Cov lus tawm tswv yim: Hauv cov qauv nas ntawm Parkinson, kev dhia ua kom ib ce muaj zog dopamine D2 receptors. Kev muaj yees ua rau muaj kev poob qis hauv D2 receptors uas yog ib nrab ntawm txoj kev desensitization. Lwm qhov laj thawj kom tawm dag zog.
Cov Kev Mob Teeb Meem
Volume 25, Issue 16, nplooj ntawv 2777-2784, 15 Hlis 2010
Abstract
Lub hom phiaj ntawm txoj kev tshawb nrhiav tam sim no yog los tshuaj xyuas cov kev hloov hauv dopamine D2 tus neeg tuaj yeem (DA-D2R) qhia hauv cov basal ganglia ntawm MPTP cov nas uas raug mus ua qhov kev ua si nruj heev. Siv Western immunoblotting tsom ntawm kev sibtham ua ke thiab nyob rau hauv vivo positron emission tomography (Tsiaj ntawv) duab uas siv cov DA-D2R meej ligand [18F] feldpride, peb pom hais tias kev siv zog ua haujlwm nce siab ua rau muaj kev nce ntxiv hauv DA-D2R qhia uas tau tshaj tawm hauv MPTP piv rau cov tshuaj tua tau tus nas. Kev hloov ntawm kev ua haujlwm hauv DA-D2R hauv dopamine-depleted basal ganglia yog ua raws li lub luag haujlwm ntawm tus neeg txais kev pabcuam no hauv kev hloov qhov nruab nrab cov kabmob nruab nrab ntawm cov kabmob (MSNs) thiab kev coj cwj pwm. Qhov tseem ceeb, cov kev tshawb pom los ntawm txoj kev tshawb no txhawb qhov kev xav kom siv cov PET kuaj nrog [18F] fallypride los kuaj xyuas DA-D2R cov kev hloov hauv cov neeg uas muaj tus kab mob Parkinson's Disease (PD) uas siv cov kev cob qhia uas muaj kev sib tw siv high-intensity.
Kev xyaum ua kom lub cev ua tau zoo dua hauv cov neeg mob nrog Parkinson's disease (PD).1-3 Tsiaj cov qauv, xws li 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nas, muab ib lub tswv yim tseem ceeb los tshuaj xyuas cov txheej txheem ntawm kev ua kom ib ce muaj zog ntawm kev coj tus cwj pwm.4-6 Dopamine D1 thiab D2 receptors (DA-D1R thiab DA-D2R) yog lub hom phiaj ntawm dopamine nyob rau nruab nrab nruab nrab cov kab mob qog hlwb (MSNs) thiab kho cov kev mob ntawm lub cev thiab cov cellular signaling. Tshwj xeeb, DA-D2R plays lub luag haujlwm loj hauv kev nyuab siab ntev (LTD), ib daim ntawv ntawm synaptic plasticity uas yog kev koom ua ke ntawm glutamatergic thiab dopaminergic neurotransmission ua rau lub coding ntawm lub cev muaj zog nyob hauv dorsolateral striatum. Muab lub luag haujlwm ntawm DA-D2R hauv kev tswj xyuas lub cev, peb tau kuaj xyuas seb puas yuav ua kom muaj kev txhim kho ntxiv hauv kev ua kom lub cev muaj zog rau ib feem ntawm kev nce qib hauv DA-D2R.
Positron emission tomography (PET) - Kev saib xyuas nrog DA-D2R radiotracers muaj peev xwm mus nqa cov kev tshawb fawb longitudinal rau cov nyom ib ce rau tib neeg. Yav dhau los cov kev tshawb fawb nrog aerobic ce tau sim los ntsuas dopamine tso rau hauv cov tib neeg7 thiab tsis muaj kev hloov hauv kev sib tw ntawm [11C] raclopride tau pom, ua rau tus sau phau ntawv qhia tias qhov kev hloov me ntsis hauv dopamine ntau ntau tshwm sim. Txawm li cas los xij, qhov kev qoj ib ce ntawm DA-D2R kev qhia thiab kev ua haujlwm tsis tau raug kawm. Kev sib tw PET-imaging ligand [18F] Fallypride yog ib qho cuab yeej zoo los mus tshuaj xyuas qhov no vim nws siab affinity thiab tseem ceeb rau ob leeg DA-D2R thiab DA-D3R, thiab tsis zoo li [11C] raclopride, nws tsis yooj yim nkag mus los ntawm theem pib ntawm dopamine endogenous.7-10 Qhov no tau pom zoo los ntawm reserpine pretreatment ntawm cov tsiaj (kom deplete endogenous dopamine) uas tsis ntxim rau [18F] Fallypride thaij,9,11 tab sis significantly nce [11C] raclopride losis tswvyim dabtsi8 uas yog ntaus nqi mus rau qhov kev hloov hauv qhov pom tseeb affinity (Kd) ntau dua li tus nab npawb reseptor (Bmax).
