Lueptow Lindsay M, Zhan Chang-Guo, O'Donnell James M
Neuroscience Graduate Program, West Virginia University Health Sciences Center, Morgantown, WV, USA.
West Virginia University, 1 Medical Center Drive, PO Box 9128, Morgantown, WV, USA.
Psychopharmacology (Berl). 2016 Feb;233(3):447-56. doi: 10.1007/s00213-015-4129-1. Epub 2015 Nov 2.
Cyclic nucleotide phosphodiesterase-2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learning and memory, and examined underlying mechanisms.
To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[-1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 μg; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 μg; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5'-cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilator-stimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3'5'-cyclic guanosine monophosphate (cGMP) signaling.
Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG).
These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function.
环核苷酸磷酸二酯酶2（PDE2）是治疗认知功能障碍的一个潜在治疗靶点。本研究采用物体识别试验（ORT）评估了两种PDE2抑制剂Bay 60 - 7550和ND7001对学习和记忆的影响，并探究了其潜在机制。
为评估PDE2抑制对记忆各阶段的作用，分别在训练前30分钟、训练后0、1或3小时、或回忆测试前30分钟给予Bay 60 - 7550（3 mg/kg）。为评估环核苷酸在PDE2抑制剂增强记忆巩固中的作用，在给予PDE2抑制剂Bay 60 - 7550（3 mg/kg）或ND7001（3 mg/kg）前30分钟，腹腔注射一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME；20 mg/kg）、可溶性鸟苷酸环化酶抑制剂1H-[-1,2,4]恶二唑并-[4,3-a]喹喔啉-1-酮（ODQ；20 mg/kg）、蛋白激酶G抑制剂KT5823（2.5 μg；脑室内注射（ICV））或蛋白激酶A抑制剂H89（1 μg；ICV）。测定丝氨酸133位点的3',5'-环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）和丝氨酸239位点的血管舒张刺激磷蛋白（VASP）的磷酸化变化，以确认cAMP和3',5'-环磷酸鸟苷（cGMP）信号通路的激活。
当在训练前30分钟、训练后立即或回忆前30分钟给予Bay 60 - 7550（3 mg/kg）时，可增强小鼠在ORT中的记忆。cGMP信号通路抑制剂可阻断Bay 60 - 7550（3 mg/kg）和ND7001（3 mg/kg）对早期巩固过程的记忆增强作用。Bay 60 - 7550（3 mg/kg）可增强CREB和VASP的磷酸化，二者均为cGMP依赖性蛋白激酶（PKG）的作用靶点。
这些结果证实了PDE2或其信号通路成分作为恢复记忆功能药物研发治疗靶点的潜力。
