuas, sijhawm, thiab homhlwbraug mob. Feem ntau, cov kev tshawb fawb me me thiab cov neeg kawm feem ntau tsawg dua 200 tus neeg. Raws li qhov tshwm sim, cov kev tshawb fawb yav tom ntej tsis tshua muaj thiab cov txiaj ntsig tau sib txawv. Kev sib ntsib / ntsib ntau dua hauv cov neeg Caucasian tsawg thiab yog li ntawd feem ntau cov kev tshawb fawb pab pawg met-heterozygote thiab met-homozygote ua ke rau kev tshuaj xyuas.

suab puam cistanche cov txiaj ntsig: tiv thaivhlwbraug mob

3. Experimental TBI

Hauv seem no, peb sau cov kev paub tam sim no ntawm BDNF qhia tom qab raug mobhlwbKev raug mob (TBI) hauv cov qauv tsiaj sib txawv, nrog rau kev sib raug zoo ntawm cov kev xaiv kho tshiab TBI thiab BDNF qhia, thiab lawv cov teebmeem ntawm kev coj cwj pwm. Hauv seem ntsuas BDNF qhia tom qab TBI piv rau kev dag ntxias, peb tau xaiv kom tshem tawm cov kev tshawb fawb uas tsis tau hais meej txog qhov chaw lossis lub sijhawm ntawm BDNF kev tshuaj xyuas nrog rau cov uas tsis tau tshaj tawm cov ntaub ntawv los ntawm cov tsiaj sham.

3.1. Kev sim tsiaj ua qauv

Ntau tshaj kaum tus qauv kev raug mob sib txawv tau siv los kawm BDNF kev qhia tom qab TBI (Daim duab 1) thiab txoj kev xaiv tshaj plaws yog tswj kev cuam tshuam cortical (CCI), tom qab los ntawm cov kua dej percussion raug mob (FPI) thiab cov qauv poob phaus. Tsis muaj kev tshawb fawb tshwj xeeb txheeb xyuas seb cov qauv kev raug mob sib txawv ua rau muaj kev cuam tshuam BDNF qhia. Tus qauv xaiv tau txiav txim siab los ntawm hom kev raug mob twg yog nrhiav kom tau emulated, piv txwv li, blunt quab yuam los yog nkag mus rau raug mob. Peb tau sim kos cov lus xaus hais txog qhov sib txawv ntawm qhov kev raug mob ntawm BDNF qhia tab sis muaj qhov tsis sib haum xeeb hauv cov ntaub ntawv tshuaj xyuas. Piv txwv li, Colak et al. siv tus qauv tswj kev cuam tshuam cortical whereas Wang li al. siv cov kua dej percussion thiab ob leeg pom tias kev raug mob nce BDNF mRNA qhia hauv thawj hnub tom qab raug mob (DPI) hauv cov ntaub so ntswg ipsilateral rau qhov raug mob [43,44]. Ntawm qhov tod tes, Boone et al. kuj tau siv cov qauv percussion kua thiab pom qhov txo qis BDNF mRNA kev qhia hauv ipsilateral hippocampus tom qab 20 h tab sis tsis muaj kev cuam tshuam qhov qhia tawm ntawm 4, 8, 16 thiab 24 teev tom qab raug mob [45]. Hauv cov ntsiab lus, txhawm rau kos cov lus xaus yuav tsum tau muaj kev tshawb fawb tshwj xeeb uas txheeb xyuas cov qauv sib txawv ntawm qhov cuam tshuam ntawm BDNF qhia.

Daim duab 1. Cov qauv kev raug mob hauv cov kev tshawb fawb soj ntsuam.

3.2. Anatomical Regions ntawm BDNF Kev Ntsuam Xyuas

Hauv cov ntaub ntawv tshuaj xyuas, cov cheeb tsam anatomical tau sib txawv heev. Txhawm rau sib piv thiab tshuaj xyuas cov xwm txheej hauv cov ntaub ntawv luam tawm, cov cheeb tsam anatomical tau muab ua ke ua ke (Daim duab 2). Cov kev tshawb fawb soj ntsuam cov cheeb tsam sib txawv, piv txwv li, ob qho tib si ipsilateral thiab contralateral hippocampus (HC), raug suav cais rau txhua cheeb tsam txheeb xyuas. BDNF qhia feem ntau tau txheeb xyuas hauv ipsilateral hippocampus thiab ipsilateral cortex, hauv 36

thiab 31 kev tshawb fawb, feem. Hauv 7 txoj kev tshawb fawb ipsilateral- thiab contralateral hippocampi tau ua ke rau kev kuaj biochemical thiab tau sau tias "ob tog HC".

