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最近在Neuropsychopharmacology杂志发表的文章报道，抑制磷酸二酯酶4B（PDE4B）的活性将有望改进对认知障碍疾病的治疗方法。 PDE4B在脊椎动物身体的多个器官（包括脑在内）中存在，可以介导脑部学习、记忆和高级认知的功能。研究人员通过突变小鼠PDE4B基因的水解结构域，可以抑制PDE4B的活性。 与普通小鼠相比，PDE4B酶活性受到抑制的小鼠在行为测试中表现出认知能力增强，它们学得更快、记忆时间更长、并且能进行更为复杂的运动。同时，这些PDE4B酶突变的小鼠对恐惧的健忘时间也更长。这一发现，或许对寻找治疗病理性恐惧症的研究人员来说会有帮助。 PDE4B酶活性受到抑制的小鼠也表现出了较少的焦虑。他们会长时间地呆在宽敞明亮的地方。另外，与普通老鼠天性怕猫相比，PDE4B活性受到抑制的小鼠对猫尿的恐惧反应降低，这一结果显示：抑制PDE4B或许能增加他们的冒险力。 本研究是在小鼠内验证的，目前还没有在人体中测试，但是PDE4B也存在于人体中。目前研究人员正在继续研制抑制PDE4B活性的药物。这类药物将要首先进行动物实验，之后决定是否进行临床试验。此研究成果将有望改进对认知障碍疾病的治疗方法。 Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition Neuropsychopharmacology, 2015 Abstract Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with acatalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24h, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory. 参考链接： http://www./npp/journal/vaop/ncurrent/full/npp2015240a.html |
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