Raws li kev sib koom tes (BP) ntawm [18F] Fallpride tiv taus cov kev hloov vim kev poob ntawm dopamine, tawm tswv yim me ntsis rau nws Kd or Bmax ntawm lub hauv paus los yog lub xeev raug, peb siv [18F] fallypride los ntsuas peb qhov kev xav tias DA-D2R qhia tsub kom nyob hauv MPTP mouse qauv nrog kev qoj ib ce.9,10,12,13 Tsis tas li ntawd, los txhawb peb tus PET ntsuas kev ntsuas, peb siv cov txheej txheem txuas ntxiv ntawm cov tshuaj tiv thaiv kab mob ntsws ntawm cov tshuaj tiv thaiv kab mob hauv cov tshuaj tiv thaiv cov tshuaj tiv thaiv kabmob ntsig txog kev hloov hauv DA-D2R protein nyob rau theem ntawm kev ua rau tib tsiaj. Peb qhia ntawm no cov teebmeem ntawm kev ua haujlwm ntawm DA-D2R kev qhia thiab [18F] fallypride nyob rau hauv ib pawg ntawm cov nas tau kho nrog saline los yog MPTP.
METHODS
Cov Tsiaj Txhu, Cov Pab Kho Mob, thiab MPTP Tsav Xwm
Txiv neej C57BL / 6 cov nas 8 lub lis piam (Charles River Laboratories, Wilmington, MA) yog pawg neeg nyob hauv qhov chaw tswj qhov ntsuas kub hauv 12 h light / 12 h dark circles. Tag nrho cov txheej txheem tau ua tiav raws li NIH Phau Ntawv Qhia rau Kev Tu Neeg Mob thiab Kev Siv Cov Kuaj Zis tsiaj raws li kev pom zoo los ntawm USC IACUC. 164 cov nas tsuag tau siv hauv plaub hom kev kho mob: 1 ntsev dej (n = 42), (2) saline ntxiv rau qoj ib ce (n = 55), (3) MPTP (n = 57), thiab (4) MPTP ntxiv ce (n = 42). Rau cov nqaij ntuag, cov nas tsuag tau txais plaub zaug ntawm cov tshuaj 20 mg / kg MPTP (dawb-puag; Sigma-Aldrich, St. Louis, MO) yaj hauv xNUMX% saline, ntawm 0.9-h sib nrug lossis plaub intraperitoneal los ntawm 2 ml 0.1% NaCl raws li kev tswj. Lesioning tau tso cai los ntawm HPLC tsom ntawm cov qib dopamine. Tom 0.9 hnub tom qab MPTP cov neeg khiav dej num, muaj 10% dopamine depletion hauv MPTP cov nas tsuag (82.2 ± 48.0 ng / mg ntawm protein) piv rau cov nas tsuag (8.4 ± 269.5 ng / mg ntawm cov protein). Qhov kawg ntawm txoj kev tshawb no, tsis muaj qhov txawv txav ntawm cov qib dopamine ntawm MPTP ntxiv cov nas tsuag (24.9 ± 69.8 ng / mg ntawm protein) piv rau MPTP (11.7 ± 77.9 ng / mg ntawm cov protein). Txawm li cas los xij, muaj cov kab mob ntsev ntxiv hauv cov roj ntsha ntxiv nrog rau 12.0 ± 315.2 ng / mg ntawm cov protein ntau nrog cov kua ntsev (9.0 ± 246.9 ng / mg ntawm protein)F(3,16) = 7.78; P <0.05).
Treadmill Exercise
Kev xyaum pib 5 hnub tom qab lesioning. Mice los ntawm ob pawg exercise (saline plus exercise thiab MPTP ntxiv rau kev ua si) raug cob qhia khiav tawm ntawm 100-cm motorized treadmill (Exer 6M, Columbus Instruments, OH) ntawm cov xaum xaum (6 hnub / vas thiv) kom ncav sijhawm ntawm 5 min / hnub thiab kev ceev ntawm 60-18 m / min.5,6
Sib Nqus Resonance Imaging
Lub plab volumetric T1-weighted magnetic resonance (MR) duab ntawm lub hlwb tau txais nrog 7-T micro-MRI (Bruker Biospin, Billerica, MA). Parameters ntawm cov duab duab tau: TE = 46.1 ms, TR = 6292.5 ms, 0.4-mm nplua tuab, 0.45-hli interslice thickness, 128 × 128 × 128 matrix loj.
Xov tooj cua
Synthesis ntawm [18F] fallypride tau ua raws li yav tas los tau piav qhia los ntawm kev sib hloov nucleophilic hloov ntawm cov tosyl precursor nrog [18F] siv ib lub xov tooj cua uas tsim tawm.12 Purification tau tiav los ntawm thim rov qab HPLC ntawm C8 (2) Phenomenex Luna column siv acetonitrile thiab sodium phosphate tsis raws mobile theem (55: 45). UV absorbance yog ntsuas ntawm 254 nm thiab AUFS 0.05. Xov tooj cua peak (retention time 17 min) sib thooj li [18F] Fallypride, tau sau thiab hnoos tawm ntawm cov evaporator teb. Qhov khoom kawg tau raug kuaj rau pyrogenicity, sterility, pH, thiab tshem tawm cov organic solvents los ntawm roj chromatography. Kev ua haujlwm tshwj xeeb thiab cov pchoschemical purity raug soj ntsuam nrog lub tshuab ntxuav HPLC uas siv lub C8 (2) Phenomenex Luna analytical. Kev ua si tshwj xeeb yog nyob rau hauv qhov ntau ntawm 3,000-12,000 Ci / mmol.
Kev ntsuas tus tsiaj thiab kev sojntsuam duab
(N = 6 saline; n = 3 saline ntxiv rau qoj ib ce; n = 5 MPTP; thiab n = 6 MPTP ntxiv zog). Scans tau nrhiav tau nrog lub Concorde microPET R4 scanner (CTI Concorde Microsystems, Knoxville, TN) nrog 60-min daim ntawv sau kis tau tus kabmob tom qab 20-min kis kab mob rau kev tuaj yeem kho 68D qhov chaw. [18F] feldpride (10.92-11.28 MBq) tau txhaj ntawm lub cev ntiv nplhaib (ib qho bolus) thaum pib ntawm lub tso tawm scans. Cov nas muaj tshuaj anesthetized nrog 2% isofluorane thiab 98% oxygen. Cov ntaub ntawv teev npe ntawm cov ntaub ntawv tau raug xa mus rau cov teeb meem ntawm xNUMX (26 × 6 sec, 20 × 4 sec, 40 × 6 min, thiab 1 × 10 min) thiab reconstructed los ntawm ob iterations ntawm OSEM (yuam subsets expectation maximization) raws li 5 iterations ntawm daim ntawv (cov nyiaj pab ntau tshaj ib qho posteriori) kev tsim kho kev pom dua algorithm.14 Cov duab tau ntxig tau ntxig rau lub taub hau thiab tawm hauv lub cev Z-qhov kev tsim tawm ib 128 × 128 × 63 duab nrog isotropic 0.4 × 0.4 × 0.4 mm3 voxels. High-resolution losis tswvyim dabtsi (BP) cov dluab ntawm cov striatum raug xam los ntawm cov txheej txheem dynamic reconstructed siv tus qauv siv ntau hom nqaij tawv nqaij15 thiab Logan plots16 nrog rau siab ua si nyob rau hauv lub striatum thiab ua tsawg heev nyob rau hauv lub cerebellum (reference cheeb tsam). Anatomical thaj tsam ntawm kev txaus siab (striatum thiab cerebellum) tau txhais hais tias nyob hauv ob qho tib si hemispheres hauv cov tsiaj ntawv muaj coregistered nrog MRI siv Rview (version 8.21Beta).17 Quantification ntawm kev cog lus ntawm [18F] fallypride nyob rau hauv tus nas striatum tau siv BP tus nqi uas muab ib qho kev ntsuas ntawm qhov kev sib qog ntawm qhov meej / tsis sib haum xeeb ntawm kev sib npaug.18,19 Yuav ua kom pom tseeb tshwj xeeb hauv qhov tseeb, plaub nas tau raug tua 60 min tom qab ligand txhaj tshuaj, plaw sai sai khov hauv cov kua nitrogen, seem ntawm 30-μm thickness, thiab cov ntawv xa rau phospho-imager (Typhoon 9200, GE Healthcare Inc., Piscataway , NJ) (Daim duab. 1). Cov kev tshawb fawb pom tau tias [18F] fallypride khi rau DA-D2R, thiab yog tsawg heev DA-D3R yog nyob rau hauv cov lus qhuab qhia, thwj toob txhais DA-D2R nyob hauv.9,10,12,13