Daim duab 2. Anatomical cheeb tsam raug tshuaj xyuas nyob rau hauv cov ntaub ntawv tshuaj xyuas.

3.3. Kev ntsuam xyuas ntawm BDNF Expression

Ob qho tib si mRNA thiab protein qhia ntawm BDNF raug soj ntsuam. Txoj hauv kev zoo tshaj plaws rau mRNA tsom xam yog nyob rau hauv situ hybridization thiab ntau npaum li cas tiag-lub sij hawm polymerase saw cov tshuaj tiv thaiv (qPCR). Rau BDNF protein quantification Western blot thiab enzyme-linked immunosorbent assay (ELISA) feem ntau siv (Table A2). Nyob rau hauv feem ntau ntawm cov ntaub ntawv tshuaj xyuas, BDNF protein qhia tsis tau qhia meej meej rau hauv mature-, pro- lossis preBDNF. Thaum tsis tau qhia lwm yam, peb xav tias txoj kev tshawb no hais txog tag nrho BDNF protein qhia. Tsis tas li ntawd, tshwj tsis yog tias muaj lwm yam tshwj xeeb, cov kev tshawb fawb tau tshuaj xyuas nas lossis nas cov ntaub so ntswg.

3.3.1. Hippocampus

BDNF mRNA qhia hauv ipsilateral hippocampus tau tshuaj xyuas ntawm 16 lub sijhawm sib txawv thiab BDNF protein qhia hauv ipsilateral hippocampus tau tshuaj xyuas ntawm 23-lub sijhawm cov ntsiab lus (2 h- 56 d) (Daim duab 3a). Peb ntawm cov kev tshawb fawb qhia tau nce BNDF mRNA qhia hauv thawj 1 mus rau 6 h tom qab raug mob [44,46,47], whereas ib qho qhia txog kev txo qis mRNA ntawm 20 h tom qab raug mob hauv ob pawg TBI thiab sham [45]. Ntawm tag nrho lwm cov ntsiab lus tom ntej, BDNF mRNA qhia nyob rau hauv ipsilateral hippocampus tau tshaj tawm tias yuav txo qis los yog tsis cuam tshuam piv rau tus sham (Daim duab 3a) [9,47–52]. Interestingly, BDNF protein qhia tsis tau qhia ib qho tseem ceeb nce kev qhia nyob rau hauv thawj hnub tom qab raug mob thiab pom tau txo los yog tsis hloov qhia nyob rau hauv lub lis piam tom ntej no (Daim duab 3b). Ib txoj kev tshawb fawb tau qhia txog qhov tsis muaj txiaj ntsig cuam tshuam rau cov sij hawm tom qab kev raug mob tab sis pom muaj protein ntau ntxiv ntawm 26 teev tom qab raug mob [46]. BDNF protein qhia nyob rau hauv ipsilateral hippocampus tau rov qhia dua tias tsis muaj qhov cuam tshuam los ntawm kev raug mob ntawm 5 h tom qab raug mob nrog rau 1, 7, 11, 15, 21, 26, thiab 37 DPI. Txawm li cas los xij, ntau qhov kev tshawb fawb tau qhia txog qhov txo qis ntawm cov protein ntawm 4, 7, 8, 10, 13, 14, thiab 28 DPI [53–69]. Cov ntaub ntawv qhia los ntawm txhua hnub feem ntau yog los ntawm ib qho kev kawm ib hnub, nrog rau yuav luag tsuas yog los ntawm CCI lossis FPI kev raug mob. Tsis muaj qhov sib txawv meej ntawm pawg neeg raug mob los ntawm cov ntaub ntawv muaj.

Daim duab 3. Txheej txheem cej luam ntawm lub sij hawm cov ntsiab lus nyob rau hauv uashlwb-derived neurotrophicfactor (BDNF) qhia tau tshuaj xyuas nyob rau hauv cov ntaub ntawv tshuaj xyuas, thiab seb TBI tseem ceeb nce, txo qis los yog tsis tseem ceeb hloov BDNF qhia piv rau sham-injured tsiaj. (a) BDNF mRNA qhia hauv ipsilateral hippocampus. (b) BDNF protein qhia nyob rau hauv ipsilateral hippocampus. (c) BDNF mRNA qhia nyob rau hauv contralateral hippocampus. (d) BDNF protein qhia nyob rau hauv contralateral hippocampus. (e) BDNF mRNA qhia hauv ipsilateral cortex (f) BDNF protein qhia nyob rau hauv ipsilateral cortex.

