Jimicsi kor u qaadista dopamine D2 ee qaabka jiirka ee cudurka Parkinsons In vivo sawirka (18F) falepride (2010)

Faallooyin: Qaabka jiirka ee cudurka Parkinson, jimicsiga treadmill wuxuu kordhiyay daawadayaasha dopamine D2. Maandooriyeyaashu waxay sababaan hoos u dhac ku yimaada soo-dhoweynta D2 taas oo qayb ahaan sabab u ah miyir beelid. Sabab kale oo loo jimicsado.

Xanuunka Movement

Volume 25, Issue 16, boggaga 2777-2784, 15 December 2010

Nooca ugu dambeeya ee daabacan daabacaha qoraalkan ayaa laga heli karaa at Nidaamka Nafaqada
Eeg qoraalada kale ee PMC in culayskan maqaalkii la daabacay.

aan la taaban karin

Ulajeedada daraasaddan hadda waxay ahayd in la baaro isbeddelka dopamine D2 (DA-D2R) ee ku jira ganglia basal ee jiirka yar ee MPTP oo lagu daboolay jimicsi xoogan ee treadmill. Isticmaalidda falanqaynta tallaalka galmada ee galmada ee synaptoneurosomes iyo in vivo sawirka sawir-shaxanka (PET) sawir-qaadista ee DA-D2R gaar ah [18F] falepride, waxaan ogaanay in jimicsiga treadmill ee xooggan uu horseeday korodhka xayeysiiska DA-D2R ee ugu caansan MPTP marka la barbardhigo jadeecada loo yaqaan "saline". Isbeddellada jimicsiga ee ku yimaada DA-D2R ee ganglia-ku-dopamine-ka ah ayaa waxay la socotaa doorka suurtagalka ah ee aqbalaadkan si loo xakameeyo hawlaha maskaxda ee dhexdhexaadka ah (MSNs) iyo soo kabashada dhaqanka. Muhiimadda, helitaanka daraasaddan waxay taageertaa himilada loogu talagalay isticmaalka PET sawirada [18F] fespride si loo eego isbeddelada DA-D2R ee shakhsiyaadka qaba cudurka 'Parkinson's Disease' (PD) oo tababbaraya treadmill High-intensity.

Keywords: shaxanka positron emission, ganglia basal, neuroplasticity, jimicsiga treadmill

Jimicsigu wuxuu hagaajiyaa waxqabadka gawaarida ee bukaanada qaba cudurka Parkinson (PD).1-3 Moodooyinka xayawaanka ah, sida 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mareegta, waxay bixisaa qalab muhiim ah oo lagu baadho hababka molecular ee horumarinta jimicsiga-korodhka dabeecadda mootada.4-6 Dopamin D1 iyo D2 reseptors (DA-D1R iyo DA-D2R) ayaa ah bartilmaameedyada ugu muhiimsan ee dopamine ee dhexdhexaadinta nuucyada dhexdhexaadka ah (MSNs) oo u bedelaya guryaha nafaqada iyo taleefanka gacanta. Gaar ahaan, DA-D2R ayaa kaalin weyn ka qaadata niyadjabka muddada dheer (LTD), oo ah nooc ka mid ah baaxadda synaptic ee ku lug leh isdhexgalka glutamatergic iyo dopaminergic neurotransmission taasoo keentay in cod-bixinta hawshu ku socoto qaylo-dhaan-wadareed. Iyadoo la eegayo kaalinta DA-D2R ee xakameynta mootada, waxaanu raadinay in la eego in jimicsiga kor u qaadey kor u qaadista shaqada mashiinka ay qayb ka tahay korodhka xayiraadda DA-D2R.

Baadhitaanka xasaasiyadda Positron (PET) -marka la dhigo DA-D2R radotracers wuxuu awood u leeyahay inuu sameeyo daraasad dheer oo ku saabsan saamaynta jimicsiga ee aadanaha. Daraasado hore oo lagu sameeyay jimicsiga aerobic ayaa isku dayey in ay cabbiraan dopamine ee shakhsiyaadka caadiga ah7 oo aan beddelmin,11C] raclopride ayaa la arkay, taasoo keentay in qorayaasha ay soo jeediyaan in isbedel yar ee heerarka dopamin uu dhacay. Si kastaba ha ahaatee, saameynta jimicsiga ee ku saabsan bandhigga DA-D2R iyo hawlaha qalabixinta looma baarin. Natiijada PET-sawirada [18F] falepride waa qalab aad u fiican oo lagu baadho tan iyadoo ay ugu wacan tahay jacaylkiisa iyo qaas ahaanba labadaba DA-D2R iyo DA-D3R, oo ka duwan [11C] raclopride, ma aha mid si fudud loo barokiciyay heerarka aasaasiga ah ee dopamine endogenous.7-10 Tani waxaa la xaqiijiyay in ay sameysmaan geedi socodka xayawaanka (si loo yareeyo dopamine endogenous) oo aan saameyn ku lahayn [18F] farepride farta,9,11 laakiin si aad ah u kordhay [11C] raclopride qasab8 taas oo loo aaneynayo isbeddel ku yimid muuqaal caqli-gal ah (Kd) halkii aad ka qaadan lahayd lambarka rafcaanka (Bmax).

