Protective effects of phosphodiesterase 2 inhibitor against A β < sub > 1-42 < /sub > induced neuronal toxicity

Neuropharmacology. 2022 May 16:109128. doi: 10.1016/j.neuropharm.2022.109128. Online ahead of print.ABSTRACTOur 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 Aβ oligomers (Aβo)-induced neuronal damage and memory impairment. The results suggested that exposure of primary cortical neurons to Aβo 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 Aβo-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 Aβo 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 Aβo-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 eigh...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Source Type: research