Ravenstijn Paulien G M, Merlini Mario, Hameetman Marjolijn, Murray Tracey K, Ward Mark A, Lewis Hywel, Ball Gareth, Mottart Cathy, de Ville de Goyet Christine, Lemarchand Thomas, van Belle Kristel, O'Neill Michael J, Danhof Meindert, de Lange Elizabeth C M
Leiden Amsterdam Center for Drug Research, Leiden University, Division of Pharmacology, Leiden, The Netherlands.
J Pharmacol Toxicol Methods. 2008 Mar-Apr;57(2):114-30. doi: 10.1016/j.vascn.2007.10.003. Epub 2007 Nov 13.
In search for a suitable rat model to study potentially affected blood-brain barrier (BBB) transport mechanisms in the course of Parkinsons disease (PD) progression, experiments were performed to characterise Parkinsons disease markers following subcutaneous (SC) and intracerebral (IC) infusion of the toxin rotenone in the rat.
Studies were performed using Male Lewis rats. SC infusion of rotenone (3 mg/kg/day) was performed via an osmotic minipump. IC infusion of rotenone occurred directly into the right medial forebrain bundle at three different dosages. At different times following rotenone infusion, behaviour, histopathology (tyrosine hydroxylase and alpha-synuclein immunocytochemistry), peripheral organ pathology (adrenals, heart, kidney, liver, lung, spleen and stomach) were assessed. In part of the SC and IC rats, BBB transport profiles of the permeability marker sodium fluorescein were determined using microdialysis.
SC rotenone failed to produce dopaminergic lesions and led to extensive peripheral organ toxicity. BBB permeability for fluorescein following SC rotenone was changed, however due peripheral toxicity. In contrast, IC rotenone produced a progressive lesion of the nigrostrial dopaminergic pathway over 28 days with no associated peripheral toxicity. IC rotenone also exhibited a large increase in amphetamine induced rotational behaviour. In addition, a few IC rats showed alpha-synuclein immunoreactivity and aggregation. Following IC rotenone, no changes in BBB permeability were detected after 14 days.
SC rotenone only produced peripheral toxicity. IC rotenone appeared to create a progressive lesion of the rat nigrostrial pathway, and may therefore be a more appropriate model of Parkinson's disease progression, compared with the most commonly used 6-OH-DA rat model.
为了寻找一种合适的大鼠模型来研究帕金森病（PD）进展过程中可能受影响的血脑屏障（BBB）转运机制，我们进行了实验，以表征大鼠皮下（SC）和脑内（IC）注射鱼藤酮毒素后的帕金森病标志物。
使用雄性Lewis大鼠进行研究。通过渗透微型泵进行鱼藤酮的皮下注射（3mg/kg/天）。以三种不同剂量将鱼藤酮直接脑内注射到右侧内侧前脑束。在鱼藤酮注射后的不同时间，评估行为、组织病理学（酪氨酸羟化酶和α-突触核蛋白免疫细胞化学）、外周器官病理学（肾上腺、心脏、肾脏、肝脏、肺、脾脏和胃）。在部分皮下和脑内注射的大鼠中，使用微透析测定通透性标志物荧光素钠的血脑屏障转运情况。
皮下注射鱼藤酮未能产生多巴胺能损伤，但导致广泛的外周器官毒性。皮下注射鱼藤酮后荧光素的血脑屏障通透性发生了变化，但这是由于外周毒性所致。相比之下，脑内注射鱼藤酮在28天内产生了黑质纹状体多巴胺能通路的进行性损伤，且无相关外周毒性。脑内注射鱼藤酮还使苯丙胺诱导的旋转行为大幅增加。此外，少数脑内注射的大鼠显示出α-突触核蛋白免疫反应性和聚集。脑内注射鱼藤酮14天后，未检测到血脑屏障通透性的变化。
皮下注射鱼藤酮仅产生外周毒性。脑内注射鱼藤酮似乎造成了大鼠黑质纹状体通路的进行性损伤，因此与最常用的6-OH-DA大鼠模型相比，可能是更合适的帕金森病进展模型。
