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PDE4 as a target for cognition enhancement

机译：PDE4作为认知增强的目标

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Introduction: The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning, and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered: PDE4 is the largest of the 11 mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion: PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.
机译：简介：第二个信使cAMP和cGMP介导与记忆，学习和认知功能有关的脑功能的基本方面。因此，灭活环状核苷酸的酶环状核苷酸磷酸二酯酶（PDEs）是开发认知增强药物的有希望的目标。覆盖范围：PDE4是11个哺乳动物PDE家族中最大的。这篇综述涵盖了PDE4系列的特性和功能，重点介绍了与PDE4灭活相关的认知和记忆增强作用。专家意见：PAN选择性PDE4抑制剂在临床前模型中发挥许多记忆和认知增强作用，并具有神经保护和神经再生特性。其临床应用的主要障碍是将抑制剂靶向与特定认知障碍相关的特定PDE4亚型，以实现治疗潜力，同时避免副作用，尤其是呕吐和恶心。 PDE4家族包含四个基因PDE4A-D，每个基因均表达为多种变体。迄今为止的进展源于对啮齿类动物模型的表征以及对单个PDE4亚型的选择性切除，从而揭示了单个亚型在大脑中发挥着独特且非冗余的功能。因此，靶向特定的PDE4亚型，以及剪接变体或构象状态，代表了将治疗益处与PAN-PDE4抑制剂的副作用分开的有前途的策略。

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