Yizhi Qingxin Formula Extract Ameliorates Cognitive Decline in Aged Rats via the Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Pathway.

Lina Ma,Feixue Wang,Zhiyong Wang,Hao Li,Yang Yang,Hui Pei,Zehui Li,Yu Cao

doi:10.3389/fphar.2020.00510

Abstract

Cognitive impairment and decline in old age are primarily driven by the accumulation of age-related neuropathologies, and old age is thus the primary risk factor for neurodegenerative diseases such as AD. Here, we investigated the effects of Yizhi Qingxin formula (YQF) extract on cognitive impairment in aged rats and determine the role of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway underlying the neuroprotective effects of the YQF extract. Fifty male Wistar rats were randomly divided into five groups: Control group, Model group, Donepezil group, and YQF extract groups (treatment with YQF extract at two different doses). After treatment with YQF extract for 8 weeks, learning and cognitive abilities were assessed using the Morris water maze. Morphological changes in the hippocampus were observed using hematoxylin-eosin. Activated microglia and astrocytes were assessed using immunohistochemistry. Expressions of proteins and genes were examined using western blotting and real-time PCR. The results revealed that oral treatment with YQF extract dramatically improved spatial learning and memory ability and ameliorated histopathological and morphological characteristics in aged rats. YQF extract significantly increased acetylcholine and interleukin (IL)-10 levels but markedly decreased amyloid-β peptide, tumor necrosis factor alpha (TNFα), IL-2, and IL-6 levels. In addition, it inhibited the excessive activation of microglia and astrocytes, downregulated the expressions of TNFα and IL-2, and upregulated nerve growth factor, BDNF, and TrkB expressions. Furthermore, hippocampal extracellular signal-related kinase (Erk) and protein kinase B (Akt), the upstream signaling of BDNF/TrkB, were also activated by treatment with YQF extract. Our findings indicate that YQF extract activates the BDNF/TrkB pathway through the upregulation of Erk and Akt signaling, and the activated signaling pathway might contribute to the protective effects of YQF extract on cognitive impairment in aged rats.

Highlights

With the population of older adults is increasing greatly worldwide, “Aging & Disease” has become a hot topic in our society (Shetty et al, 2019), and aging is the predominant risk factor for various age-related diseases (Franceschi et al, 2018), including cancer, cardiovascular disorder, diabetes mellitus, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease (AD)
In the central nervous system, cognitive impairment and decline in old age are primarily driven by the accumulation of age-related neuropathologies, and old age is the primary risk factor for neurodegenerative diseases such as AD (Boyle et al, 2017)
The main active ingredients of Yizhi Qingxin formula (YQF) extract were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS), and alkaloids like berberine, palmatine, worenine, and protopine, and ginsenosides like Rg1, Re, Rb1, Rd, and Rc were found in plasma, while berberine, palmatine, epiberberine, coptisine, and ginsenoside Rb1 were found in brain tissue (Yang et al, 2019)

Summary

Introduction

With the population of older adults is increasing greatly worldwide, “Aging & Disease” has become a hot topic in our society (Shetty et al, 2019), and aging is the predominant risk factor for various age-related diseases (Franceschi et al, 2018), including cancer, cardiovascular disorder, diabetes mellitus, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease (AD). AD is a severe neurodegenerative disease and the most prevalent form of dementia, with specific neuropathological features, including amyloid protein deposits, neurofibrillary tangles, synaptic dysfunction (Marsh and Alifragis, 2018), and neuronal loss (Ossenkoppele et al, 2015). Current United States Food and Drug Administration (FDA)approved drugs for the treatment of AD, such as memantine, rivastigmine, and donepezil, are known to be effective only in mild and moderate AD patients by improving clinical symptoms without slowing disease progression (Godyń et al, 2016; Epperly et al, 2017). Accumulating evidence indicates that dysfunction of the BDNF/TrkB system is involved in a variety of brain diseases, including AD and depressive disorder (Zhang et al, 2016; Yin et al, 2018). The activation of the BDNF/TrkB pathway can be strategically positioned to improve memory deficits (Luo et al, 2019; Tang et al, 2019)

Methods

Results

Conclusion