Prickaerts J, van Staveren W C G, Sik A, Markerink-van Ittersum M, Niewöhner U, van der Staay F J, Blokland A, de Vente J
Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience EURON, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Neuroscience. 2002;113(2):351-61. doi: 10.1016/s0306-4522(02)00199-9.
The present study investigated the effects of two cyclic GMP-specific phosphodiesterase enzyme type 5 inhibitors, sildenafil and vardenafil, on the memory performance in the object recognition task. Both compounds were given per orally (1, 3 and 10 mg/kg sildenafil; 0.1, 0.3, 1 and 3 mg/kg vardenafil) immediately after the exposure to two identical objects. The memory for the objects was tested 24 h later. Vehicle-treated rats spent equal times exploring a new and the familiar object demonstrating that they did not remember the familiar one. However, sildenafil improved the object discrimination performance of the rats with a high discrimination performance at a dose of 3 mg/kg. Rats treated with vardenafil also showed an improved object discrimination performance. Compared with sildenafil, vardenafil appeared to be even more potent in this respect since it already produced a high discrimination performance at a dose of 0.3 mg/kg. The effects of both compounds on cyclic GMP and cyclic AMP accumulation were studied in rat hippocampal slices incubated in vitro. Cyclic GMP levels were increased after incubation with the highest concentration of 100 microM vardenafil (together with 0.1 mM sodium nitroprusside), although no changes in cyclic GMP levels were detected after incubation with different concentrations of sildenafil. Both compounds had no effect on cyclic AMP levels. Additional cyclic GMP immunocytochemistry showed that incubation with vardenafil (in the presence of sodium nitroprusside) resulted in a concentration-dependent staining of cyclic GMP. Staining was predominantly found in neuronal fibres in the hippocampal CA2/CA3 region. It was already detected at a concentration of 0.1 microM vardenafil. Also positive fibres were detected after incubation with sildenafil but at a higher concentration of 10 microM. Taken together, these results suggest that inhibition of phosphodiesterase enzyme type 5 improves object recognition memory. This effect might be explained by increased levels of central cyclic GMP.
本研究调查了两种5型环鸟苷酸特异性磷酸二酯酶抑制剂西地那非和伐地那非对物体识别任务中记忆表现的影响。在接触两个相同物体后，立即口服给予这两种化合物（西地那非1、3和10 mg/kg；伐地那非0.1、0.3、1和3 mg/kg）。24小时后测试对物体的记忆。给予赋形剂处理的大鼠探索新物体和熟悉物体的时间相同，表明它们不记得熟悉的物体。然而，西地那非在3 mg/kg剂量时改善了具有高辨别能力大鼠的物体辨别表现。给予伐地那非处理的大鼠也表现出物体辨别能力的改善。与西地那非相比，伐地那非在这方面似乎更有效，因为它在0.3 mg/kg剂量时就已经产生了高辨别表现。在体外培养的大鼠海马切片中研究了这两种化合物对环鸟苷酸和环磷酸腺苷积累的影响。与最高浓度100 microM伐地那非（与0.1 mM硝普钠一起）孵育后，环鸟苷酸水平升高，尽管与不同浓度西地那非孵育后未检测到环鸟苷酸水平的变化。这两种化合物对环磷酸腺苷水平均无影响。额外的环鸟苷酸免疫细胞化学显示，与伐地那非（在硝普钠存在下）孵育导致环鸟苷酸的浓度依赖性染色。染色主要见于海马CA2/CA3区的神经纤维。在0.1 microM伐地那非浓度时就已检测到。与西地那非孵育后也检测到阳性纤维，但浓度较高，为10 microM。综上所述，这些结果表明抑制5型磷酸二酯酶可改善物体识别记忆。这种作用可能是由中枢环鸟苷酸水平升高所解释。
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