7-Pyrrolidinethoxy-4'-Methoxyisoflavone Prevents Amyloid β-Induced Injury by Regulating Histamine H3 Receptor-Mediated cAMP/CREB and AKT/GSK3β Pathways.

Linlin Wang,Hailun Jiang,Qian Wang,Jiansong Fang,Zhuorong Li,Rui Liu,Situ Xue

doi:10.3389/fnins.2019.00334

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 β (Aβ)-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 Aβ-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 Aβ 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/GSK3β pathways. Furthermore, the beneficial effects of LC1405 on Aβ-mediated toxicity and H3R-mediated cAMP/CREB and AKT/GSK3β axes were reversed after pharmacological activation of H3R. In conclusion, our results demonstrated that LC1405 blocked Aβ-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.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia in elderly population, is characterized by complicated and multifactorial pathophysiological alterations, primarily including senile plaque deposits, Tau protein hyperphosphorylation, high oxidative stress, metal ion dyshomeostasis, and neurotransmitter system irregularities (Ballard et al, 2011; Chiang and Koo, 2014)
We investigated its action against amyloid β (Aβ)-induced neurotoxicity, and the underlying mechanisms of action against Aβ toxicity correlated with H3 receptor (H3R)-modulated signaling both in amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and copper-induced Aβ toxicity in APP Swedish mutation overexpressing SH-SY5Y cells
Subsequent post hoc comparison illustrated that treatment with 3 mg/kg of LC1405 was considerable in improving the spatial learning ability in APP/PS1 mice compared to APP/PS1 control mice (p < 0.05)

Summary

Introduction

Alzheimer’s disease (AD), the most common cause of dementia in elderly population, is characterized by complicated and multifactorial pathophysiological alterations, primarily including senile plaque deposits, Tau protein hyperphosphorylation, high oxidative stress, metal ion dyshomeostasis, and neurotransmitter system irregularities (Ballard et al, 2011; Chiang and Koo, 2014). The principal treatment to combat AD in clinical practice involves the administration of acetylcholinesterase (AChE) inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, which resulted in limited symptomatic improvement. No effective treatment strategy is available that results in recovery or even retardation in the progression of the disease. Among the diverse H3R antagonists investigated up to now, two small H3R antagonists, ABT-239 and A-431404, showed procognitive effects in ketamine and MK801-induced animal models (Brown et al, 2013). Pre-clinical studies demonstrated that several H3R antagonists ameliorate cognitive deficits and related behaviors in a substantial number of animal models characterized by learning or memory dysfunction (Browman et al, 2004)

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