Iyada oo laga yaabo inay noqoto mid xoojinaysa (BP) ee [18F] falepride waxay u adkaysataa isbeddelka sababtoo ah dhicinta dopamine, oo soo jeedinaysa saameyn yar Kd or Bmax marka loo eego gundhigga ama gobolka oo dhan, waxaan isticmaalnay [18F] falepride si loo tijaabiyo sharaxaadkayaga in tusaalooyinka DA-D2R uu kordho mashiinka MPTP oo leh jimicsi xoogan.9,10,12,13 Intaa waxaa dheer, si aan u taageerno tallaabooyinka PET sawirada, waxaan isticmaalnay farsamooyinka dhammeystiran ee falanqaynta galbeedka ee tallaabooyinka loo yaqaan 'synaptoneurosomal preparations' si loo cabbiro isbeddellada ku yimaada saamiga DA-D2R ee muujinaysa muuqaalka xayawaanka ee isla xayawaanka. Waxaan halkaan ku soo sheegeynaa saameynta jimicsiga ee kudhacaya DA-D2R iyo [18F] falefit ee kooxaha jiirarka lagu daweeyo saline ama MPTP.

FARSAMADA

Xayawaanka, Kooxaha Daaweynta, iyo Maamulka MPTP

Labadii toddobaad ee Xamdi 57 (Charles River Laboratories, Wilmington, MA) waxay ahaayeen koox qolol leh oo heerkulka lagu xakameynayo oo ka hooseeya 6 h iftiin / 8 h wareeg mugdi ah. Dhammaan nidaamyada waxaa loo sameeyey si waafaqsan Nidaamka NIH ee Daryeelka iyo Isticmaalka Xayeysiinta Shaybaarka sida ay ansaxisay USC IACUC. Wadarta jadeecada 12 ayaa loo adeegsaday afar kooxood oo daweyn ah: (12) Saline (n = 164), Saline iyo Layli (N = 1), (42) MPTP (n = 2), iyo (55) MPTP oo lagu daray jimicsiga (n = 3). Dhibaatada, jiirarka waxaa la siiyay afar qalab oo kala duwan oo ah 57 mg / kg MPTP (oo lacag la'aan ah; Sigma-Aldrich, St. Louis, MO) oo lagu kala direy 4% saline, kala duwanaanshaha 42-h ama afar afuuf oo ah 20 ml 0.9% NaCl sida xakamaynta. Dareerida waxaa lagu ansixiyey falanqaynta HPLC ee heerarka cabbirka dopamine. 2 post post-MPTP maamulka, waxaa jiray 0.1% dopamine oo ku jirta jiirka MPTP (0.9 ± 10 ng / mg ee protein) marka la barbar dhigo jiirka jilicsan (82.2 ± 48.0 ng / mg of protein). Dhamaadkii daraasadda, ma jirin wax isbedel ah oo ku yimid heerarka dopamine-ka ee u dhexeeya MPTP iyo jiirka jimicsiga (8.4 ± 269.5 ng / mg ee protein) marka la barbar dhigo MPTP (24.9 ± 69.8 ng / mg of protein). Si kastaba ha ahaatee, waxaa jiray koror xoog leh oo ku yimid dopamine-ka ee saline iyo jiirka jimicsiga (11.7 ± 77.9 ng / mg oo protein ah) marka la barbar dhigo saline (12.0 ± 315.2 ng / mg of protein)F(3,16) = 7.78; P <0.05).

Jimicsiga Treadmill

Jimicsigu wuxuu bilawdey 5 ka dib markii uu dhaawacmay. Mouse labadii jimicsi (saline iyo jimicsi iyo MPTP oo lagu daray jimicsi) ayaa loo tababaray inay ku ordaan xawaare 100M ah (Exer 6M, Columbus Instruments, OH) xawaare sarreeya ee toddobaadka 6 (5 maalmaha / usbuuca) si loo gaaro mudada 60 min / maalin iyo xawaaraha 18-20 m / min.5,6

Magnetic Resonance Imaging

Sawirka maskaxda ee miisaanka maskaxda ee miisaanka maskaxda ee miisaanka maskaxda (MRI) ee lagu magacaabo T1-miisaanka miisaanka maskaxda (MR) ayaa la helay nidaam 7-T micro-MRI (Bruker Biospin, Billerica, MA). Qodobbada wax soo iibsiga waxaa ka mid ah: TE = 46.1 ms, TR = 6292.5 ms, dhumucda xNUMX-mm dhumucdiis, 0.4-mm dhumucda xuduudaha, 0.45 × 128 128 size size matrix.

Rugta sheyga

Qodobka [18F] Falepride waxaa loo sameeyay sida hore loogu sharxay fal-celinta beddelka nukleophilic ee horey u-soo-saarka tosyl leh [18F] adigoo isticmaalaya qalabka farsamaynta farsamada gacanta.12 Nadiifinta waxaa lagu gaarsiiyey HPLC dib-u-hagaajin ah oo ku salaysan C8 (2) Tiirka Phenomenex Luna iyadoo la isticmaalayo acetonitrile iyo sodium phosphate buffer sida wajiga wareega (55: 45). Neefsashada UV waxaa lagu qiyaasey 254 nm iyo AUFS 0.05. Heerka Rakaabka ah (waqtiga xajinta 17 min) oo u dhiganta [18F] falepride, ayaa la uruuriyey oo lagu xareeyey qalabka nalka loo yaqaan "rotary evaporator". Waxyaabaha ugu dambeeya ee la soo saaray ayaa la baaray for pyrogenicity, sterility, pH, iyo ka saarista dareeraha organic by chromatography gaaska. Waxqabadyada gaarka ah iyo nadiifinta raadiyaha waxaa lagu qiimeeyay nidaam Waters HPLC iyada oo la adeegsanayo C8 (2) Phenomenex Luna. Waxqabadyada gaarka ah waxay ku jirtey qiyaasta 3,000-12,000 Ci / mmol.

Cabbiraadyada PET iyo Falanqaynta Sawirrada

Toddobaatan jiir ayaa loo isticmaalay sawirada PET (n = 6 saline; n = SUNUM cusbo iyo jimicsi; n = 3 MPTP; n = 5 MPTP oo lagu daray jimicsi). Tijaabooyinka waxaa lagu iibsaday scanner Concorde microPET R6 (CTI Concorde Microsystems, Knoxville, TN) oo leh 4-min liiska nidaamka liisaska liiska ka dib markii 60-min lagu baarayo qalabka lagu saxo hagaajinta 68Source source [18F] falepride (10.92-11.28 MBq) ayaa la isku duraa iyada oo loo maro xididada dabada (halus bolus) bilawga shaandhada hawada. Mice ayaa lagu suuxiyay 2% isofluorane iyo 98% oxygen. Xogta dhaqdhaqaaqa liiska waxqabadka waxaa loo kala soocay sinogyada 26, 6 20, 4 40 sec, 6 1, 10 5 min iyo 18 XNUMX min) iyo dib-u-cusboonaysiiyay laba qalab oo OSEM ah Miisaaniyadda MAP (ugu badnaantii posteriori) dib-u-hagaajinta algorithm.14 Sawirada dib loo habeeyay ayaa la jarjaray si loo xakameeyo madaxa iyo si qumman u dhexgalaan Z-shaxaynta si loo soo saaro 128 × 128 63 image oo leh isotropic 0.4 × 0.4 0.4 mm3 voxels. Qodobka ugu sarreeya ee xallinta khilaafaadka (BP) ee sawirada quman ayaa laga soo qaatay muuqaallada dib loo dhisay oo isticmaalaya habka loo yaqaan 'multilinear'15 iyo qoraallada Logan16 oo leh hawl firfircoon oo ka mid ah isugeynta iyo dhaqdhaqaaq aad u hooseeya oo ku yaala cerebellum (gobolka tixraaca). Goobaha dareenka ee xiiseeya (striatum iyo cerebellum) ayaa loo adeegsadey labadaba labada sawir ee sawirada PET oo leh MRI iyadoo la adeegsanayo Rview (version 8.21Beta).17 Kantaroolka waxqabadka gaarka ah [18F] falepride miisaanka miisaanka ayaa la sameeyay iyada oo la isticmaalayo qiimaha BP taas oo bixisa qiyaasta saamiga gaarka ah ee aan isku midka ahayn ee isku xidhan.18,19 Si aad u muujisid qeexitaan gaar ah ee qallalka, afar jiir ayaa laga goostay 60 min kadib markii la isku duro lakin kadib, maskaxda si deg deg ah loo xakameeyo nitrogen dareeraha ah, qaybta 30-μm dhumucdeeda, iyo qaybaha loo soo gaabiyo fosfo-imager (Typhoon 9200, GE Healthcare Inc., Piscataway , NJ) (Berdihii. 1). Daraasadaha ayaa muujiyey in [18F] flespride ayaa si gaar ah ugu xirta DA-D2R, iyo sida DA-D3R aad u yar oo ku yaal qiiqa, waxa ay tilmaamaysaa degitaanka DA-D2R.9,10,12,13

FIG. 1 

[18F] Falefidu waxay muujinaysaa gaar ahaan qaddarinta qaddarinta qiiqa. Qaybta bidixda waxay muujinaysaa qaabka anatomical ee qaybta qaliinka ee qiyaasta qiyaasta xNUMX. Qeybta saxda ah waxay muujineysaa autoradiograph wakiil leh calaamad xoog leh oo u dhiganta ...

Qaybta Nudaha ee HPLC iyo Falanqaynta Protein

Dhamaadka daraasadda, maskaxda ayaa si deg deg ah looga saarey isla markaana la yiraahdo striatum qiyaasta cusub ee u dhiganta gobollada anatomical ee bregma 1.2 illaa 0.6 oo leh xuubka xuduudaha ee xuduudaha xuduudaha, dhinaca dambe ee koontada looxaha ah ee xuduudda xiga, iyo kor u kaca bakhaarada hore xuduudaha xuduudaha.20

Baaritaanka HPLC ee Dopamine iyo Metabolites

Heerarka Dopamine ee Homogenates (n = 4 koox kasta) ayaa lagu go'aamiyey HPLC iyadoo la ogaanayo qalabka korontada.6 Nidaamka wuxuu ka kooban yahay ESA auto-scampler (ESA, Chelmsford, MA) oo leh qalabka 150 3.2 mm ee dib-u-celinta C-18 (xadka 3mm) iyo CoulArray 5600A (ESA, Chelmsford, MA), oo leh afar - kanaladaha falanqaynta farsamada gacanta oo leh awoodo lagu dejiyo -75, 50, 220, iyo 350 mV.

Falanqaynta Immunoblot ee Galbeedka

Waxyeelada jimicsiga ee ku saabsan bandhigga muuqaalka ah ee DA-D1R iyo DA-D2R ayaa lagu falanqeeyay diyaar garowga daawada synaptoneurosome oo cusub oo laga sameeyay sideed sideed loo yaqaan 'storatum'.21 Nidaamkan waxaa lagu sameeyay seddex jiir oo jiir ah wadarta jimicsiga 24 koox kasta oo tijaabo ah (n = 3 prepes kooxkiiba). Calaamadaha maskaxeed ee borotiinka ee DA-D1R (~ 50 kDa), DA-D2R (~ 50 kDa), tyrosine hydroxylase (58 kDa), gaadiidka dopamine (68 kDa), iyo α-tubulin (50 kDa) waxaa lagu falanqeeyay qiyaasaha galmada ee reer galbeedka22 iyada oo la adeegsanayo farsamooyinka asaasiga ah ee lagama maarmaanka ah (polyclonal bakteeriyada iyo fareebka monoklonal, Millipore, Temecula, CA). Xakameynta Protein ayaa waxaa lagu sawiray by ariiga ariga ah ee ariga loo yaqaan pure anti-bakeyle ama antibodies anti-farsamada isku xidhka si IRDye680 ama IRDye800 (Rockland, Gilbertsville, PA). Calaamadaha fluorescent-ka ayaa la ogaadey iyagoo raadinaya shaandhaynta LI-COR Odyssey oo u dhow mashiinka korontada sawir-gacmeedka oo lagu qiyaaso isticmaalka software Odyssey 2.1 (LI-COR Biotechnology, Lincoln, NE). Natiijooyinka waxaa lagu muujiyey heerarka muujinta qiyaasta marka la barbardhigo kooxda daaweynta salineedka (oo loo dhigay 100%).

Falanqaynta tirakoobka

Kala duwanaanta kooxaha u dhaxaysa BP [18Qiyaasaha protein, DA-D1R, iyo DA-D2R ayaa lagu falanqeeyey iyadoo la adeegsanayo falanqaynta laba-dhinac ee isbeddel (ANOVA) iyadoo la daaweynayo maadada maadada (saline MPTP), iyo jimicsiga maadada maadada jimicsi). Imtixaanka xawaaraha qadarka ah ee treenmill, waqtiga waxaa loo adeegsaday maaddada maadada (toddobaadkii 1, 2, iwm.) Waxaana daaweynta loo isticmaalay maadada maadada (saline vs MPTP). Baadhitaanka hordhaca ah ee Bonferroni ayaa loo isticmaalay si loo saxo isbarbardhigyo badan marka la qiimeeyo muhiimadda xiisaha. Heer aad u sarreeya ayaa loo qoondeeyay P <0.05. Si loo sahamiyo muhiimadda wax ku oolka ah ee kala duwanaanshaha kooxeed, qiyaasta baaxadda farqiga u dhexeeya kooxaha ayaa la xisaabiyay iyadoo la adeegsanayo cabirka saamaynta (ES) (ES = MicnaheeduKooxda 1 - MacnaheeduKooxda 2/ SDururiyay). ES-ku wuxuu ka tarjumayaa saameynta daaweynta ee dadka xiisaha leh waxaana lagu soo warramey iyadoo loo eegayo shuruudaha la dejiyey sida yar (<0.41), dhexdhexaad (0.41-0.70), ama weyn (> 0.70).23 Falanqaynta waxaa la sameeyay iyada oo la adeegsanayo Prism5 ee Windows (GraphPad, San Diego, CA).

