7-Pyrrolidinethoxy-4'-Methoxyisoflavone Prevents Amyloid ?-Induced Injury by Regulating Histamine H3 Receptor-Mediated cAMP/CREB and AKT/GSK3? Pathways.

ABSTRACT: In studies on the treatment of Alzheimer's disease (AD), in which cognition is enhanced even modestly or selectively, it has been considered that the histamine H3 receptor (H3R) may be a potential target. In this study, we aimed at evaluating the ability of 7-pyrrolidinethoxy-4'-methoxyisoflavone (indicated as LC1405), a novel potential H3R antagonist identified from our H3R antagonist screening system, to ameliorate amyloid ? (A?)-induced cognitive deficits, and to explore the underlying mechanisms that are related to H3R-modulated signaling. Our results demonstrated that LC1405 effectively reduced the progression of A?-associated disorders, such as improved learning and memory capabilities, preserved tissues from suffering neurodegeneration and ultrastructural abnormalities, and ameliorated cholinergic dysfunction in an APP/PS1 double transgenic mouse model of AD. In an in vitro model, LC1405 protected neuronal cells against copper-induced A? toxicity, as demonstrated by the improvement in cell viability and decrease in neuronal apoptotic ratio. In addition, treatment with LC1405 resulted in the up-regulation of acetylcholine (ACh) or histamine release and provided neuroprotection through cellular signaling cascades involving H3R-mediated cAMP/CREB and AKT/GSK3? pathways. Furthermore, the beneficial effects of LC1405 on A?-mediated toxicity and H3R-mediated cAMP/CREB and AKT/GSK3? axes were reversed after pharmacological activation of H3R. In conclusion, our results demonstrated that LC1405 blocked A?-induced toxicity through H3R-modulated signaling transduction both in vitro and in vivo. The results also suggested that LC1405 might have translational potential as a complementary therapy to control disease progression in AD patients who developed cognitive deficits with H3R-related ACh neurotransmission abnormality.

SUBMITTER: Wang L 

PROVIDER: S-EPMC6468582 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature