First Author | Wang L | Year | 2019 |
Journal | Front Neurosci | Volume | 13 |
Pages | 334 | PubMed ID | 31024245 |
Mgi Jnum | J:309752 | Mgi Id | MGI:6759581 |
Doi | 10.3389/fnins.2019.00334 | Citation | Wang L, et al. (2019) 7-Pyrrolidinethoxy-4'-Methoxyisoflavone Prevents Amyloid beta-Induced Injury by Regulating Histamine H3 Receptor-Mediated cAMP/CREB and AKT/GSK3beta Pathways. Front Neurosci 13:334 |
abstractText | 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 beta (Abeta)-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 Abeta-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 Abeta 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/GSK3beta pathways. Furthermore, the beneficial effects of LC1405 on Abeta-mediated toxicity and H3R-mediated cAMP/CREB and AKT/GSK3beta axes were reversed after pharmacological activation of H3R. In conclusion, our results demonstrated that LC1405 blocked Abeta-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. |