Natiijooyinka

Jir-dhiska Treadmill Exercise Habdhaqanka Gawaarida Wanaagsan ee Mareegta MPTP-La-Maskaxda

Ka hor inta aan la bilaabin MPTP-bilaabis jimicsi, jimicsiga caadiga ah ee jadeecada ee jadeecada oo dhan laba kooxood oo jimicsi ah ayaa la mid ah (saline iyo jimicsi: 11.7 ± 1.1 m / min, MPTP iyo jimicsiga: 11.2 ± 1.1 m / min). Jimicsi maalinle ah oo loogu talagalay toddobaadyada XNUM wuxuu hagaajiyay xayeysiinta ugu badan ee treadmills ee labadaba kooxo jimicsi leh oo leh salineed iyo jiirka jimicsiga oo muujinaya xajmiga xajmiga ugu sarreeya marka la barbardhigo MPTP iyo jiirka jimicsiyada toddobaadyada 6 iyada oo 1 (Berdihii. 2). Si kastaba ha ahaatee, MPTP iyo jiirarka jimicsiga waxay u dhigmeen xawaare sarreeya sida salineinka iyo jimicsiga jimicsiga toddobaadka (MPTP oo lagu daray jimicsi: 5 ± 17.2 m / min iyo saline iyo jimicsi: 3.6 ± 22.0 m / min) iyo usbuuca 1.5 ± 6 / min iyo 19.2 ± 1.2 m / min, siday u kala horreeyaan). Sidii hore loo soo sheegay, jiirarka MPTP-lesioned oo aan ku qaadan tababarka treadmill soo bandhigay aan dib u soo kabashada dhaqdhaqaaqa dhaqdhaqaaqa leh xawaaraha ugu sarreeya ee 22.2 ± 0.9 m / min dhamaadka xilliga 7.0 ee usbuuca.5

FIG. 2 

Jimicsigu wuxuu hagaajiyaa dabeecadaha muraayadda MPTP. Xawaaraha ugu sareeya ee salineedka (n = 12) iyo MPTP (n = 12) jiirarka ku yaal treadmill ayaa lagu tijaabiyay dhammaadkii toddobaad kasta. Dhaqdhaqaaqyada treadmill ee aasaasiga ah ayaa la qiyaasay ka hor inta aan la ogeyn MPTP. ...

Jimicsiga Treadmill Exercise-ka Dheeriga ah ee Daawada DA-D2R oo sii kordhiyay, laakiin maaha DA-D1R Protein

Jimicsiga xoojinta sareeya wuxuu si aad ah u saameeyaa DA-D2R iyo DA-D1R ee daawooyinka loo yaqaano synaptoneurosomal ah oo ka yimid qanjidhada dulinka ah sida lagu muujiyay falanqaynta reer galbeedka (Berdihii. 3). MPTP iyo jadeecada jimicsiga ayaa waxay lahaayeen 48.8% kororka DA-D2R marka la barbar dhigo jiirka MPTP (Sawirka 3B), iyo isdhexgalka weyn ee u dhexeeya jimicsiga iyo MPTP-da dhaawaca heerka DA-D2R (F(1,8) = 6.0; P <0.05). Taa bedelkeeda, ma jirin wax saameyn jimicsi ah oo ku saabsan heerarka borotiinka DA-D1R ee u dhexeeya kooxaha (Sawir 3A; F(1,8) = 0.1, P = 0.78). Dhibaatada MPTP oo keliya looma beddelin wax DA-D2R ah (F(1,8) = 0.0; P = 0.88) ama muujinta DA-D1R (F(1,8) = 0.0; P = 0.92). Intaa waxaa dheer, laba calaamado oo kala duwan oo ah borotiinka dopaminergic, dareenka xayawaanka, tyrosine hydroxylase (TH; Sawirka 3C) iyo gaadiidka dopamine (DAT; Sawirka 3D), waxay muujisay in MPTP si weyn hoos ugu dhacay protein (TH) (F(1,8) = 757.3; P <0.05) iyo muujinta DAT (F(1,8) = 218.0; P <0.05).

