1. 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.
- Author
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Zhang, Lijun, Seo, Jae Hong, Li, Huan, Nam, Ghilsoo, and Yang, Hyun Ok
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PHOSPHODIESTERASE inhibitors , *AMNESIA , *CARRIER proteins , *OXIDATIVE stress , *WESTERN immunoblotting , *DIAGNOSIS , *PROTEIN metabolism , *NUCLEOTIDE metabolism , *ANIMAL experimentation , *BIOLOGICAL models , *CELLULAR signal transduction , *COMPARATIVE studies , *LEARNING , *RESEARCH methodology , *MEDICAL cooperation , *MEMORY , *MICE , *MOLECULAR structure , *RESEARCH , *RESEARCH funding , *EVALUATION research , *PHARMACODYNAMICS - 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. [ABSTRACT FROM AUTHOR]- Published
- 2018
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