Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation.,SYNAPSE

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Phosphodiesterase inhibitors roflumilast and vardenafil prevent sleep deprivation-induced deficits in spatial pattern separation.
SYNAPSE ( IF 1.6 ) Pub Date : 2020-03-03 , DOI: 10.1002/syn.22150
Pim R A Heckman ₁ , Femke Roig Kuhn ₁ , Frank Raven ₁ , Youri G Bolsius ₁ , Jos Prickaerts ₂ , Peter Meerlo ₁ , Robbert Havekes ₁

Affiliation

Sleep deprivation (SD) is known to impair hippocampus-dependent memory processes, in part by stimulating the phosphodiesterase (PDE) activity. In the present study, we assessed in mice whether SD also affects spatial pattern separation, a cognitive process that specifically requires the dentate gyrus (DG) subregion of the hippocampus. Adult male mice were trained in an object pattern separation (OPS) task in the middle of the light phase and then tested 24 hr thereafter. In total, we conducted three studies using the OPS task. In the first study, we validated the occurrence of pattern separation and tested the effects of SD. We found that 6 hr of SD during the first half of the light phase directly preceding the test trial impaired the spatial pattern separation performance. As a next step, we assessed in two consecutive studies whether the observed SD-induced performance deficits could be prevented by the systemic application of two different PDE inhibitors that are approved for human use. Both the PDE4 inhibitor roflumilast and PDE5 inhibitor vardenafil successfully prevented SD-induced deficits in spatial pattern separation. As a result, these PDE inhibitors have clinical potential for the prevention of memory deficits associated with loss of sleep.

中文翻译：

磷酸二酯酶抑制剂罗氟司特和伐地那非可防止睡眠剥夺引起的空间模式分离缺陷。

众所周知，睡眠剥夺 (SD) 会损害海马依赖的记忆过程，部分是通过刺激磷酸二酯酶 (PDE) 活性。在本研究中，我们在小鼠中评估 SD 是否也影响空间模式分离，这是一种特别需要海马齿状回 (DG) 亚区的认知过程。成年雄性小鼠在光照阶段的中间接受了对象模式分离 (OPS) 任务的训练，然后在 24 小时后进行了测试。总的来说，我们使用 OPS 任务进行了三项研究。在第一项研究中，我们验证了模式分离的发生并测试了 SD 的影响。我们发现，在测试试验之前的光阶段的前半部分，6 小时的 SD 损害了空间模式分离性能。作为下一步，我们在两个连续的研究中评估了观察到的 SD 诱导的性能缺陷是否可以通过系统应用两种不同的 PDE 抑制剂来预防，这些 PDE 抑制剂被批准用于人类。PDE4 抑制剂罗氟司特和 PDE5 抑制剂伐地那非均成功地防止了 SD 诱导的空间模式分离缺陷。因此，这些 PDE 抑制剂具有预防与睡眠不足相关的记忆缺陷的临床潜力。

更新日期：2020-04-22

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