最新论文
更多信息
[已阅读520次]
神经药理及新药发现课题组在Neuropharmacology上发表研究论文

 

神经药理及新药发现课题组在Neuropharmacology上发表研究论文

 

    神经药理及新药发现徐江平教授课题组于近日在Neuropharmacology上发表了题为“FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects”的研究论文。
    磷酸二酯酶4(PDE4) 是一个良好的改善认知障碍的药物研发靶点,但到目前为止还没有针对这一靶点的药物用于临床治疗老年性痴呆,究其原因主要为这类化合物具有难以忍受的致呕吐副反应。该项研究利用APP/PS1转基因鼠探索了新型PDE4抑制剂FFPM (University of North Carolina提供)对认知障碍模型小鼠学习记忆能力的改善作用。研究发现FFPM口服给药后2 h,血浆药物浓度达到峰值,并能透过血脑屏障进入中枢神经系统。通过神经行为学实验证实在0.25-0.5mg/kg的剂量下,FFPM能显著改善小鼠的记忆能力,且不缩短xylazine/ketamine诱导的麻醉时间,不影响小鼠翻正反射,提示其致呕吐的可能性很小。进一步发现FFPM可增加小鼠海马组织中cAMP含量、增加PKA及CREB磷酸化、增加BDNF的表达;并降低海马组织中NF-κB p65、iNOS、TNF-α 及 IL-1β的水平。目前,课题组正在研究这一化合物在神经胶质细胞中调控炎症因子水平(分泌)的机制。这些研究为将FFPM开发为新型改善认知障碍的药物提供实验依据。
    此论文受到国家自然科学基金面上项目、国家自然科学基金青年基金、新药创制重大专项及广东省科技计划等基金资助。2011级硕博连读生郭海彪为本论文的第一作者,徐江平教授、汪海涛博士为该论文的共同通讯作者。Neuropharmacology 为小类药学1区杂志,IF=4.936。

Guo H, Cheng Y, Wang C, Wu J, Zou Z, Niu B, Yu H, Wang H, Xu J. FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. Neuropharmacology. 2017 Jan 5. pii: S0028-3908(17)30004-7. doi: 10.1016/j.neuropharm.2017.01.004. [Epub ahead of print]
Abstract
Thus far, phosphodiesterase-4 (PDE4) inhibitors have not been approved for application in Alzheimer's disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing. A 3 week treatment with FFPM, at doses of 0.25 mg/kg and 0.5 mg/kg, significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the Morris water maze and the Step-down passive avoidance task. Interestingly, we found that while rolipram (0.5 mg/kg) reduced the duration of the α2 adrenergic receptor-mediated anesthesia induced by xylazine/ketamine, FFPM (0.5 mg/kg) or the vehicle did not have an evident effect. FFPM increased the cAMP, PKA and CREB phosphorylation and BDNF levels, and reduced the NF-κB p65, iNOS, TNF-α and IL-1β levels in the hippocampi of APP/PS1 trangenic mice, as observed by ELISA and Western blot analysis. Taken together, our data demonstrated that the reversal effect of FFPM on cognitive deficits in APP/PS1 transgenic mice might be related to stimulation of the cAMP/PKA/CREB/BDNF pathway and anti-inflammatory effects. Moreover, FFPM appears to have potential as an effective PDE4 inhibitor in AD treatment with little emetic potential.