Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, NL-6200 Maastricht, The Netherlands.
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Torri Biologiche Via S. Sofia, 89, 95123 Catania, Italy.
Eur J Pharmacol. 2017 Dec 15;817:59-70. doi: 10.1016/j.ejphar.2017.05.058. Epub 2017 May 31.
The response of a biological system to an endogenous or exogenous molecule depends upon the dose. For this reason, performing dose-response curves is crucial to understand physiological and pathophysiological phenomena, and to predict the effect of a drug. Most of the studies in pharmacological research have been performed according to the classical threshold model, focusing on higher doses able to ensure a biological effect. However, recent evidences pointed out the need to investigate the effect of low doses. Indeed, several molecules behave in a hormetic fashion, i.e. low-doses stimulate whereas high-doses inhibit a biological response. This is particularly interesting in CNS, where several physiological molecules involved in neuronal transmission during learning and memory have shown a biphasic effect that might represent the link between physiology and pathology. In this review we will focus on cholinergic, glutamatergic and nitrinergic transmission, because of their central role in learning and memory and their impairment in neurodegenerative disorders such as Alzheimer's disease. Pre-clinical studies performed on healthy adult animals and aged animals, as well as transgenic animal models of AD, have suggested a biphasic DR for acetylcholine, glutamate and nitric oxide. This stresses the relevance to perform DR curves when studying the mechanisms underlying synaptic plasticity and memory, the pharmacological profile of cognitive-enhancing drugs acting on these systems, and the possibility to combine low/ineffective doses of drugs that might have additive/synergistic effects, reducing the unwanted side effects associated to the high doses.
生物系统对外源或内源性分子的反应取决于剂量。因此，进行剂量反应曲线的研究对于理解生理和病理生理现象以及预测药物的效果至关重要。药理学研究中的大多数研究都是根据经典的阈值模型进行的，重点关注能够确保生物学效应的较高剂量。然而，最近的证据表明需要研究低剂量的影响。事实上，有几种分子表现出 hormesis 效应，即低剂量刺激而高剂量抑制生物反应。这在中枢神经系统中尤其有趣，因为几种参与学习和记忆过程中神经元传递的生理分子表现出双相效应，这可能代表了生理学和病理学之间的联系。在这篇综述中，我们将重点关注胆碱能、谷氨酸能和硝能传递，因为它们在学习和记忆中起着核心作用，并且在阿尔茨海默病等神经退行性疾病中受到损害。在健康成年动物和老年动物以及 AD 的转基因动物模型上进行的临床前研究表明，乙酰胆碱、谷氨酸和一氧化氮存在双相 DR。这强调了在研究突触可塑性和记忆的机制、作用于这些系统的认知增强药物的药理学特征以及组合低/无效剂量药物的可能性时，进行 DR 曲线的重要性，这些药物可能具有相加/协同作用，从而减少与高剂量相关的不必要的副作用。
