Homberg Judith R, Kyzar Evan J, Stewart Adam Michael, Nguyen Michael, Poudel Manoj K, Echevarria David J, Collier Adam D, Gaikwad Siddharth, Klimenko Viktor M, Norton William, Pittman Julian, Nakamura Shun, Koshiba Mamiko, Yamanouchi Hideo, Apryatin Sergey A, Scattoni Maria Luisa, Diamond David M, Ullmann Jeremy F P, Parker Matthew O, Brown Richard E, Song Cai, Kalueff Allan V
a Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour , Radboud University Medical Centre , Nijmegen , The Netherlands.
b Department of Psychiatry, College of Medicine , University of Illinois at Chicago , Chicago , IL , USA.
Expert Opin Drug Discov. 2016;11(1):11-25. doi: 10.1517/17460441.2016.1115834. Epub 2015 Dec 2.
Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task.
Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies.
To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.
神经发育障碍(NDDs)很常见且严重致残。其慢性性质以及对遗传和环境因素的依赖使得研究NDDs及其治疗成为一项具有挑战性的任务。
在此,作者讨论了NDDs的神经生物学机制,并提出了关于其转化研究和治疗的建议,这些建议由国际压力与行为协会概述。目前用于治疗NDDs的各种药物也代表了一个高度多样化的群体。这些药物作用于各种神经递质和生理系统,往往缺乏作用特异性,并且通常用于治疗多种其他精神疾病。在开发治疗NDDs的新型药物方面也进展相对较少。基于NDDs的临床、临床前和转化模型,我们的建议涵盖了广泛的方法学方法和概念策略。
为了改善NDDs的药物治疗和药物发现,我们需要更加强调针对多种内表型,更好地剖析遗传/表观遗传因素或“隐藏遗传率”,并仔细考虑脑内神经递质的潜在发育/营养作用。通过发现新的(行为、生理和神经影像学)生物标志物、应用适当的环境富集、拓宽模型生物的范围、针对NDD相关行为的发育轨迹以及超越传统NDDs的共病情况,可以提高动物NDD模型的有效性。虽然这些建议不能一次性全部解决,但我们对NDD病理生物学的进一步理解可能会引发创新的跨学科研究,超越传统方法和概念。