FIG. 3 

Jimicsiga si xushmad leh ayuu u kantaroolaa DA-D2R, laakiin ma aha DA-D1R-ga oo lagu magacaabo "steratal". Guddi (A) waxay muujinaysaa falanqaynta galbeedka immunoblot ee diyaargarowga synaptoneurosomka laga soo qaado qanjidhada dulinka ee DA-D1R. Ma jirin farqi u dhexeeya garashada xisaabta ...

Jimicsiga Treadmill Exercise Cufnaanta Dhiirrigelinta [18F] Qalabaynta Qalabaynta Xiriirka (BP)

In kastoo falanqaynta tallaalka ee galbeedka ee lagu qiyaaso saamiga protein-ka lagu aqbali karo qiyaasta antibody epitopes (dukaamada gudaha iyo gudaha gudaha), in vivo PET-sawirada leh alaarmiga sare-dukaanka DA-D2R-ga gaarka ah [18F] falepride waxay qeexi kartaa saameynta jimicsiga ee helitaanka DA-D2R si loogu xiro laydh (Berdihii. 4). Falanqaynta tirakoobka ayaa muujisay inay jirtey saameyn aad u weyn oo jimicsi ah (F(1,16) = 12.3; P <0.05) iyo sidoo kale MPTP lesion (F(1,16) = 160.3; P <0.05) oo aan lahayn isdhexgal weyn oo u dhexeeya MPTP iyo jimicsi (F(1,16) = 3.5; P = 0.07) on [18F] fakepride BP. Falanqaynta hoch-yada Bonferroni ayaa muujisay farqiga u dhexeeya qiimaha BP ee u dhexeeya MPTP iyo MPTP iyo jiirka jimicsiga (t = 1.1, Df = 1, 16; P <0.01), iyo farqi weyn oo u dhexeeya cusbada iyo cusbada oo lagu daray jiirka jimicsiga (t = 4.1, Df = 1, 16; P > 0.05). Gaar ahaan, MPTP oo lagu daray jiirka jimicsiga wuxuu lahaa koror 73.1% ah18F] fespride BP marka la barbar dhigo jiirka MPTP (qiimaha celceliska BP ee MPTP iyo jimicsiga: 7.1 ± 0.7; qiimaha celceliska BP ee jiirarka MPTP: 4.1 ± 0.3)Sawirka 4B). Intaa waxaa dheer, saline iyo jiirka jimicsiga ayaa lahaa xNUMX% kororka [18F] faleprid BP (13.2 ± 1.0) marka la barbardhigo jiirka salineed (12.2 ± 0.3). Iyadoo la raacayo natiijooyinkan "xisaabta saamiga" saameyntu waxay muujisay saameyn ballaadhan oo udhaxeeya kooxaha MPTP (ES = 2.61) marka loo eego kuwa u dhexeeya kooxaha salineeska (ES = 0.94).

FIG. 4 

Jimicsi waxay doortaa kororka [18F] faleprid waxay ku xirantahay awoodda xakamaynta (BP) ee qiyaasta jiirka MPTP. Guddi (A) wuxuu muujinayaa [18F] sawir-qaadaha sawirrada BP-ga ee jihada koronta (dhinaca bidixda) iyo hagaajinta jiifka (dhinaca midig). Miisaanka miisaanka ...

DHIBAATOOYINKA

Daraasadani waxa ay muujineysaa in jimicsiga treadmill-sare uu keenayo kororka [18F] falepride BP (DA-D2R helitaanka) ee graungka ee jiirka jadeecada MPTP. Taa beddelkeeda, ma jirin wax isbeddel ah oo isbeddel ah oo lagu sameeyay heerarka dopamine-ka ee u dhexeeya MPTP iyo jimicsiga marka la barbar dhigo MPTP jade jimicsi. [18F] falepride waa DA-D2 / D3R daacad u ah oo BP ay ka muuqato in vivo qiyaasta dib-u-dejiyeyaasha la heli karo (Bmax) / qashin-saarid (Kd). Sababtoo ah DA-D2Rs waa nooc hoos udhaca dopamine ee qaabka daaweynta dopamine ee ku jirta qanjirada 'storatum', oo kor u kaca oo jimicsi [18F] Fakepride BP waxay u dhigantaa korodhka tirada DA-D2R waxayna taageertaa kororka muujinta borotiinka iyadoo la adeegsanayo immunobloomka reer galbeedka iyo daraasadaheena hore oo muujinaya korodhka xayeysiiska DA-D2R mRNA iyadoo la adeegsanayo taariikhda isdhexgalka ee situ.5 Fasiraadda Tilmaamaha BP waxaa lagu taageeray xaqiiqda ah in barokaca [18F] falepride by dopamine maaha inay ku dhacdo jiirka MPTP maaddaama heerarka dopamine ay hoos u dhacaan.24 Sidaa awgeed, isbeddellada is-beddelidda ee muuqda (Kd) waa kuwo liita oo aan u badneyn inay saameyn ku yeeshaan BP. Saameynta korodhsan ee jimicsiga ee jiirarka MPTP ayaa laga yaabaa inay ka tarjumaan iskudaridda maskaxda dhaawacantay si loo yareeyo dopaminergic neurotransmission iyada oo loo marayo nambarka kordhay iyada oo la kordhinayo heerarka dopamine. Kordhinta jawaab-celinta jiirka MPTP ee jimicsiga ayaa muujinaya suurtogalnimada awoodda ugu badan ee dhaawaca ka soo horjeeda maskaxda ku jirta si loo qaado neuroplasticity, taas oo aan laga maarmi karin marka wareegga wareegga uu yahay mid cakiran. Xaqiiqda ah in heerarka dopamine aysan si weyn u badalin jimicsiga jiirka MPTP waxay muujineysaa in isbeddelada ku-bedelashada ee DA-D2R ay muhiim u tahay jimicsiga la xiriira kor u qaadista waxqabadkiisa.

