Neuropharmacology Div., Department of Pharmacology, ISF College of Pharmacy, Moga-142001, Punjab, India.
Pharmacol Biochem Behav. 2012 Apr;101(2):239-45. doi: 10.1016/j.pbb.2012.01.004. Epub 2012 Jan 20.
Cyclic nucleotides viz cGMP and cAMP are known to play an important role in learning and memory processes. Enhancement of cyclic nucleotide signalling through inhibition of phosphodiesterases (PDEs) has been reported to be beneficial in several neurodegenerative disorders associated with cognitive decline. The present study was undertaken to investigate the effect of RO-20-1724-a PDE4 inhibitor on streptozotocin (STZ) induced experimental sporadic dementia of Alzheimer's type. The STZ was injected twice intracerebroventrically (3 mg/kg i.c.v.) on alternate days (day 1 and day 3) in rats. The STZ injected rats were treated with RO-20-1724 (125, 250 and 500 μg/kgi.p.) for 21 days following first i.c.v. STZ administration. Learning and memory in rats were assessed by passive avoidance [PA (days 14 and 15)] and Morris water maze [MWM (days 17, 18, 19, 20 and 21)] following first i.c.v. STZ administration. On day 22 rat cerebral homogenate was used for all the biochemical estimations. The pharmacological inhibition of PDE4 by RO-20-1724 significantly attenuated STZ induced cognitive deficit and oxidative stress. RO-20-1724 was found to not only improve learning and memory in MWM and PA paradigms but also restore STZ induced elevation in cholinesterase activity. Further, RO-20-1724 significantly reduced malondialdehyde and nitrite levels, and restored the glutathione levels indicating attenuation of oxidative stress. Current data complement previous studies by providing evidence for a subset of cognition enhancing effects after PDE4 inhibition. The observed beneficial effects of RO-20-1724 in spatial memory may be due to its ability to restore cholinergic functions and possibly through its antioxidant mechanisms.
环核苷酸，即 cGMP 和 cAMP，已知在学习和记忆过程中发挥重要作用。通过抑制磷酸二酯酶（PDEs）增强环核苷酸信号已被报道对几种与认知能力下降相关的神经退行性疾病有益。本研究旨在探讨 PDE4 抑制剂 RO-20-1724 对链脲佐菌素（STZ）诱导的实验性散发性阿尔茨海默病型痴呆的影响。STZ 以脑室注射（3mg/kg i.c.v.）的方式在两天内（第 1 天和第 3 天）两次注射到大鼠中。在第一次 i.c.v. STZ 给药后，用 RO-20-1724（125、250 和 500μg/kg i.p.）对 STZ 注射大鼠进行 21 天的治疗。在第一次 i.c.v. STZ 给药后，通过被动回避[PA（第 14 天和第 15 天）]和 Morris 水迷宫[MWM（第 17、18、19、20 和 21 天）]评估大鼠的学习和记忆。在第 22 天，用大鼠脑匀浆进行所有生化测定。RO-20-1724 对 PDE4 的药理学抑制显著减轻了 STZ 引起的认知障碍和氧化应激。结果发现，RO-20-1724 不仅可以改善 MWM 和 PA 范式中的学习和记忆，而且可以恢复 STZ 诱导的乙酰胆碱酯酶活性升高。此外，RO-20-1724 显著降低了丙二醛和亚硝酸盐水平，并恢复了谷胱甘肽水平，表明氧化应激得到了缓解。目前的数据通过提供 PDE4 抑制后认知增强作用的子集的证据，补充了以前的研究。RO-20-1724 在空间记忆方面的有益作用可能是由于其恢复胆碱能功能的能力，并且可能通过其抗氧化机制。