Daim Ntawv Teev Tseg rau HPLC thiab Cov Khoom Siv Tshuaj
Qhov kawg ntawm txoj kev tshawb no, plaw tau sai tshem tawm thiab dorsal striatum thaij tshiab coj los siv rau thaj tsam ntawm 1.2 rau 0.6 nrog lub corpus callosum li dorsal ciam teb, rau ib sab ntawm lub corpus callosum li lateral ciam, thiab sab saum toj ntawm cov neeg sab nrauv lub ventral ciam teb.20
HPLC kev soj ntsuam ntawm Dopamine thiab nws cov Metabolites
Dopamine qib nyob rau hauv homogenates striatal (n = 4 ib pawg) tau txiav txim los ntawm HPLC nrog electrochemical nrhiav kom tau.6 Cov txheej txheem ntawm ESA pib-sampler (ESA, Chelmsford, MA) muaj xws li 150 × 3.2 mm rov qab theem C-18 sab (3mm diameter) thiab CoulArray 5600A (ESA, Chelmsford, MA), muaj ib qho plaub -channel analytical cell nrog potentials teem ntawm -75, 50, 220, thiab 350 mV.
Western Immunoblot Analysis
Kev siv dag zog rau ntawm kev qhia tawm ntawm DA-D1R thiab DA-D2R tau soj ntsuam hauv kev npaj ua tiav hauv kev sib tw ua ke ntawm cov kev ua si ntawm dorsolateral striatum.21 Cov txheej txheem no tau ua rau ntawm peb cov nas tsuag rau tag nrho cov 24 nas ib pab pawg kws kho mob (n = 3 preps ib pawg). Tus txheeb ze cov proteins rau DA-D1R (~ 50 kDa), DA-D2R (~ 50 kDa), tyrosine hydroxylase (58 kDa), dopamine transporter (68 kDa), thiab α-tubulin (50 kDa) (raws li kev tswj kev tswj) tau soj ntsuam los ntawm Western immunoblot22 siv cov tshuaj tua tau cov tshuaj tua kabmob (luav polyclonal thiab mouse monoclonal antibodies, Millipore, Temecula, CA). Protein bands tau pom tau los ntawm affinity lim tshis los tiv thaiv kab tshoob los yog anti-nas siab antibodies conjugated rau IRDye680 lossis IRDye800 (Rockland, Gilbertsville, PA). Fluorescent teeb liab tau pom los ntawm kev xa cov lim hauv LI-COR Odyssey ze qhov chaw nruab nrab ntawm infrared thiab ntau yam siv Odyssey 2.1 software (LI-COR Biotechnology, Lincoln, NE). Cov txiaj ntsig tau qhia tau tias muaj kev qhia txog kev sib piv nrog cov pab pawg neeg ntsev (teev rau 100%).
statistical Analysis
Sib txawv ntawm cov pawg hauv BP [18F] Fallpride, DA-D1R, thiab DA-D2R protein ntau qhov kev ntsuam xyuas tau siv ob txoj kev ntsuas ntawm variance (ANOVA) nrog kev kho mob sib txawv (saline vs. MPTP), thiab ua kom ib ce muaj li hauv qhov kev muaj feem cuam tshuam (tsis qoj ib ce thiab lwm yam) ce). Rau qhov kev xeem ceev ceev, qhov sij hawm tau siv los ntawm qhov kev sib tw (lub lis piam 1, 2, thiab lwm yam) thiab kev kho tau siv rau hauv qhov kev kawm (saline vs. MPTP). Txoj kev xeem ntawm Bonferroni yog siv los kho qhov sib txawv ntawm kev sib piv thaum thom nug qhov tseem ceeb ntawm kev txaus siab. Qhov theem tseem ceeb tau teem tseg P <0.05. Txhawm rau tshawb xyuas qhov tseem ceeb ntawm cov pab pawg sib txawv, kev kwv yees ntawm qhov ntau ntawm qhov sib txawv ntawm cov pab pawg tau suav los ntawm kev siv cov txiaj ntsig loj (ES) (ES = Qhov tseem ceebPawg 1 - txhais tau tiasPawg 2/ SDpooled)). Lub ES cuam tshuam txog kev cuam tshuam ntawm kev kho mob nyob rau hauv cov pejxeem ntawm kev txaus siab thiab raug tshaj tawm raws li cov qauv tsim muaj tsawg (<0.41), nruab nrab (0.41–0.70), lossis loj (> 0.70).23 Kev sojntsuam tau siv Prism5 rau Windows (GraphPad, San Diego, CA).
