Chlorbipram: a novel PDE4 inhibitor with improved safety as a potential antidepressant and cognitive enhancer.
Chlorbipram: a novel PDE4 inhibitor with improved safety as a potential antidepressant and cognitive enhancer.
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DOI：
10.1016/j.ejphar.2013.09.055
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发表时间：
2013-12
影响因子：
5
通讯作者：
Ming-zi Zhang;Zhong-Zhen Zhou;Xin Yuan;Yufang Cheng;B-T Bi;Mei-Fang Gong;Yupin Chen;Jiang-Ping Xu
中科院分区：
文献类型：
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作者：
Ming-zi Zhang;Zhong-Zhen Zhou;Xin Yuan;Yufang Cheng;B-T Bi;Mei-Fang Gong;Yupin Chen;Jiang-Ping Xu
重度抑郁症是一种常见但严重的精神功能障碍，影响全球21%的人口。Rolipram是第一代磷酸二酯酶-4（PDE 4）抑制剂，已被证明具有显著的抗抑郁和认知增强作用;然而，由于PDE 4依赖性副作用如恶心和呕吐，其在临床试验中不成功。在这项研究中，我们研究了新型PDE 4抑制剂氯比普兰和经典PDE 4抑制剂咯利普兰的神经药理学。采用抗抑郁药敏感性行为学试验，证明氯比普兰（0.075- 0.6mg/kg）急性单次给药可产生抗抑郁药样作用，表现为昆明种小鼠强迫游泳和悬尾试验中不动持续时间缩短，而自发活动无明显变化。在Morris水迷宫实验中，用不同剂量的氯比普仑（0.5-1.5 mg/kg）处理Sprague道利大鼠后，东莨菪碱诱导的认知功能障碍也显著减轻。此外，我们评估了氯比普兰在比格犬中的呕吐潜力。经口给药后，0.5 mg/kg咯利普兰在20分钟内在所有犬中显示呕吐特征，而氯比普兰在120分钟观察期内未诱导任何呕吐，即使在1.0 mg/kg剂量下也是如此。总之，我们的数据表明，氯比普兰是一种新型的抗抑郁药和认知增强剂，几乎没有或没有催吐效力。
Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075–0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5–1.5 mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5 mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0 mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency.