Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.
Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.
复制标题
DOI：
10.1371/journal.pone.0110432
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Chin CL
中科院分区：
文献类型：
--
作者：
Seah S;Asad AB;Baumgartner R;Feng D;Williams DS;Manigbas E;Beaver JD;Reese T;Henry B;Evelhoch JL;Chin CL
药理学磁共振成像(PhMRI)是一种神经成像技术，药物诱导的血流动力学反应可以代表药物动力学生物标记物，以描绘药物作用的潜在生物学后果。在大多数临床前研究中，动物在图像采集过程中被麻醉以最大限度地减少运动。然而，已经证明麻醉可以减弱基础神经元的活动，这可能会混淆对药物诱导的大脑激活模式的解释。在啮齿动物和非人灵长类动物(NHP)中建立清醒成像已经做出了重大努力。虽然已经开发了各种平台来对清醒的NHP进行成像，但将phMRI数据作为跨物种的翻译生物标记物的比较和验证仍有待探索。我们已经建立了一个清醒的NHP成像模型，它包含了一个专门的动物限制器的全面驯化过程。我们用基于脑血容量(CBV)的phMRI方法，在清醒和麻醉条件下，测定了全身给药丁丙诺啡(0.03 mg/kg静脉注射)引起的脑激活的差异反应。丁丙诺啡是一种部分的µ-阿片受体激动剂。此外，还进行了感兴趣区分析，以确定药物诱导的局部CBV时程数据和相应的曲线下面积(AUC)值，这些数据来自µ-阿片受体密度较高的脑区。在清醒的NHP中，小组水平的分析显示丁丙诺啡显著激活了大脑区域，包括丘脑、纹状体、额叶和扣带皮质(配对t检验，与生理盐水载体，p<；0.05，n = 4)。这一观察结果与[6-O-[11C]甲基]丁丙诺啡([11C]BPN)正电子发射断层扫描成像研究所描述的[6-O-[11C]甲基]丁丙诺啡([11C]BPN)在狒狒体内的µ-阿片受体分布非常一致。此外，我们的发现与之前在人类和清醒大鼠上进行的丁丙诺啡phMRI研究一致，这些研究共同证明了清醒成像的跨物种可译性。相反，在麻醉状态下成像的相同动物的大脑激活区域没有发现显著变化。我们的数据强调了唤醒NHP成像作为药物研究的翻译成像生物标记物的实用性和重要性。
Pharmacological MRI (phMRI) is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP). Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored. We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV)-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v.), a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC) values from brain areas with high density of µ-opioid receptors. In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4). This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[11C]methyl]buprenorphine ([11C]BPN) positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively demonstrate the cross-species translatability of awake imaging. Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition. Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.
登录
查看更多内容
影响因子：
6.7
作者：
Hargreaves, R. J.
通讯作者：
Hargreaves, R. J.
影响因子：
5.7
作者：
De Simoni, S.;Schwarz, A. J.;Mehta, M. A.
通讯作者：
Mehta, M. A.
影响因子：
0.7
作者：
Lee, Jae-Il;Shin, Jun-Seop;Kim, Sang-Joon
通讯作者：
Kim, Sang-Joon
影响因子：
7.6
作者：
Febo, M;Segarra, AC;Ferris, CF
通讯作者：
Ferris, CF
影响因子：
5.7
作者：
Leite, FP;Tsao, D;Mandeville, JB
通讯作者：
Mandeville, JB