Lijun Zhang1,2, Jae Hong Seo3, Huan Li1,2, Ghilsoo Nam2,4, Hyun Ok Yang1,2. 1. Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Korea. 2. Division of Bio-medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea. 3. Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do, Republic of Korea. 4. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.
Abstract
BACKGROUND AND PURPOSE: Inhibition of PDE5 improves synaptic plasticity and memory via enhancing cGMP expression, thus activating the cGMP/cAMP response element binding protein (CREB) signalling pathway. This study investigated the effects of a PDE5 inhibitor on scopolamine-induced cognitive dysfunction, using memory-related behavioural tests and biochemical assays. EXPERIMENTAL APPROACH: In mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine. The learning and memory abilities of mice were tested using the Morris water maze test, the Y-maze test, the passive avoidance test and the novel object recognition test in sequence. Expression of memory-related bio-molecules and oxidative stress parameters in brain tissue were measured using Western blot and spectrophotometry respectively. KEY RESULTS: KJH-1002, a novel and potent inhibitor of PDE5 (IC50 0.059 ± 0.04 nmol·L-1 ), was synthesized. In the behavioural tests, it markedly improved the memory performance impaired by scopolamine, indicating a restoration of cognitive function in the mice. Moreover, KJH-1002 increased cGMP levels in the cortex and the scopolamine-reduced expression of phosphorylated CREB, Levels of ERK 1/2, Akt and brain-derived neurotrophic factor in the cortex and hippocampus were restored by KJH-1002 treatment. In addition, KJH-1002 administration increased the activities of SOD, glutathione peroxidase and glutathione reductase, and decreased the level of malondialdehyde. CONCLUSION AND IMPLICATIONS: KJH-1002 restored cognitive function in scopolamine-induced amnesia mice by activating the cGMP/CREB signalling pathway and attenuating oxidative stress. The beneficial effects of KJH-1002 on cognition indicate its potential as a therapeutic candidate for Alzheimer's disease.
BACKGROUND AND PURPOSE: Inhibition of PDE5 improves synaptic plasticity and memory via enhancing cGMP expression, thus activating the cGMP/cAMP response element binding protein (CREB) signalling pathway. This study investigated the effects of a PDE5 inhibitor on scopolamine-induced cognitive dysfunction, using memory-related behavioural tests and biochemical assays. EXPERIMENTAL APPROACH: In mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine. The learning and memory abilities of mice were tested using the Morris water maze test, the Y-maze test, the passive avoidance test and the novel object recognition test in sequence. Expression of memory-related bio-molecules and oxidative stress parameters in brain tissue were measured using Western blot and spectrophotometry respectively. KEY RESULTS:KJH-1002, a novel and potent inhibitor of PDE5 (IC50 0.059 ± 0.04 nmol·L-1 ), was synthesized. In the behavioural tests, it markedly improved the memory performance impaired by scopolamine, indicating a restoration of cognitive function in the mice. Moreover, KJH-1002 increased cGMP levels in the cortex and the scopolamine-reduced expression of phosphorylated CREB, Levels of ERK 1/2, Akt and brain-derived neurotrophic factor in the cortex and hippocampus were restored by KJH-1002 treatment. In addition, KJH-1002 administration increased the activities of SOD, glutathione peroxidase and glutathione reductase, and decreased the level of malondialdehyde. CONCLUSION AND IMPLICATIONS: KJH-1002 restored cognitive function in scopolamine-induced amnesiamice by activating the cGMP/CREB signalling pathway and attenuating oxidative stress. The beneficial effects of KJH-1002 on cognition indicate its potential as a therapeutic candidate for Alzheimer's disease.
Authors: Michael J Curtis; Steve Alexander; Giuseppe Cirino; James R Docherty; Christopher H George; Mark A Giembycz; Daniel Hoyer; Paul A Insel; Angelo A Izzo; Yong Ji; David J MacEwan; Christopher G Sobey; S Clare Stanford; Mauro M Teixeira; Sue Wonnacott; Amrita Ahluwalia Journal: Br J Pharmacol Date: 2018-04 Impact factor: 8.739
Authors: F Josef van der Staay; Kris Rutten; Lars Bärfacker; Jean Devry; Christina Erb; Heike Heckroth; Dagmar Karthaus; Adrian Tersteegen; Marja van Kampen; Arjan Blokland; Jos Prickaerts; Klaus G Reymann; Ulrich H Schröder; Martin Hendrix Journal: Neuropharmacology Date: 2008-07-12 Impact factor: 5.250
Authors: Dong-Hun Lee; Ji Young Lee; Dong-Yong Hong; Eun Chae Lee; Sang-Won Park; Yu Na Jo; Yu Jin Park; Jae Young Cho; Yoo Jin Cho; Su Hyun Chae; Man Ryul Lee; Jae Sang Oh Journal: Biomedicines Date: 2022-06-08