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Br J Pharmacol. 2018 Aug;175(16):3347-3360. doi: 10.1111/bph.14377. Epub 2018 Jul 10.

The phosphodiesterase 5 inhibitor, KJH-1002, reverses a mouse model of amnesia by activating a cGMP/cAMP response element binding protein pathway and decreasing oxidative damage.

Zhang L1,2, Seo JH3, Li H1,2, Nam G2,4, Yang HO1,2.

Author information

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.

PMID:
29847860
PMCID:
PMC6057906
DOI:
10.1111/bph.14377

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