5 research outputs found

    In vivo PET quantification of the dopamine transporter in rat brain with [¹⁸F]LBT-999.

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    INTRODUCTION: We examined whether [(18)F]LBT-999 ((E)-N-(4-fluorobut-2-enyl)2β-carbomethoxy-3β-(4'-tolyl)nortropane) is an efficient positron emission tomography (PET) tracer for the quantification of the dopamine transporter (DAT) in the healthy rat brain. METHODS: PET studies were performed using several experimental designs, i.e. test-retest, co-injection with different doses of unlabelled LBT, displacement with GBR12909 and pre-injection of amphetamine. RESULTS: The uptake of [(18)F]LBT-999 confirmed its specific binding to the DAT. The non-displaceable uptake (BP(ND)) in the striatum, between 5.37 and 4.39, was highly reproducible and reliable, and was decreased by 90% by acute injection of GBR12909. In the substantia nigra/ventral tegmental area (SN/VTA), the variability was higher and the reliability was lower. Pre-injection of amphetamine induced decrease of [(18)F]LBT-999 BP(ND) of 50% in the striatum. CONCLUSIONS: [(18)F]LBT-999 allows the quantification of the DAT in living rat brain with high reproducibility, sensitivity and specificity. It could be used to quantify the DAT in rodent models, thereby allowing to study neurodegenerative and neuropsychiatric diseases

    18F]Mefway 양전자방출단층촬영술로 측정한 갑상선기능저하증이 쥐 뇌의 세로토닌 1A 수용체에 미치는 영향

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    Dept. of Medicine/박사This study investigated the effects of hypothyroidism on the brain serotonin (5-HT) 1A receptor using animal disease models and 4-(trans-[18F]fluoranylmethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexane-1-carboxamide ([18F]Mefway) positron emission tomography (PET) imaging. Five surgically thyroidectomized male Sprague-Dawley rats were assigned to the hypothyroidism group, and five sham-operated male Sprague-Dawley rats were assigned to the control group. Hypothyroid status was confirmed by thyroid function tests. After anesthesia with 2.0% isoflurane in oxygen, fluconazole was infused at a constant rate for one hour to prevent defluorination of the radioligand. Then [18F]Mefway of 8.6–11.1 MBq was administered at a rate of 1 ml/min and dynamic PET scans were performed over the course of 120 min. PET data were reconstructed in user-defined time frames using a two-dimensional ordered-subset expectation maximization algorithm. All PET data were spatially normalized to T2-weighted magnetic resonance imaging templates, and then time-activity curves of the hippocampus, septum, and cerebellum were extracted using predefined volume of interest templates. Non-displaceable binding values in the hippocampus and septum were calculated using a multilinear reference tissue model, with the cerebellum as the reference tissue, and a ligand-specific parametric map was constructed. Time-activity curves revealed that the hippocampal and septal uptakes in the hypothyroidism group were 25–52% higher than those in the control group, and non-displaceable binding potentials in the same regions of thyroidectomized rat brains were about 30% higher than those in controls. In conclusion, hypothyroidism increased the density of postsynaptic 5-HT1A receptors in the hippocampus and septum. Upregulation of postsynaptic 5-HT1A receptors may be responsible for the increased radioligand uptake as an early response to the reduced synaptic concentration of 5-HT caused by hypothyroidism. 이 연구는 동물 질병 모델 및 4-(trans-[18F]fluoranylmethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexane-1-carboxamide ([18F]Mefway) 양전자방출단층촬영술(PET)을 사용하여 갑상선기능저하증이 뇌의 세로토닌 1A 수용체에 미치는 영향을 연구하였다. 갑상선절제술을 받은 Sprague-Dawley 수컷 쥐 5마리를 갑상선기능저하증 집단에 배정하였고, 모의 수술(sham operation)을 받은 Sprague-Dawley 수컷 쥐 5마리를 대조군으로 설정하였다. 갑상선기능저하 상태는 갑상선 기능 검사로 확인하였다. 산소에 2%의 아이소플루레인을 혼합하여 마취를 시킨 후, [18F]Mefway의 탈불소화를 방지하기 위하여, 1시간 동안 플루코나졸을 투여하였다. 그 다음 8.6–11.1 MBq의 [18F]Mefway를 1 ml/min 속도로 투여한 후, PET 영상을 120분간 연속적으로 획득하였다. PET 영상은 2차원 정칙화된 기댓값 최대화 알고리즘(ordered subsets expectation maximization algorithm)을 이용하여 재구성하였다. 모든 PET 영상은 T2 강조 자기공명영상 틀(template)에 공간정규화 한 후 사전 정의된 관심영역 틀을 이용하여 해마, 사이막(septum), 소뇌의 시간방사능곡선을 추출하였다. 해마와 사이막의 수용체 결합능(non-displaceable binding potential)은 소뇌를 참조조직으로 삼아 다중선형 참조조직 모형(multilinear reference tissue model)을 통하여 계산하였고 리간드-특정 모수지도(parametric map)를 작성하였다. 시간방사능곡선에서 갑상선기능저하증 집단의 해마와 사이막 섭취는 대조군보다 25-52% 더 많았고 이 부위의 결합능은 갑상선절제술을 받은 쥐에서 대조군에 비하여 30% 가량 더 높았다. 결론적으로, 갑상선기능저하증은 해마와 사이막의 시냅스후 세로토닌 1A 수용체 밀도를 증가시켰다. 이는 갑상선기능저하증으로 인해 시냅스의 세로토닌 농도가 감소하고 이에 따른 초기 반응으로써 시냅스후 세로토닌 1A 수용체가 상향조절 되었기 때문일 것이다.ope