KEV SIV
High-Intensity Treadmill Exercise Improved Motor Behavior nyob rau hauv MPTP-Lesioned Mice
Ua ntej MPTP-lesioning thiab pib kev qoj ib ce, nruab nrab baseline velocities ntawm tag nrho cov nas nyob hauv ob pawg neeg ib ce muaj ntsis zoo sib xws (saline plus ce: 11.7 ± 1.1 m / min, thiab MPTP ntxiv rau kev ua si: 11.2 ± 1.1 m / min). Txhua lub sijhawm ua haujlwm rau 6 lub lis piam txhim kho cov kabmob uas muaj xoos tshaj plaws nyob rau hauv ob pawg neeg ua si nrog saline ntxiv rau cov nas tsuag tso tawm ntau tshaj qhov ua kom tiav MPTP ntxiv exercise nas nyob rau lub lim tiam 1 mus txog 4 (Daim duab. 2). Txawm li cas los xij, MPTP ntxiv exercise cov nas muaj ntsis zoo li cov maximal treadmill speeds xws li cov roj ntsha ntxiv rau hauv lub lim tiam 5 (MPTP plus exercise: 17.2 ± 3.6 m / min thiab saline ntxiv rau ce: 22.0 ± 1.5 m / min) thiab lub lim tiam 6 (19.2 ± 1.2 m / min thiab 22.2 ± 0.9 m / min, feem). Raws li yav tas los qhia, MPTP-lesioned nas uas tsis nyob hauv kev cob qhia kev qhia tsis pom kev tsis muaj kev mob rov qab ntawm tus cwj pwm tsav nrog lawv qhov tshaj tawm ntawm 7.0 ± 0.3 m / min tom kawg ntawm lub sij hawm 6 lub lim tiam.5
Kev Tiv Thaiv Ib Nrab Tawm Ntau Zuj Zus Ntxiv Striatal DA-D2R tab sis tsis DA-D1R Protein
Siv high-treadmill qoj ib ce sib txawv los cuam tshuam DA-D2R thiab DA-D1R theem hauv kev npaj cov tshuaj tiv thaiv los ntawm dorsal striatum raws li pom los ntawm Western blot analysis (Daim duab. 3). MPTP ntxiv exercise cov nas muaj 48.8% nce hauv striatal DA-D2R piv nrog MPTP nas (Daim duab 3B), thiab kev sib cuam tshuam loj ntawm kev qoj ib ce thiab MPTP qhov hnyav ntawm DA-D2R protein theem (F(1,8) = 6.0; P <0.05). Hloov siab, tsis muaj kev tawm dag zog rau DA-D1R qib protein ntau ntawm cov pawg (Daim duab 3A; F(1,8) = 0.1, P = 0.78). MPTP qhov teeb meem tsis muaj kev hloov tsis tau los ntawm DA-D2R (F(1,8) = 0.0; P = 0.88) los yog DA-D1R qhia (F(1,8) = 0.0; P = 0.92). Tsis tas li, ob hom protein ntau ntawm midbrain dopaminergic fibrable integrity, tyrosine hydroxylase (TH; Daim duab 3C) thiab dopamine transporter (DAT; Daim duab 3D), pom tau hais tias MPTP qhov hnyuv qis heev TS (F(1,8) = 757.3; P <0.05) thiab DAT qhia (F(1,8) = 218.0; P <0.05).
