Schizandrin improves PTSD-like behaviors via 5-HT1A receptor

다국어 초록 (Multilingual Abstract)

Post-traumatic stress disorder (PTSD) is a severe mental illness characterized by increased arousal, intrusion, avoidance, and negative cognitive alterations following exposure to fatal stresses or psychological trauma. In this study, I explored the ameliorating effects of schizandrin on PTSD-like behaviors in PTSD model mice induced by single prolonged stress (SPS). A single dose of schizandrin (10 mg/kg, p.o.) ameliorated PTSD-like behaviors as assessed using the elevated plus-maze test, Y-maze test, tail suspension test, and fear extinction test. Using network pharmacology, I identified 6 core protein targets among 47 candidates. Molecular docking analysis further revealed that schizandrin binds most stably to the 5-HT1A receptor, a key modulator of fear and stress responses. I discovered that schizandrin normalized downstream signaling of the 5-HT1A receptor in the amygdala by modulating the PKA-CREB and PI3K-Akt- mTOR pathways. Furthermore, antagonism study confirmed the specificity of schizandrin’s action as 5-HT1A receptor agonist. These results suggest that schizandrin could be an effective treatment for PTSD via 5-HT1A receptor activation, addressing the limitations of current PTSD medications.

목차 (Table of Contents)

• Contents i
• Figure contents iii
• Table contents iv
• Abstract v
• Abbreviations vi
• 1. Introduction 1
• 1.1. What is PTSD? 1
• 1.2. Pharmacological review of active compounds in Schisandrae Fructus 1
• 1.3. The aim of present study 2
• 2. Materials and Methods 3
• 2.1. Animals 3
• 2.2. Materials 3
• 2.3. Inducing a PTSD-like Mouse with SPS 4
• 2.4. Drug administration 4
• 2.5. Elevated plus-maze (EPM) test 6
• 2.6. Y-maze test 6
• 2.7. Tail suspension test (TST) 7
• 2.8. Open field test (OFT) 7
• 2.9. Fear extinction test 8
• 2.10. Network pharmacology 9
• 2.10.1. Identification of schizandrin and PTSD targets 9
• 2.10.2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis 9
• 2.10.3. Protein-Protein Interaction (PPI) network construction and screening of coretargets 9
• 2.11. Molecular docking analysis 10
• 2.12. Western blot 10
• 2.13. Data and statistical analysis 11
• 3. Results 12
• 3.1. The effects of active constituents in Schisandrae Fructus on SPS-induced fear memory extinction deficits 12
• 3.2. The effects of schizandrin on SPS-induced emotional and cognitive dysfunctions 14
• 3.3. The effects of schizandrin on SPS-induced fear memory extinction deficits 16
• 3.4. Molecular target prediction of schizandrin and PTSD 18
• 3.4.1. KEGG pathway analysis and GO enrichment analysis of overlapping genes from schizandrin and PTSD- related genes 18
• 3.4.2. Protein-protein interaction (PPI) network of overlapping genes from schizandrin and PTSD-related genes 22
• 3.4.3. Molecular docking analysis 22
• 3.5. Schizandrin normalizes 5-HT1A receptor signaling pathways in the amygdala 27
• 3.5.1. Schizandrin normalizes PKA-CREB pathway in the amygdala 27
• 3.5.2. Schizandrin normalizes PI3K-Akt-mTOR pathway in the amygdala 27
• 3.6. Schizandrin facilitated fear memory extinction via the 5-HT1A receptor activation 30
• 4. Discussion 32
• 5. References 35
• 6. 국문초록 38
• Figure 1. Chemical structure of Schizandrin 4
• Figure 2. Schematic illustration of the experimental process 5
• Figure 3. Active constituents in Schisandrae Fructus alleviates fear extinction deficits in the SPS model of PTSD 13
• Figure 4. Schizandrin alleviates emotional and cognitive impairments in PTSD model mice without hyperactivity 15
• Figure 5. Schizandrin alleviates fear extinction deficits in the SPS model of PTSD 17
• Figure 6. The representative pictures of Venn diagram, KEGG analysis, and GO analysis ·· 20
• Figure 7. The overlapping genes in the KEGG map 21
• Figure 8. The representative images of PPI network and top 20 networks by degree among 47 overlapping genes 23
• Figure 9. Results of molecular docking between schizandrin and predicted targets 25
• Figure 10. Schizandrin normalizes PKA-CREB pathway 28
• Figure 11. Schizandrin normalizes PI3K-Akt-mTOR pathway 29
• Figure 12. WAY-100635 blocks the fear extinction deficits ameliorating effects of schizandrin 31
• Table 1. List of overlapping genes between PTSD and schizandrin 19
• Table 2. List of top 20 proteins based on degree 24
• Table 3. Results of molecular docking between schizandrin and predicted targets 26