    Neuroimaging of fetal cell therapy in Parkinson’s disease

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    Parkinson’s disease is the second most common neurodegenerative disease characterised by the elevated formation of α-synuclein-immunopositive intraneuronal proteinaceous inclusions (Lewy pathology) and the progressive loss of neuromelanin-laden dopaminergic cells of the substantia nigra pars compacta, resulting in the loss of striatal dopaminergic terminals and emergence of cardinal motor features including bradykinesia, rigidity, tremor and postural instability. Dopaminomimetic agents provide effective symptomatic relief in the early stages of illness, yet due to the inherently progressive nature of the disease and the induction of debilitating side effects their efficacy is eventually lost. Cellular restorative strategies involving intrastriatal transplantation of human fetal ventral mesencephalic (hfVM) tissue gained traction from the early 1990’s, when several multi-disciplinary teams reported drastic motoric improvements concomitant with graft-derived dopaminergic re-innervation. However, outcomes of double-blind randomised controlled trials and the presentation of novel dyskinetic movements persisting in the “off-state” called for substantial revision of cell delivery strategies. The current thesis utilises positron emission tomography to examine the effects of hfVM implantation under the Transeuro protocol on dopaminergic ([18F]FDOPA, [11C]PE2I) and serotonergic ([11C]DASB) systems in patients with Parkinson’s disease and elucidate the neural underpinnings of its clinical impact. The main findings are; 1) implanted hfVM tissue led to increases in putamenal dopamine synthesis and storage capacity, dopamine and serotonin transporter density as compared to non-transplanted patients; 2) modification to surgical procedures provided inhomogenous and inconsistent re-innervation; 3) hfVM transplantation was associated with clinical improvements in measures of bradykinesia, rigidity and tremor; 4) graft-related changes in posterior putamenal dopamine and serotonin transporter density predicted symptomatic relief of bradykinesia and tremor; 5) heterogeneity of posterior putamenal re-innervation may impact upon potential clinical benefit; 6) graft-induced dyskinesia was associated with greater post-operative increases in dopamine transporter expression in the anterior putamen; 7) there was no evidence that graft-induced dyskinesia was related to serotonergic hyperinnervation. The novel findings presented in this thesis have major implications for cell-based restorative strategies beyond the hfVM era and will likely foster informed [re]consideration of many aspects of therapeutic delivery and trial design. For its ability to provide mechanistic insight in vivo, neuroimaging may continue to play a central role in the optimisation of future interventions.Open Acces

    Nicotinic acetylcholine receptors in experimental models of Parkinson’s disease and levodopa-induced dyskinesia : focus on α5 subunit-containing receptors