Hippocampus contralateral rau qhov raug mob raug soj ntsuam ntawm rau-lub sij hawm cov ntsiab lus rau BDNF mRNA qhia thiab peb rau BDNF protein qhia, xws li ntawm 1 h mus rau 56 hnub. Rostami thiab al. tshaj tawm tias BDNF mRNA qhia tau nce ntawm 1, 3, thiab 14 hnub tom qab raug mob nyob rau hauv contralateral hippocampus, tab sis tsis nyob rau hauv lub sij hawm ntev ntsuas ntawm 56 hnub tom qab raug mob [9]. Thawj hnub tom qab raug mob, Yang et al. qhia txog kev nce BDNF mRNA qhia ntawm 1, 3, thiab 5 h tom qab raug mob. Ob qhov kev tshawb fawb pom tias BDNF cov protein qhia tsis muaj qhov cuam tshuam los ntawm kev raug mob ntawm lub sijhawm 7, 21 [58], thiab 26 DPI [68].

3.3.2. Cortex

Lub ipsilateral cortex qhia cov qauv zoo sib xws ntawm kev qhia raws li ipsilateral hippocampus. Thaum thawj hnub tom qab raug mob, BDNF mRNA qhia tau tshwj xeeb tshaj tawm raws li nce [47,70]. Koob et al. qhia txog kev nce BDNF mRNA qhia siv rt-PCR ntawm 2, 6, thiab 24 teev tom qab raug mob, tab sis tsis muaj qhov hloov pauv tseem ceeb ntawm hnub 3 thiab 14 [71]. Raws li pom hauv daim duab 3e-f, qhov pib nce hauv ipsilateral BDNF mRNA tsis tau nrog rau qhov kev txiav txim siab nce ntxiv hauv BDNF protein qhia. Tsis tas li ntawd, plaub txoj kev tshawb fawb tau tshaj tawm tias BDNF cov protein qhia tau txo qis rau thawj hnub, thiab lwm yam txo qis los yog tsis hloov pauv los ntawm kev raug mob ntawm lub sijhawm cov ntsiab lus 4, 7, 8, 25, 28, 30, thiab 35 DPI [57,69,72– 87] ib. Cov kev zam yog Cekic li al. leej twg pom tias CCI ua rau muaj qhov nce hauv cov protein BDNF paub tab tom qab 24 teev thiab 7 hnub [88], nrog rau Nagatomo-Combs li al. leej twg soj ntsuam tus naj npawb ntawm BDNF-protein-expressing hlwb nyob rau hauv rhesus liab ntawm lub sij hawm ntev cov ntsiab lus tom qab raug mob thiab pom muaj ntau ntxiv ntawm BDNF-expressing hlwb ntawm 1, 6, thiab 12 lub hlis tom qab raug mob [89].

Ib zaug ntxiv, sab contralateral tsis zoo li tshuaj xyuas. Corne et al. tshuaj xyuas lub cortical mRNA-qhia nyob rau hauv contralateral parietal lobe ntawm 21 hnub tom qab raug mob thiab qhia txog qhov txo qis ntawm tag nrho cov BDNF exons hauv TBI pawg piv rau sham [90], thaum Yang li al. pom tsis muaj qhov hloov pauv tseem ceeb hauv BDNF mRNA tshwj xeeb hauv cov contralateral neocortex ntawm 1, 3, thiab 5 h tom qab lateral cortical cuam tshuam raug mob piv rau cov tsiaj raug mob sham [47].

Los txiav txim siab, ntau qhov kev tshawb fawb pom tias BDNF mRNA qhia tau nce hauv ipsilateral hippocampus thiab cortex hauv thawj 1-2 hnub tom qab raug mob thiab tias BDNF mRNA nce hauv contralateral hippocampus hnub 1-14 tom qab raug mob. Qhov kev nce hauv BDNF mRNA tsis yog nrog los ntawm kev nce ntxiv hauv BDNF protein nyob rau hauv ob qho tib si cortex lossis hippocampi, txawm li cas los xij, cov ntaub ntawv tseem tsis txaus los kos cov lus xaus.

