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

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-? peptide, tumor necrosis factor alpha (TNF?), IL-2, and IL-6 levels. In addition, it inhibited the excessive activation of microglia and astrocytes, downregulated the expressions of TNF? 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.

SUBMITTER: Ma L

PROVIDER: S-EPMC7203446 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

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

Ma Lina L Cao Yu Y Wang Feixue F Li Zehui Z Wang Zhiyong Z Yang Yang Y Pei Hui H Li Hao H

Frontiers in pharmacology 20200430

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)/t<i>ropomyosin receptor kinase B</i> (TrkB) pathway underlying the neuroprotective effects of the YQF extract. Fif ...[more]

PMID: 32425777

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Project description:Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 months, middle-aged F344 rats were fed diets containing low, medium (typical amount) or high vitamin D3 (100, 1000 or 10,000 IU/kg diet, respectively) and then hippocampal-dependent learning and memory were tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication and G-protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function and suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging. Sixty, middle-aged male F344 rats were divided into three groups, each receiving for 5-6 months a different dietary amount of cholecalciferol (vitamin D3; VitD3). Purified AIN-93G (Harlan-Teklad) diet was modified to contain low, medium or high VitD3 (IU/kg diet): High = 10,000, Standard (Control) = 1000; Low = 100. Animal weight and amount of food consumed was recorded 2-3 times/week. Serum levels of 25-hydroxy vitamin D were determined using liquid chromatography/tandem mass spectrometry (ZRT Laboratory). Hippocampal RNA was isolated, quantified and checked for RNA integrity. One low VitD3 sample failed RNA quality control. Remaining RNA samples were applied to Affymetrix Rat Gene 1.0 ST arrays (one array/subject). Pre-statistical filtering removed poorly annotated probe sets, low intensity signals, and outlier values (>2SD of the group mean). Filtered data were analyzed by 1-way ANOVA to identify significant differences and the False Discovery Rate (FDR) procedure was used to estimate the error of multiple testing. FDR was compared at 0.31 and 0.17. Significant genes were assigned to one of four idealized expression patterns using Pearson’s test and separated by the sign of their correlation; relative gene expression values are provided on the log-2 scale. Functional categorization for significant genes was determined using DAVID bioinformatic tools. Please note that 'Marked' and 'Unmarked' (in the sample titles) refers to whether the rat had a mark on its tail. The rats were pair-housed and this is how two rats in one cage were distinguished.

Dataset Information

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

Publications

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

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