Oral Administration of Gintonin Protects the Brains of Mice against Aβ-Induced Alzheimer Disease Pathology: Antioxidant and Anti-Inflammatory Effects.

Muhammad Ikram,Min Woo Kim,Myeong Ok Kim,Tae Ju Park,Ibrahim Khan,Myeung Hoon Jo,Min Gi Jo,Yueliang Zhao

doi:10.1155/2021/6635552

Abstract

The study was aimed at analyzing the protective effects of gintonin in an amyloid beta- (Aβ-) induced Alzheimer's disease (AD) mouse model. For the development of the Aβ-induced AD mouse model, the amyloid-β (Aβ1-42) peptide was stereotaxically injected into the brains of mice. Subsequently, gintonin was administered at a dose of 100 mg/kg/day/per oral (p.o) for four weeks daily, and its effects were evaluated by using western blotting, fluorescence analysis of brain sections, biochemical tests, and memory-related behavioral evaluations. To elucidate the effects of gintonin at the mechanistic level, the activation of endogenous antioxidant mechanisms, as well as the activation of astrocytes, microglia, and proinflammatory mediators such as nuclear factor erythroid 2-related factor 2 (NRF-2) and heme oxygenase-1 (HO-1), was evaluated. In addition, microglial cells (BV-2 cells) were used to analyze the effects of gintonin on microglial activation and signaling mechanisms. Collectively, the results suggested that gintonin reduced elevated oxidative stress by improving the expression of NRF-2 and HO-1 and thereby reducing the generation of reactive oxygen species (ROS) and lipid peroxidation (LPO). Moreover, gintonin significantly suppressed activated microglial cells and inflammatory mediators in the brains of Aβ-injected mice. Our findings also indicated improved synaptic and memory functions in the brains of Aβ-injected mice after treatment with gintonin. These results suggest that gintonin may be effective for relieving AD symptoms by regulating oxidative stress and inflammatory processes in a mouse model of AD. Collectively, the findings of this preclinical study highlight and endorse the potential, multitargeted protective effects of gintonin against AD-associated oxidative damage, neuroinflammation, cognitive impairment, and neurodegeneration.

Highlights

Alzheimer’s disease (AD) is a common cause of dementia that advances with aging
Our data showed a marked decrease in lipid peroxidation (LPO) and reactive oxygen species (ROS) levels in cells treated with Aβ+gintonin at a dose of 10 μg/mL (Figures 1(a) and 1(b))
We evaluated the levels of nuclear factor erythroid-2 related factor-2 (NRF-2) and heme oxygenase-1 (HO-1) as endogenous oxidative stress regulators

Summary

Introduction

Alzheimer’s disease (AD) is a common cause of dementia that advances with aging. At the molecular level, AD shows three major pathological hallmarks: intracellular neurofibrillary tangle formation, amyloid beta (Aβ) peptide plaque formation, and neuronal degeneration [1, 2]. Multiple factors play important roles in the progression of neurodegeneration, including elevated oxidative stress and neuroinflammation [4]. Elevated levels of reactive oxygen species (ROS) may induce AD pathology in the brain, since the neuronal system shows the highest oxygen demand while containing the lowest levels of antioxidants, making the brain the most susceptible organ to oxidative damage [5]. NRF-2 binds with antioxidant response elements (AREs) to activate various cytoprotective genes against elevated oxidative damage [6] by accelerating the activation of heme oxygenase-1 (HO-1). NRF-2 regulates proteostasis [7], neuroinflammation [8], neurogenesis [9], and bioenergetic homeostasis [10] in the central nervous system and activates NRF-2-dependent genes and enzymes, which confer neuroprotective effects in neurodegenerative diseases [11, 12]

Methods

Results

Discussion

Conclusion