cistanche stems

3.4. Kev Xeem Cwj Pwm

Ntau qhov kev tshawb fawb soj ntsuam kev sib raug zoo ntawm BDNF-kev nthuav qhia thiab TBI tau ua cov kev ntsuam xyuas tus cwj pwm los ntsuam xyuas cov txiaj ntsig kev ua haujlwm, raws li pom hauv daim duab 4. Hauv cov ntaub ntawv tshuaj xyuas, feem ntau txoj hauv kev ntawm kev ntsuas kev ua haujlwm yogNeurologicalSeverity Score (NSS), uas suav nrog kev sib xyaw ntawm lub cev muaj zog, kev hnov ​​​​lus, reflex, thiab ntsuas qhov sib npaug, nrog rau Morris Water Maze (MWM), ntsuas qhov chaw nco. Novel object recognition, tshuaj xyuas cov khoom tsis-spatial paub, rotarod, ntsuas qhov sib npaug thiab kev sib koom ua ke, Qhib teb kev sim, ntsuas tus cwj pwm coj tus cwj pwm thiab kev ntxhov siab, Elevated Plus Maze, ntsuas kev ntxhov siab ntau ntau thiab thaum kawg, Beam taug kev kuaj, uas tau siv rau hauv kev sib npaug, ntau tshaj 5 ntawm cov kev tshawb fawb soj ntsuam. Cov pab pawg hu ua "Lwm yam" suav nrog cov kev sim uas tsuas yog siv rau hauv ib txoj kev tshawb fawb, xws li kev sim sucrose noj, kev xeem viav vias, thiab tonic-clonic qaug dab peg. Cov lus piav qhia ze dua hais txog kev ntsuas tus cwj pwm yuav ua raws li hauv ntu tom ntej nrog rau hauv Table A1.

Daim duab 4. Kev ntsuam xyuas tus cwj pwm raug tshuaj xyuas nyob rau hauv cov ntaub ntawv tshuaj xyuas.

3.5. Kev kho mob ntawm TBI

Tag nrho ntawm 73 cov kev tshawb fawb tau siv ntau yam kev cuam tshuam los tshuaj xyuas lawv cov txiaj ntsig ntawm BDNF-

kev nthuav qhia thiab kev ua haujlwm tau zoo tom qab TBI, raws li pom hauv daim duab 5. Qhov kev soj ntsuam ntau tshaj plaws yog cov txiaj ntsig ntawm kev tawm dag zog thiab kev noj haus, ua raws li cov qia cell thiab gonado corticoid kho. Txhawm rau tshuaj xyuas txhua yam kev kho mob muaj nyob hauv kev puas tsuajhlwbKev raug mob yog dhau ntawm qhov kev tshuaj xyuas no, thiab peb tau tsom mus rau kev tshuaj xyuas kev tawm dag zog, noj zaub mov, thiab kev kho mob qia cell nrog rau kev cuam tshuam cuam tshuam rau txoj hauv kev hauv lub cev tom qab BDNF-receptor activation.

