Evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches.

Hongda Liu, Le Yang, Chunlei Wan, Zhineng Li, Guangli Yan et al.

Other Frontiers in pharmacology 2022 9 件の引用

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Study Design

研究タイプ: preclinical animal study

介入: Evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and ur not specified (multiple doses likely tested)
比較対照: Placebo
効果の方向: Positive
バイアスリスク: Unclear

Abstract

Ciwujia Tablets (CWT) are produced by concentrating and drying the extract solution of the dried rhizome of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim [Araliaceae; E. senticosus radix et rhizoma]. Besides, CWT is included in the 2020 edition of Chinese Pharmacopoeia and is widely used in the treatment of insomnia. It mainly contains eleutheroside B, eleutheroside E, isofraxidin, eleutheroside C, ciwujiatone, and chlorogenic acid, as well as other chemical components. Although the clinical efficacy of CWT in treating insomnia has been confirmed, its functions and pharmacological effects have not been systematically evaluated and its mechanism of action in the treatment of insomnia remains unclear. Therefore, in this study, behavioral, energy metabolism, and metabonomics methods were applied to systematically evaluate the effect of CWT on insomnia. Additionally, urine metabonomics based on UPLC-Q-TOF-MS/MS were utilized to identify potential endogenous biomarkers of insomnia, detect the various changes before and after CWT treatment, explore the metabolic pathway and potential target of CWT, and reveal its pharmacological mechanism. Results revealed that CWT increased inhibitory neurotransmitter (5-HT and GABA) content and reduced the content of excitatory neurotransmitters (DA and NE). Moreover, CWT enhanced autonomous behavioral activity, stabilized emotions, and promoted the return of daily basic metabolic indexes of insomniac rats to normal levels. The urine metabolomics experiment identified 28 potential endogenous biomarkers, such as allysine, 7,8-dihydroneopterin, 5-phosphonooxy-L-lysine, and N-acetylserotonin. After CWT treatment, the content of 22 biomarkers returned to normal levels. The representative markers included N-acetylserotonin, serotonin, N-methyltryptamine, and 6-hydroxymelatonin. Additionally, the metabolic pathways in rats were significantly reversed, such as tryptophan metabolism, folate biosynthesis, phenylalanine metabolism, and tyrosine metabolism. Ultimately, it is concluded that CWT regulated tryptophan metabolism, folate biosynthesis, phenylalanine metabolism, and other metabolic levels in the body. This drug has been confirmed to be effective in the treatment of insomnia by regulating the content of serotonin, 6-hydroxymelatonin, N-acetylserotonin, and N-methyltryptamine to a stable and normal level in tryptophan metabolism.

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FIGURE 1

Conceptual diagram summarizing the relationship between evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches and the biological processes described in this research.

diagram

FIGURE 2

Visual summary of the pathways and interactions relevant to evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches, as discussed in the context of ciwujia Tablets (CWT) are produced by concentrating and drying the extract solution of the dried rhizome of Eleuthero.

diagram

FIGURE 3

Schematic representation highlighting the mechanisms underlying evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches and their potential therapeutic implications.

diagram

FIGURE 4

Diagram illustrating the key biological concepts related to evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches, synthesizing evidence presented in the study.

diagram

FIGURE 5

Illustrative overview of the mechanisms involved in evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches, depicting key molecular and cellular pathways.