High-Intensity Treadmill ce muaj zog ntau zog Striatal [18F] Fallypride Binding Potential (BP)
Thaum lub sijhawm immunoblotting thaj ntawm cov roj ntsha kev ntsuas tau ntsuas tag nrho cov tshuaj antibody epitopes (cov khw muag zaub thiab lub khw muag khoom), nyob rau hauv vivo Tus tsiaj-pom nrog high-affinity DA-D2R hom radioligand [18F] Fallypride tuaj yeem xyuas txog cov teebmeem ntawm kev qoj ib ce rau ntawm DA-D2R kom khi ligand (Daim duab. 4). Cov kev tshawb fawb tau tshwm sim qhia tias muaj ib qho tseem ceeb ntawm kev qoj ib ce (F(1,16) = 12.3; P <0.05) as well as MPTP lesion (F(1,16) = 160.3; P <0.05) uas tsis muaj kev cuam tshuam tseem ceeb ntawm MPTP thiab kev tawm dag zog (F(1,16) = 3.5; P = 0.07) rau [18F] Fallypride BP. Tus nais khus Bonferroni hoc tsom pom qhov sib txawv ntawm BP qhov tseem ceeb ntawm MPTP thiab MPTP ntxiv rau cov nas (t = 1.1, DF = 1, 16; P <0.01), thiab tsis muaj qhov sib txawv ntawm saline thiab saline ntxiv rau kev qoj ib ce nas (t = 4.1, Df = 1, 16; P > 0.05). Tshwj xeeb, MPTP ntxiv rau kev qoj ib ce nas tau nce 73.1% hauv [18F] festpride BP piv rau MPTP nas (piv txwv BP qhov tseem ceeb rau MPTP plus exercise: 7.1 ± 0.7; nruab nrab BP qhov tseem ceeb rau MPTP nas: 4.1 ± 0.3) (Daim duab 4B). Tsis tas li ntawd, saline ntxiv rau cov nas muaj zog muaj 8.2% nce rau [18F] fespride BP (13.2 ± 1.0) piv rau cov ntses dej qab zib (12.2 ± 0.3). Txaus siab rau cov kev tshawb pom "cov nyhuv loj" cov lus teb tau pom cov nyhuv loj ntawm MPTP tej pawg (ES = 2.61) dua li kev pom ntawm cov pab pawg neeg ntsev (ES = 0.94).
SIB THAM
Txoj kev tshawb no pom tau hais tias qhov kev siv qoj siab siv zog ua rau kev nce qib hauv [18F] Fallypride BP (DA-D2R txaus) nyob rau hauv cov striatum ntawm MPTP kho nas. Conversely, muaj tsis muaj qhov hloov loj hauv tag nrho striatal dopamine theem ntawm MPTP ntxiv zog nrog piv nrog MPTP tsis muaj cov nas nas. [18F] Fallpride yog ib qho Xaiv D-D2 / D3R antagonist heev uas BP qhia ib qho nyob rau hauv vivo ntsuas cov neeg muaj cuab kavBmax) / binding affinity (Kd). Raws li DA-D2Rs yog dopamine receptor subtype li ntawm dorsal striatum, ib ce ua rau nce qib [18F] Fallypride BP sawv cev rau kev nce hauv DA-D2R tus naj npawb thiab tau txais kev txhawb los ntawm kev nce hauv protein qhia siv Western tiv thaiv kab mob thiab peb cov kev tshawb xyuas yav dhau los uas qhia nce ntxiv hauv DA-D2R mRNA transcript qhia siv hauv situ hybridization histochemistry.5 Qhov kev txhais ntawm BP nce siab no txhawb ntxiv los ntawm qhov tseeb tias tawm ntawm [18F] Fallpride los ntawm dopamine yuav tsis tshwm sim nyob rau hauv MPTP cov nas li dopamine qib nyob qis qis.24 Li no, cov kev hloov pauv ntawm affinity (Kd) yog negligible thiab tsis zoo rau kev mob BP. Cov kev ua kom muaj zog hauv MPTP hauv kev pom muaj zog tuaj yeem cuam tshuam kev sim ntawm lub paj hlwb kom optimize dopaminergic neurotransmission los ntawm kev nce tus naj npawb reseptor thaum lub sij hawm dopamine nyob twj ywm. Ua kom muaj peev xwm ua kom MPTP cov nas muaj zog los qhia tias muaj kev raug mob ntawm qhov raug mob ntawm lub hlwb kom ua rau lub cev tsis muaj zog, uas tej zaum yuav tsis yog qhov tseem ceeb thaum muaj tus kabmob ntsig tsis muaj zog. Qhov tseeb tias dopamine qib tsis pauv ho nrog qoj ib ce hauv MPTP nas pom tias cov kev hloov hauv kev hloov hauv DA-D2R yog qhov tseem ceeb rau kev ua kom paub txog kev ua haujlwm zoo dua qub.