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    No cure exists for Parkinson’s disease (PD), a disease marked by the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNC), a loss of dopamine in the dorsal striatum, and resulting motor symptoms. Furthermore, treatment of PD with levodopa is often complicated by abnormal involuntary movements (levodopa-induced dyskinesia, LID). Novel treatment options for PD and LID are thus greatly needed. Nicotinic acetylcholine receptors represent one possible novel treatment target, given the complex control they exert over dopaminergic neurotransmission, protective effects of smoking against PD, and extensive preclinical evidence of neuroprotective and antidyskinetic effects by nicotinic receptor ligands. Nicotinic receptor subtypes essential for nigrostriatal dopaminergic neurotransmission include those containing the α5 subunit, which have not been previously studied in the context of PD. In this thesis, further preclinical investigations of the role of nicotinic receptors in PD and LID were carried out. An extensive in vivo and ex vivo characterization of the role of α5-containing receptors in mouse models of PD was performed. The effects on LID by chronic nicotine treatment in drinking water and other drug treatments were studied in vivo utilizing mouse models of both moderate and severe PD and LID. The mechanisms of action underlying LID and the antidyskinetic effects of nicotine were studied by ex vivo measurements of striatal dopamine release and corticostriatal brain-derived neurotrophic factor (BDNF). In parallel, methods for stereotactic surgery and postoperative care were significantly improved. Mice lacking α5-containing nicotinic receptors were found to be less susceptible to unilateral nigrostriatal neurodegeneration, the resulting interhemispheric motor imbalance, and LID. Striatal dopamine uptake measurements suggested reduced dopamine transporter function as a possible mechanism of neuroprotection. Nicotine was found to inhibit LID, with findings suggesting a role for α6β2* nicotinic receptors. However, neither nicotinic receptor agonists nor the clinically used drug amantadine alleviated severe LID associated with near-total dopaminergic denervation. The findings also confirmed a correlation between striatal BDNF and LID. The present findings suggest the potential usability of α5-containing nicotinic receptors as a drug target against PD and LID. The findings also confirm the preclinical potential of nicotine as an antidyskinetic drug while suggesting limited efficacy in advanced PD. In addition, the findings expand previous knowledge on the possible mechanisms of LID and the antidyskinetic effects of nicotine.Parkinsonin taudin motoriset oireet aiheutuvat mustatumakkeen dopamiinihermosolujen rappeutumisesta ja dopamiinin puutoksesta aivojuoviossa. Sairaudelle ei ole löydetty parantavaa hoitoa. Lisäksi tahdottomat liikkeet (dyskinesia) vaikeuttavat usein sairauden hoitoa levodopa-lääkeaineella. Uusia mahdollisuuksia Parkinsonin taudin ja dyskinesian hoitoon siis tarvitaan. Asetyylikoliinin nikotiinireseptorit voisivat tarjota yhden mahdollisen uuden lääkevaikutuskohteen, sillä ne säätelevät aivojen dopamiinijärjestelmää, tupakoinnin tiedetään suojaavan Parkinsonin taudilta, ja laaja prekliininen näyttö viittaa nikotiinireseptoriligandeilla olevan hermosoluja suojaavia ja dyskinesiaa lieventäviä vaikutuksia. Dopaminergisen hermovälityksen kannalta oleellisiin nikotiinireseptoriala-tyyppeihin kuuluvat α5-alayksikön sisältävät reseptorit, joiden yhteyttä Parkinsonin tautiin ei aiemmin ole tutkittu. Tässä väitöskirjassa tutkittiin nikotiinireseptorien merkitystä Parkinsonin taudissa ja levodopan aiheuttamassa dyskinesiassa. α5-alayksikön sisältävien nikotiinireseptorien merkitystä Parkinsonin taudin ja dyskinesian hiirimalleissa tutkittiin kattavin in vivo- ja ex vivo-kokein. Juomaveden kautta annetun pitkäkestoisen nikotiinikäsittelyn ja muiden lääkehoitojen vaikutuksia tutkittiin sekä kohtalaisen että pitkälle edenneen Parkinsonin taudin ja dyskinesian hiirimalleissa. Dyskinesian ja nikotiinin dyskinesiaa lievittävien vaikutusten mekanismeja tutkittiin mittaamalla ex vivo dopamiinin vapautumista aivojuoviosta sekä aivoperäisen hermokasvutekijän (BDNF) pitoisuuksia aivoissa. Samanaikaisesti stereotaktisten leikkausten ja leikkauksen jälkeisen hoidon menetelmiä kehitettiin merkittävästi. α5-poistogeenisten hiirten havaittiin olevan vähemmän herkkiä dopamiinihermojen toispuoleiselle tuhoutumiselle, siitä johtuvalle aivopuoliskojen motoriselle epätasapainolle sekä levodopan aiheuttamalle dyskinesialle. Dopamiinin soluunottoa aivojuoviossa mitanneiden kokeiden perusteella dopamiinin kuljettajaproteiinin heikentynyt toiminta saattoi olla yksi hermosoluja suojaava mekanismi. Nikotiinin todettiin lievittävän levodopan aiheuttamaa dyskinesiaa, ja α6β2* nikotiinireseptorit voivat olla tärkeitä tämän vaikutuksen välittäjiä. Nikotiinireseptorien agonistit tai kliinisesti käytetty lääkeaine amantadiini eivät kuitenkaan lievittäneet vakavaa, lähes täydelliseen dopamiinihermokatoon liittyvää dyskinesiaa. Tutkimuslöydökset myös vahvistivat yhteyden BDNF:n ja levodopan aiheuttaman dyskinesian välillä. Tutkimuksen tulokset viittaavat siihen, että α5-alayksikön sisältävät nikotiinireseptorit voisivat olla mahdollinen uusi vaikutuskohde Parkinsonin taudin hoidossa. Löydökset myös vahvistavat nikotiinin olevan mahdollinen levodopan aiheuttaman dyskinesian hoitomuoto, mutta viittaavat siihen, että hoitovaste pitkälle edenneessä Parkinsonin taudissa voi olla heikko. Lisäksi tutkimus laajentaa aiempaa tietämystä dyskinesian ja nikotiinin dyskinesiaa lievittävien vaikutusten mahdollisista mekanismeista
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