Abstract
Background: To explore the effect and mechanisms of Pantao Pill (PTP) on cognitive impairment. Methods: Network pharmacology was performed to analyze the mechanism of PTP treating cognitive impairment. The targets of PTP and cognitive impairment were predicted and used to construct protein-protein interaction (PPI) networks. The intersection network was selected, and the core network was obtained through topological analysis. Enrichment analysis was conducted to obtain the GOBP terms and KEGG pathways. We then performed experiments to validate the results of the network pharmacology by using an APP/PS1 transgenic mouse model. The APP/PS1 mice were divided into four groups: the model group, the high-dose PTP (3.6 g/kg·d) group, the low-dose PTP (1.8 g/kg·d) group, and the positive control group (donepezil hydrochloride, 2 mg/kg·d). Wild-type (WT) C57 mice served as a normal control group. PTP and donepezil were administered by gavage for 8 weeks. Results: Network pharmacology showed that PTP might improve cognitive impairment by regulating autophagy, apoptosis, and oxidative stress. For the Morris water maze test, a significant difference was shown in the total swimming distance among groups (p < 0.05) in the positioning navigation experiment, and with training time extension, the swimming speed increased (p < 0.01). In the space probe test, PTP administration significantly reduced the swimming path length and the escape latency of APP/PS1 mice (p < 0.05 or p < 0.01), whereas it had no effect on the swimming speed (p > 0.05). PTP (3.6 g/kg/d) rescued the reduction of norepinephrine and acetylcholine levels (p < 0.05), and increased the acetylcholinesterase concentration (p < 0.05) in the brain tissue. PTP (1.8 g/kg/d) increased the norepinephrine level (p < 0.01). PTP rescued the activity reduction of superoxide dismutase in the brain tissue (p < 0.01) and the neuron cell pyknosis in the hippocampal CA region (p < 0.05). PTP reduced ATG12 and PS1 expression (p < 0.05 or p < 0.01), and increased Bcl-2 expression in the brain tissue (p < 0.05). Conclusion: PTP can significantly improve the learning and memory abilities of APP/PS1 mice, and the mechanism may be related to the increase of neurotransmitter acetylcholine and norepinephrine levels, the reduction of the excessive autophagic activation, and the suppression of oxidative stress and excessive apoptotic activity.
Highlights
Cognitive impairment is one of the characteristics of human aging and often manifests as declines in attention, reasoning ability, learning ability, short-term and long-term memory, executive ability, and the perception of the surrounding environment (Kennedy et al, 2017)
Bounded by betweenness centrality (BC) > 0.00021355, closeness centrality (CC) > 0.48908, degree centrality (DC) > 124, eigenvector centrality (EC) > 0.013344, LAC >13.08955, network centrality (NC) > 14.446487, the core protein-protein interaction (PPI) network was built, which contained a total of 275 targets (Supplementary Figure S3C, Supplementary Material S5)
This study showed that the expression of B-cell lymphoma 2 (Bcl-2) in amyloid precursor protein (APP)/PS1 mice was decreased, and the expression of PS1 was increased, suggesting that apoptosis was up-regulated in brain cells
Summary
Cognitive impairment is one of the characteristics of human aging and often manifests as declines in attention, reasoning ability, learning ability, short-term and long-term memory, executive ability, and the perception of the surrounding environment (Kennedy et al, 2017). In China, the incidence of mild cognitive impairment alone is estimated to be as high as 15% among people over 60 years of age (Xue et al, 2018). Alzheimer’s disease (AD) is the most common cause of cognitive dysfunction, which has been reported to cause 50–75% of dementia cases. According to the Alzheimer’s Association Report 2021, more than 12 million people in the United States will suffer from Alzheimer’s and other dementias by 2050 (Alzheimer’s and association, 2021). The main pathological manifestations of AD are the formation of senile plaques caused by the deposition of amyloid β protein (Aβ) and the neurofibrillary tangling caused by the hyperphosphorylation of tau protein. Mutations in the amyloid precursor protein (APP) and presenilin (PS1) genes can increase the production and accumulation of Aβ. To explore the effect and mechanisms of Pantao Pill (PTP) on cognitive impairment
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