Siv cov duab PET, peb tau pom tias muaj kev txo qis hauv DA-D2R BP tom qab MPTP lesioning txheeb ze cov nas tsuag-kho. Qhov no yog qhov sib txawv rau Western immunoblotting uas tsis muaj kev hloov hauv DA-D2R protein qhia tau pom. DA-D2R tshwm sim nyob rau hauv ib qho kev sib npaug ntawm qhov nruab nrab ntawm sab nrauv thiab intracellular, nrog rau cov tom kawg tsis muaj feem xyuam rau kev tiv thaiv kab npuas hlau. Hauv xeev dopamine-depleted, mechanisms compensatory yuav ua rau cov kev hloov hauv lub pas dej ua ke rau DA-D2R, uas yuav tsis muaj rau [18F] Fallypride los tiv thaiv, tab sis tseem muaj nyob rau hauv kev pom nyob rau hauv Western immunoblotting.
Tsis zoo li peb cov kev pom zoo, qhov kev nce rau hauv DA-D2R tau raug tshaj qhia rau cov neeg uas muaj PD thiab tom qab kev tswj hwm ntawm MPTP hauv cov neeg tsis muaj kev ntseeg, lossis 6-OHDA hauv cov nas tsuag.25 Hauv cov ntawv nyeem, poob DA-D2Rs vim yog qhov degeneration ntawm dopaminergic neurons, qhov nce ntawm DA-D2Rs tau los ntawm kev nce ntxiv rau cov seem uas yog cov dopaminergic terminals thiab / los yog cov khoom sib ntxiv hauv cov striatopallidal neurons lossis cholinergic interneurons. Qhov tsis sib haum ntawm peb txoj kev tshawb fawb PET, thiab cov ntaub ntawv ntawm cov ntaub ntawv, yuav yog vim muaj qhov sib txawv ntawm qhov teebmeem ntawm qhov kev tshawb fawb.11 Tshwj xeeb, poob ntawm ntau dua ntawm cov txheej txheem DAIM D2Rs los ntawm MPTP vim raug mob tsis txaus yuav offset txhua qhov kev hloov ntawm cov kev hloov los ntawm qhov tawm ntawm qhov chaw xeeb tub ib leeg. Xwb, peb tsis muaj peev xwm soj ntsuam qhov nce hauv DA-D2R BP thiab qhia ntau ntau hauv MPTP (tsis yog-ce) cov nas yuav yog vim muaj kev mob rov qab ntawm dopamine qib tom kawg ntawm txoj kev tshawb no (82% dopamine depletion tom 10 hnub tiv thaiv 68 % kev poob haujlwm ntawm 42 hnub postlesion). Txawm li cas los xij, qhov no tsis zoo li MPTP ntxiv rau cov nas, uas pom tau tias me me rov qab los ntawm dopamine (tsis txawv los ntawm MPTP tsis muaj cov nas tsuag) muaj nce DA-D2R BP.
Feem ntau ntawm DA-D1Rs thiab D2Rs tau hais txog dendritic spines ntawm MSNs nrog ntau tus neeg tawm tsam hais txog cholinergic interneurons thiab terminals ntawm glutamatergic thiab dopaminergic neurons uas yog los ntawm cortex (los yog thalamus) thiab cov thev nigra pars compacta.26 Lub luag hauj lwm loj ntawm dopamine yog hloov kho corticostriatal los sis thalamostriatal glutamatergic neurotransmission ntawm MSN. Glutamateric neurotransmission yog kho los ntawm DA-D1Rs thiab diminished ntawm DA-D2Rs.27-29 Nyob rau hauv kev mob ntawm dopamine depletion, spines thiab synaptic sib txuas yog xaiv poob rau DA-D2R uas muaj MSNs ntawm txoj kev tsis ncaj.30 Qhov kev poob qis no yog nrog lub xeev cov kev mob hyperexcitability hauv MSNs vim muaj kab mob glutamatergic corticostriatal neurotransmission.31-33 Hauv cov qauv tsiaj ntawm PD, qhov no nce glutamatergic tsav nrog cov cwj pwm parkinsonian-xws li kev coj cwj pwm.34 Txoj kev qaug zog ntawm lub xeev no yog siv los ntawm kev siv dopamine los yog nws cov agonists ua rau kev hloov ntawm qhov chaw nres tsheb ntawm motorinsonian deficits.35,36 Nyob rau hauv lub teeb ntawm cov ntawv tshaj tawm no thiab peb cov kev tshawb pom, peb xav tias cov txiaj ntsim ntawm kev siv zog siv yog los txhawb kev dopaminergic signaling los ntawm kev nce DA-D2R kev qhia nyob rau hauv txoj kev ncaj (tab sis tsis yog DA-D1R ncaj qha) hluav cov glutamatergic excitability.
