Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, The Netherlands.
Neurobiol Learn Mem. 2012 May;97(4):370-9. doi: 10.1016/j.nlm.2012.02.008. Epub 2012 Mar 8.
A promising target for memory improvement is phosphodiesterase type 5 (PDE5), which selectively hydrolyzes cyclic guanosine monophosphate (cGMP). In rodents, PDE5 inhibitors (PDE5-Is) have been shown to improve memory performance in many behavioral paradigms. However, it is questioned whether the positive effects in animal studies result from PDE5 inhibition in the central nervous system or the periphery. Therefore, we studied the effects of PDE5 inhibition on memory and determined whether compound penetration of the blood-brain barrier (BBB) is required for this activity. Two selective PDE5-Is, vardenafil and UK-343,664, were tested in the object recognition task (ORT) in both a MK-801- and scopolamine-induced memory deficit model, and a time-delay model without pharmacological intervention. Compounds were dosed 30 min before the learning trial of the task. To determine if the PDE5-Is crossed the BBB, their concentrations were determined in plasma and brain tissue collected 30 min after oral administration. Vardenafil improved object recognition memory in all three variants of the ORT. UK-343,664 was ineffective at either preventing MK-801-induced memory disruption or time-dependent memory decay. However, UK-343,664 attenuated the memory impairment of scopolamine. Vardenafil crossed the BBB whereas UK-343,664 did not. Further, co-administration of UK-343,664 and scopolamine did not alter the brain partitioning of either molecule. This suggests that the positive effect of UK-343,664 on scopolamine-induced memory decay might arise from peripheral PDE5 inhibition. The results herein suggest that there may be multiple mechanisms that mediate the efficacy of PDE5 inhibition to improve memory performance in tasks such as the ORT and that these involve PDE5 located both within and outside of the brain. To further elucidate the underlying mechanisms, the cellular and subcellular localization of PDE5 needs to be determined.
一种有前途的改善记忆的靶点是磷酸二酯酶 5（PDE5），它选择性地水解环鸟苷单磷酸（cGMP）。在啮齿动物中，已经证明 PDE5 抑制剂（PDE5-Is）在许多行为范式中改善记忆表现。然而，人们质疑动物研究中的积极影响是否来自中枢神经系统或外周的 PDE5 抑制。因此，我们研究了 PDE5 抑制对记忆的影响，并确定这种活性是否需要 PDE5 抑制剂穿透血脑屏障（BBB）。两种选择性 PDE5-Is，伐地那非和 UK-343,664，在 MK-801 和东莨菪碱诱导的记忆缺陷模型以及没有药物干预的时间延迟模型中的物体识别任务（ORT）中进行了测试。化合物在任务的学习试验前 30 分钟给药。为了确定 PDE5-Is 是否穿过 BBB，在口服给药后 30 分钟收集的血浆和脑组织中测定其浓度。伐地那非改善了 ORT 的所有三种变体中的物体识别记忆。UK-343,664 既不能预防 MK-801 诱导的记忆中断，也不能预防时间依赖性记忆衰退。然而，UK-343,664 减轻了东莨菪碱引起的记忆障碍。伐地那非穿过了 BBB，而 UK-343,664 则没有。此外，UK-343,664 和东莨菪碱的共同给药并未改变两种分子的脑内分布。这表明 UK-343,664 对东莨菪碱诱导的记忆衰退的积极影响可能来自外周 PDE5 抑制。本研究结果表明，在 ORT 等任务中，介导 PDE5 抑制改善记忆表现的机制可能有多种，这些机制涉及到脑内和脑外的 PDE5。为了进一步阐明潜在的机制，需要确定 PDE5 的细胞和亚细胞定位。
