The phosphodiesterase 5 inhibitor, KJH-1002,
- The phosphodiesterase 5 inhibitor, KJH-1002,
- 남길수; 양현옥; 장리준; 서재홍; 리후안
- Issue Date
- British journal of pharmacology
- VOL 175, NO 16-3360
- 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.
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.
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.
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