Thawj qhov xaus ntawm peb txoj kev tshawb xyuas yog tias kev siv dag zog ua rau kev ua kom muaj kev sib tw ceev nrooj los pab txhawb kom muaj tus cwj pwm ntawm DAI-D2Rs, tus txheej txheem feem ntau tshwm sim hauv lub hlwb raug mob. Raws li peb cov kev tshawb pom, ib qho kev tsis sib txuas nrog PET-imaging nrog [18F] yuav siv tau los tshawb xyuas seb qhov kev siv zog ntau npaum li cas yog ua rau kev hloov hauv DA-D2R rau cov tib neeg nrog PD. Peb txoj kev tshawb no qhia txog tus nqi ntawm cov kev tshawb fawb ntawm kev tshawb fawb ntawm cov qauv tsiaj txhu thiab kev tseem ceeb ntawm qhov kev tshawb nrhiav kev txhais lus rau kev muab ob qho tib si lub tswv yim thiab kev pom zoo los nkag siab txog kev nkag siab thiab kev qoj ib ce ntawm cov tib neeg nrog PD.
ACKNOWLEDGMENTS
Kev ua haujlwm no tau txais kev txhawb los ntawm kev pab los ntawm USC CTSI Daim Npav Tiav Nyiaj Txiag, thiab cov nyiaj ntau ntawm Parkinson's Disease Foundation, Pab Parkinson (Los Angeles), Parkinson Alliance, Whittier Parkinson's Disease Training Group, NINDS RO1 NS44327-1, NIA ( AG 21937) thiab US Army NETRP W81XWH-04-1-0444. MGV yog tus neeg tau txais kev pabcuam ntawm USC Neuroscience Graduate Program Merit Fellowship. Peb xav ua tsaug rau Ryan Park thiab Dr. Peter Conti los ntawm USC Me Me Cov Zaub Tsuag Tub Ntxhais rau kev pabcuam nrog micro-PET imaging thiab Dr. Rex Moats los ntawm Tsiaj Me Tsiaj Pom Kev Tshawb Fawb Hom Kev Tshawb Fawb ntawm Saban Research Institute pabcuam nrog tus nas MRI. Peb xav ua tsaug Yi-Hsuan (Lilian) Lai rau kev pabcuam nrog kev ua exercise, thiab Avery Abernathy rau nws qhov kev txawj ntse hauv HPLC tsom xam. Peb ua tsaug rau cov phooj ywg ntawm USC Parkinson's Disease Research Group nrog George thiab MaryLou Boone, Walter thiab Susan Doniger, thiab Roberto Gonzales rau lawv cov kev pabcuam siab.
Tshooj ntawv
Tej zaum muaj kev tsis sib haum xeeb: Tsis muaj dab tsi qhia.
Lus cim ntxiv hauv cov pov thawj: Tsab ntawv no tau luam tawm online ntawm 19 lub kaum hli ntuj 2010. Ib qho yuam kev ntawd tom qab nrhiav tau. Daim ntawv ceeb toom no muaj nyob rau hauv online thiab luam versions los qhia tias ob leeg tau raug kho lawm.
Qhia tawm nyiaj txiag: USC Kev Kawm Ua Haujlwm Kev Kawm Txuj Ci Kev Kawm Ua Haujlwm (MV), NINDS RO1 NS44327-1 (MV, CW, JW, MJ thiab GP), USC CTSI Puv Kev Pab Nyiaj Txiag (QL, IB, MJ, GP).
Sau Tus cwj pwm: Txhua tus sau phau ntawv tau ua paj lug nyob rau hauv kev tsim cov ntawv no. Kev Tshawb Fawb Txog Kev Tawm Tswv Yim Project: GP, BF, MJ, RL, JW. Tawm ntawm qhov Project: MV, QL, IB, CW, MJ, GP. Kev Sau, Kev Ua, Kev Txheeb Xyuas Teeb Meem: MV, QL, BF, IB, RL, MJ, GP. Kev Npaj Manuscript: MV, QL, BF, RL, JW, MJ, GP.
References
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