3.5.1. Kev tawm dag zog

Kev tawm dag zog ua ib txoj hauv kev kho mobhlwbkev raug mob raug tshuaj xyuas hauv 14 txoj kev tshawb fawb. Raws nraim li qhov kev tawm dag zog sib txawv ntawm cov kev tshawb fawb, tab sis txoj kev siv feem ntau yog lub log khiav. Qee qhov kev tshawb fawb sib txawv ntawm kev yeem thiab tsis muaj kev tawm dag zog, thiab qee cov ntawv tsis tau txhais kom meej tias hom kev tawm dag zog tau ua. Tawm ntawm cov 14, 11 cov kev tshawb fawb pom tau hais tias ob qho tib si ua ntej lossis tom qab kev tawm dag zog tau nce cerebral BDNF protein qhia nyob rau hauv ipsilateral thiab contralateral hippocampus nrog rau hauv ipsilateral cortex, piv rau cov tsiaj tsis siv [58,59,62– 64, 66–69, 71, 78, 91–93] ib. Ob txoj kev tshawb fawb pom tias BDNF kev qhia tsis tau hloov pauv qhov tseem ceeb hauv cov nas uas raug kev tawm dag zog tom qab cov dej percussion raug mob ntawm 7 lossis 11 hnub tom qab raug mob, raws li [63,78]. Thaum kawg, Wu et al. pom tias kev tawm dag zog ua ke nrog kev noj zaub mov zoo nrog docosahexaenoic acid, plasma membrane phospholipid, nce BDNF protein qhia piv rau cov tsiaj tsis muaj kev noj zaub mov zoo thiab cov tsiaj tsis muaj zog. Feem ntau ntawm cov kev tshawb fawb pom tau hais tias kev tawm dag zog kuj txhim kho kev ua haujlwm zoo tom qab raug mob. Ib txoj kev tshawb fawb tau siv lub tshuab hluav taws xob infrared-sensing khiav lub log thiab cob qhia cov nas rau peb hnub ua ntej kev phais thiab peb lub lis piam tom qab. Lawv pom tias qhov kev tawm dag zog tau txhim kho lub sij hawm luv luv-kev ntshai-ua rau muaj kev ntxhov siab thiab nco txog qhov chaw sim los ntawm kev xeem dhau kev zam thiab kev sim Y-Maze [69]. Tib txoj kev tshawb no kuj tau tshuaj xyuas HSP20 gene, ib tug gene qhia txog lub tshav kub poob siab protein 20 uas yog ib tug chaperone yav tas los paub hais tias yuav tsum tau qhia tom qab cov ntaub so ntswg kev nyuaj siab thiab yuav tiv thaiv xws li, Alzheimer's kab mob. Lawv pom tias kev ntsiag to ntawm HSP20 noob tau tso tseg qhov kev tawm dag zog ua kom muaj zog. Peb txoj kev tshawb fawb uas tau soj ntsuam kev tawm dag zog pom muaj kev sib raug zoo ntawm kev txhim kho BDNF cov protein qhia (thiab ib txoj kev tshawb nrhiav pom tias kev tawm dag zog BDNF mRNA qhia) thiab txhim kho kev txawj ntse hauv Morris Water Maze test [64,67,68,71]. Griesbach et al. tau pom tias cov nas siv zog ua tau zoo dua hauv Morris dej maze kuaj tom qab raug mob piv rau cov nas uas tsis tau tawm dag zog thiab cov nas raug mob uas tau txais cov tshuaj tiv thaiv TrkB-IgG tsis tau txais txiaj ntsig los ntawm kev tawm dag zog, ntxiv hais tias kev tawm dag zog ua rau nws muaj txiaj ntsig zoo los ntawm BDNF txoj hauv kev. [67].

Da Silva Fiorin et al. thiab Zhao et al. tsuas yog cov uas tau tshuaj xyuas qhov cuam tshuam ntawm kev tawm dag zog ua ntej. da Silva Fiorin et al. pom tias thaum FPI ib leeg tsis muaj qhov cuam tshuam rau BDNF cov protein qhia, yav dhau los kev tawm dag zog lub cev ua rau muaj kev nce hauv BDNF protein qhia hauv hippocampus ntawm 1 thiab 14 DPI. Zhao et al. pom tias khiav lub log ce rau 4 lub lis piam ua ntej kev raug mob nce BDNF mRNA qhia nyob rau hauv ipsilateral cortex ntawm ob qho tib si sham thiab raug mob tsiaj piv rau cov tsiaj tsis siv. Lawv kuj pom tau hais tias kev tawm dag zog ua ntej txhim kho lub cev muaj zog hauv kev sim taug kev thiab kev paub txog kev ua haujlwm hauv Morris dej maze thiab cov khoom tshiab paub txog cov khoom.

Griesbach et al, tau siv lub log ua haujlwm yeem thiab tshuaj xyuas cov txiaj ntsig ua haujlwm tom qab cov kua dej ntws tawm sab nraud thiab pom tsis muaj qhov cuam tshuam loj rau tag nrho lub cev muaj zog. Shen et al. tshuaj xyuas cov qauv kev cob qhia sib txawv thiab tshuaj xyuas cov txiaj ntsig kev ua haujlwm tom qab muaj kev cuam tshuam cortical hnyav thiab pom tias txawm tias tsis muaj qhov sib txawv ntawm cov pab pawg raug mob hauvNeurologicalCov qhab nia tsis txaus, cov tsiaj siv zog tsawg ua tau zoo dua hauv MWM piv rau kev tswj hwm thiab siv zog siv cov tsiaj. Griesbach et al. siv cov qauv kev raug mob rau sab nraud nrog kev yeem lub log tawm dag zog thiab pom tsis muaj qhov cuam tshuam tseem ceeb ntawm kev tawm dag zog ntawm BDNF qhia lossis qhov tshwm sim ntawm kev sim beam taug kev [59,68,78]. Hicks et al. pom tias cov dej percussion raug mob tseem ceeb txo qis hauv NSS thiab MWM, thiab qhov kev tawm dag zog tom qab tau nce BDNF protein qhia tab sis tsis muaj txiaj ntsig zoo rau NSS lossis MWM [92].

Pls nyem qhov no mus rau Ntu 2