Isticmaalka sawir-baadhista PET, waxaanu aragnaa hoos u dhac DA-D2R BP ka dib markii loo yaqaan MPTP lesioning ee jadeecada loo yaqaan "saline-treated. Tani waxay ka duwan tahay tallaalka reer galbeed ee aan wax isbeddel ah laga helin bandhigga protein DA-D2R. DA-D2R waxay ku dhex taal barxada firfircoon ee u dhexeysa qaybaha hoose iyo kan gudaha, iyada oo marka dambe aan guud ahaan la heli karin si loogu xakameeyo PET radioligands. Xaaladda dopamine-ku dhicin, qaababka mag-dhawida waxay keeni kartaa isbeddelka hudheelada gudaha ee DA-D2R, oo aan laga heli karin [18F] flespride is haysta balse weli la heli karo si loo ogaado immunoblotka galbeedka.

Si ka duwan natiijooyinka noocan ah, korodhka magdhawga ee DA-D2R ayaa lagu soo warramey shaqsiyaadka leh PD iyo ka dib markii maamulka MPTP ee asal-raaca ama kuwa 6-OHDA ee jiirka.25 Daabacaadda, luminta DA-D2Rs ayaa la sheegay inay sababtay hoos u dhigista dareenka dopaminergic, halka kororka DA-D2Rs ay ka dhalatay muujinta kordhinta terminaalka dopaminergic-ka iyo / ama kordhinta istiraatiijiyada dhexdeeda gudaha nuucyada striatopallidal ama interneurons cholinergic. Kala duwanaan la'aanta udhaxeysa barashada PET, iyo kuwa suugaanta, waxaa laga yaabaa inay u dhaxeyso kala duwanaanshaha naafonimada laf dhabarka u dhexeeya daraasadaha.11 Gaar ahaan, luminta tiro badan oo ah daawada DA-D2R ee daawada looxapintaanka ah ee loo yaqaan MPTP-ka ayaa laga yaabaa in ay ku filan tahay in lagu dhejiyo wixii isbeddel ah ee dib-u-cusbooneysiin ah ee loo yaqaan 'Repostynaptic' ee isbitaallada. Haddii kale, awood uma lihin inaanu korodno korodhka DA-D2R BP iyo heerarka muujinta ee jiirarka MPTP (aan jimicsi lahayn) waxaa laga yaabaa in ay sabab u tahay dib u soo kabashada heerarka dopamine dhamaadka daraasaddan (82% dopamine oo ka timaadda maalmaha 10 iyo 68 % dharbaaxinta xayaysiinta 42 maalmood). Si kastaba ha ahaatee, tani maaha mid la mid ah MPTP iyo jiirarka jimicsiga, taas oo sidoo kale soo bandhigtay soo kabashada yar ee dopamine (oo aan aad uga duwaneyn MPTP jadeeco jimicsiga) waxay kordhisay DA-D2R BP.

