NON-INVASIVE METHOD TO MEASURE NEURAL PHARMACOKINETICS AND PHARMACODYNAMICS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 治疗药物开发的一个关键部分是确定药物的疗效(药效学)及其在体内的寿命(药代动力学)。我们推测，视网膜电信号(ERG)是视网膜功能的活体记录，可以提供一种独特的非侵入性方法来推导新化合物的神经药效学/药代动力学，这些化合物是治疗神经疾病的候选药物。谷氨酸是大脑和视网膜中的主要兴奋性神经递质。由于G蛋白偶联的代谢性谷氨酸受体(MGluRs)在调节突触传递方面的作用，人们正在研究将其作为治疗神经疾病的新药的潜在位点。 我的合作者罗伯特·杜沃辛博士和我正在研究视网膜中第三组mGluRs的分布和功能。我们最近在小鼠身上发现，系统地给予三种新的药物作为mGluR4、-R7或-R8的选择性激动剂或调节剂，可以改变ERG振荡电位(OPS)。从胚胎学上讲，视网膜是中枢神经系统的一部分，视网膜内部的突触与皮质突触具有相似的结构和功能。血视网膜屏障和血脑屏障在结构和作用方式上也具有可比性。因此，视网膜内可测量的影响可以作为大脑功能影响的替代指标。我们认为，视网膜内神经活动产生的ERG振荡电位可以作为一种可访问的、非侵入性的功能测试来测量药物的神经效应。 非人灵长类动物模型是必不可少的，因为东半球的猴子，如恒河猴，是唯一一种视网膜与人类几乎相同的动物。这个试点项目的目标是使我们在老鼠身上开发的方法用于非人类灵长类动物，这反过来将成为将我们的技术扩展到人类临床前试验的基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A critical part of therapeutic drug development is determining the efficacy of a drug (pharmacodynamics) and its lifetime within the body (pharmacokinetics). We hypothesize that the electroretinogram (ERG), an in vivo recording of retinal function, can provide a unique non-invasive method for deriving the neural pharmacodynamics/pharmacokinetics of novel compounds that are candidate therapies for neurological disorders. Glutamate is the main excitatory neurotransmitter in both the brain and retina. Because of their role in regulating synaptic transmission, the G protein-coupled metabotropic glutamate receptors (mGluRs) are being studied as potential sites for new drugs aimed at the treatment of neurological disorders. My collaborator, Dr Robert Duvoisin and I are studying the distribution and function of group-III mGluRs in the retina. We recently found in mice that ERG oscillatory potentials (OPs), are altered by systemic administration of three new classes of drugs that act as selective agonists or modulators of mGluR4, -R7 or -R8. The retina is embryologically part of the CNS, and synapses within the inner retina share similar structure and function with cortical synapses. The blood-retina barrier and blood-brain barrier are also comparable in structure and mode of action. Thus, measurable effects within the retina could serve as a proxy for effects on brain function. We propose that the ERG oscillatory potentials, generated by neural activity within the inner retina, could serve as an accessible, non-invasive functional assay for measuring the neural effects of drugs. A non-human primate model is essential as old-world monkeys, such as the rhesus, are the only animals with a retina almost identical to the human. The goal of this pilot project is to adapt our method developed in mice for use in non-human primates, which in turn will serve as a foundation for extending our technique to pre-clinical trials in humans.