Protective effects of phosphodiesterase 2 inhibitor against Aß1-42 induced neuronal toxicity.

Our previous study suggested that inhibition of Phosphodiesterase 2 ameliorates memory loss upon exposure to oxidative stress. While whether memory enhancing effects of PDE2 inhibition on Alzheimer's disease mouse model are involved in antioxidant defense and neuronal remodeling, are largely unexplored. The present study addressed whether and how PDE2 inhibitor Bay 60-7550 rescued Aß oligomers (Aßo)-induced neuronal damage and memory impairment. The results suggested that exposure of primary cortical neurons to Aßo induced neuronal cells damage and increased PDE2 expression, which were paralleled to an increase in the oxidative parameter malondialdehyde (MDA) level and cellular apoptosis. However, this Aßo-induced oxidative damage was blocked by pre-treatment with protein kinase A or G (PKA or PKG) inhibitor, suggesting the involvement of cAMP/cGMP signaling. Moreover, microinjection of Aßo into the prefrontal cortex of mice increased the MDA level; while Bay 60-7550 reversed this effect and increased antioxidant and anti-apoptotic factors, i.e. increased trolox-equivalent-antioxidant capacity and Bcl-2/Bax ratio. Bay 60-7550 also rescued Aßo-induced synaptic atrophy and memory deficits, as evidenced by the increased synaptic proteins' levels and spine density in the prefrontal cortex, and improved cognitive behaviors by decreased working memory errors in the eight-arm maze and increased discrimination index in the novel object recognition test. These findings suggest that inhibition of PDE2 contributes to antioxidant defense and neuronal remodeling by regulation of cAMP/cGMP signaling, which provide a theoretical basis for the future use of PDE2 inhibitors as the anti-AD drugs.

Activation of monoaminergic system contributes to the antidepressant- and anxiolytic-like effects of J147.

Major depressive disorder (MDD) is a severe mental disorder, which is closely related to the deficiency of monoamine neurotransmitters. Our previous study suggested that acute treatment with J147, a novel curcumin derivative, produced antidepressant-like effects in mouse model of depression by regulation of 5-HT receptor subtypes. However, it is still unknown whether the antidepressant-like effects of J147 are involved in activation of central monoaminergic system. In this study, a series of classical behavior tests were employed to assess the involvement of monoaminergic system in antidepressant- and anxiolytic-like effects after sub-acute treatment of mice with J147 for 3 days. The results suggested that J147 at 10 mg/kg significantly reduced the immobility time in both the tail suspension and forced swimming tests, but didn't show effects in the sucrose preference test. Similarly, sub-acute treatment of J147 did not induce amelioration in novelty suppressed feeding test. J147 increased duration and crossing time in the central area, but did not show significant change in rearing counts in the open field test. In neurochemical assays, studies suggested that serotonin and noradrenaline levels were significantly increased in the frontal cortex and hippocampus after treatment of J147 by the high-performance liquid chromatography (HPLC) with an electrochemical detector. Moreover, J147-induced significant inhibition of monoamine oxidase A activity. These findings suggest that the antidepressant- and anxiolytic-like effects of J147 might be related to the monoaminergic system by the evidence that high dose of J147 inhibits monoamine oxidase (MAO)-A activity and increases synaptic monoamines in the mouse brain.