Inta badan DA-D1Rs iyo D2Rs ayaa lagu muujiyey maadooyinka dendritic ee MSNs leh recepors dheeraad ah oo lagu muujiyay internenurons cholinergic iyo terminals of glutamatergic iyo dopaminergic neurons oo ka yimid kortex (ama thalamus) iyo mawduuca nigra pars compacta, siday u kala horreeyaan.26 Doorka ugu wayn ee dopamine waa in la beddelo corticostriatal ama thalamostriatal glutamatergic neurotransmission ee MSN. Glutamatergic neurotransmission waxaa lagu hormariyaa DA-D1Rs waxaana la yareeyay DA-D2Rs.27-29 Xaaladaha dopamine-ka, dhirbaaxada iyo isku-dhafka isdhexgalka ayaa si khaas ah looga lumay DA-D2R oo ay ku jiraan MSN-yada waddada aan tooska ahayn.30 Dhimashadani waxay la socotaa gobolka xaalad nafaqo-darro oo ku jirta MSN-yada oo sabab u ah kordhinta corticostriatal neurotransmission glutamatergia.31-33 Xaaladda xayawaanka ee PD, waxay kordhinaysaa wadnaanta glutamaterka ah ee la xidhiidha dabeecadaha mootooyinka sida parkinsonian-like.34 Hoos-u-dhicinta xaaladdan la isku halleyn karo iyada oo loo marayo codsiga dopamine ama agonistayaashu waxay keenayaan dib-u-dhac ku yimaada baabuurta parkinsonian.35,36 Marka la eego warbixinnadan iyo natiijooyinkayaga, waxaannu ku dheehan nahay in faa'iidooyinka farsamooyinka xoogga leh ay tahay inay kor u qaadaan dopaminergic tilmaamaya iyada oo la kordhinayo DA-D2R ee wadada aan tooska ahayn (laakiin aan ahayn waddada tooska ah ee DA-D1R) xakamaynta sigaarka glutamatergic.

Gabagabada ugu muhiimsan ee daraasaddeena ayaa ah in jimicsiga qaabka loo yaqaan 'treadmill running' uu fududeeyo neuroplasticka iyadoo loo marayo muujin dheeraad ah oo muujinaysa DA-D2Rs, oo ah habka ugu cad ee maskaxda dhaawacmay. Iyada oo ku saleysan natiijooyinkeenna, hab aan haboonayn PET-sawir leh [18F] falepride waxaa loo isticmaali karaa in lagu baaro in jimicsiga adag ee tartiib tartiibka ah uu keeno isbeddelka ku yimaada DA-D2R ee shakhsiyaadka leh PD. Daraasaddeenna waxay muujineysaa qiimaha cilmi-baarista hore ee xeeladaha xayawaanka ee dopamine-ka ah iyo muhiimadda ay leedahay cilmi-baarista turjubaanka ee bixinta aragtida iyo fahamka xagga fahamka sawir-qaadista iyo jimicsiga shakhsiyaadka leh PD.

Mahadnaq

Shaqadani waxaay taageertay deeq ka timid Barnaamijka Deeqda USC CTSI Full Pilot Program, iyo deeqo deeqsinimo leh oo ka yimid Xarunta Cudurrada Cudurrada ee Parkinson, Los Angeles, Parkinson Alliance, Kooxda Waxbarashada Cudurka Whittier Parkinson, NINDS RO1 NS44327-1, NIA ( AG 21937) iyo US Army NETRP W81XWH-04-1-0444. MGV waa qaataha barnaamijka "USC Neuroscience Graduate Program". Waxaan rabnaa inaan u mahad celino Ryan Park iyo Dr. Peter Conti oo ka yimid USC Small Screening Core si loogu caawiyo sawirada yar-yar ee PET iyo Dr. Rex Moats oo ka socda Machadka Cilmi-baarista Xoolaha ee yar yar ee Machadka Cilmi-baarista Saban ee caawimaadda MRI-ga. Waxaan jeclaan lahaa inaan u mahad celinno Yi-Hsuan (Lilian) Lai si loogu caawiyo jimicsiga treadmill, iyo Avery Abernathy oo khibrad u leh falanqaynta HPLC. Waxaan u mahadcelinaynaa saaxiibada USC Parkinson's Research Cure Group oo ay ka mid yihiin George iyo MaryLou Boone, Walter iyo Susan Doniger, iyo Roberto Gonzales taageeradooda deeqsinimo leh.

Qoraalada

 

Iskuduwaha suurtagalka ah ee xiisaha leh: Waxba kama jiraan warbixinta.

Xusuusin caddayn: Maqaalkani waxaa lagu daabacay online on 19 October 2010. Qalab ayaa loo aqoonsaday. Ogaysiiskan waxaa ku jira qaybaha internetka iyo daabacaadda si ay u muujiyaan in labadaba la saxay.

Bixinta Maaliyadeed: Barnaamijka "USC Neuroscience Graduate Program" ee "Merit Fellowship" (MV), NINDS RO1 NS44327-1 (MV, CW, JW, MJ iyo GP), USC CTSI Barnaamijka Bixinta Wadajirka ah (QL, AN, MJ, GP).

Author Author: Dhammaan qoraayadu waxay ahaayeen qalab wax lagu soo saaro qoraalkan. Fikradda Mashaariicda Cilmi-baarista: GP, BF, MJ, RL, JW. Hirgelinta Mashruuca: MV, QL, AN, CW, MJ, GP. Ururinta Xogta, Farsamada, Falanqaynta Tirakoobka: MV, QL, BF, AN, RL, MJ, GP. Diyaarinta Manuscript: MV, QL, BF, RL, JW, MJ, GP.

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