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Tables

TABLE 1

No.	Rt min	M/Z determined	M/Z calculated	Ion species	Scan mode	Proposed composition	Postulated identity	Change trend
1	0.72	168.0633	145.1629	[M + Na]⁺	ESI+	C₆H₁₁NO₃	Allysine	↑
2	0.85	252.0502	207.1825	[M + FA-H]^-	ESI-	C₁₀H₉NO₄	4-(2-Aminophenyl)-2,4-dioxobutanoic acid	↓
3	0.87	259.0939	129.1153	[2M + H]⁺	ESI+	C₅H₇NO₃	1-Pyrroline-4-hydroxy-2-carboxylate	↓
4	0.94	256.1051	255.2314	[M + H]⁺	ESI+	C₉H₁₃N₅O₄	7,8-Dihydroneopterin	↑
5	0.96	287.0662	242.1728	[M + FA-H]^-	ESI-	C₆H₁₅N₂O₆P	5-phosphonooxy-L-lysine	↓
6	1.78	259.1661	129.1673	[2M + H]⁺	ESI+	C₆H₁₁NO₂	Pipecolic acid	↓
7	1.79	263.1029	218.2538	[M + FA-H]^-	ESI-	C₁₂H₁₄N₂O₂	N-Acetylserotonin	↑
8	2.08	240.1105	239.2304	[M + H]⁺	ESI+	C₉H₁₃N₅O₃	Dihydrobiopterin	↑
9	2.20	207.0631	184.1902	[M + Na]⁺	ESI+	C₉H₁₂O₄	Vanylglycol	↓
10	2.83	177.0567	176.2148	[M + H]⁺	ESI+	C₁₀H₁₂N₂O	Serotonin	↓
11	3.41	137.0601	136.1504	[M + H]⁺	ESI+	C₈H₈O₂	4-Hydroxyphenylacetaldehyde	↓
12	3.68	261.1317	130.1308	[2M + H]⁺	ESI+	C₆H₁₀O₃	Ketoleucine	↑
13	3.76	160.0778	137.1182	[M + Na]⁺	ESI+	C₈H₁₁NO	Tyramine	↓
14	4.03	198.1136	197.2338	[M + H]⁺	ESI+	C₁₀H₁₅NO₃	Metanephrine	↓
15	4.20	202.0467	179.1705	[M + Na]⁺	ESI+	C₉H₉NO₃	Hippuric acid	↑
16	4.22	307.1663	153.1803	[2M + H]⁺	ESI+	C₈H₁₁NO₂	Dopamine	↓
17	4.66	377.1463	376.4024	[M + H]⁺	ESI+	C₁₇H₂₀N₄O₆	Riboflavin	↓
18	4.75	301.2132	278.4107	[M + Na]⁺	ESI+	C₁₈H₃₀O₂	Alpha-Linolenic acid	↓
19	4.81	175.1239	174.2416	[M + H]⁺	ESI+	C₁₁H₁₄N₂	N-Methyltryptamine	↓
20	5.42	293.1470	146.1407	[2M + H]⁺	ESI+	C₅H₁₀N₂O₃	L-Glutamine	↑
21	5.58	323.1464	161.1638	[2M + H]⁺	ESI+	C₆H₁₁NO₄	Aminoadipic acid	↑
22	5.82	249.1236	248.2849	[M + H]⁺	ESI+	C₁₃H1₆N₂O₃	6-Hydroxymelatonin	↑
23	6.13	241.1700	121.1862	[2M-H]^-	ESI-	C₈H₁₁N	1-Phenylethylamine	↑
24	6.17	144.0778	121.1862	[M + Na]⁺	ESI+	C₈H₁₁N	Phenylethylamine	↑
25	6.46	227.2026	228.3716	[M + H]⁺	ESI-	C₁₄H₂₈O₂	Myristic acid	↑
26	7.00	269.0790	224.2104	[M + FA-H]^-	ESI-	C₁₀H₁₂N₂O₄	L-3-Hydroxykynurenine	↑
27	7.34	286.1145	241.2531	[M + FA-H]^-	ESI-	C₉H₁₅N₅O₃	Tetrahydrobiopterin	↑
28	9.78	277.2173	276.4016	[M + H]⁺	ESI+	C₁₈H₂₈O₂	Stearidonic acid	↑

TABLE 2

No.	Pathway name	Biomarker matching quantity
No.	Pathway name	CWT	Diazepam
1	Lysine degradation	4	2
2	Tryptophan metabolism	4	1
3	Folate biosynthesis	3	3
4	Phenylalanine metabolism	2	1
5	Tyrosine metabolism	3	3
6	Riboflavin metabolism	1	0
7	D-Glutamine and D-glutamate metabolism	1	1
8	Nitrogen metabolism	1	1
9	Valine, leucine, and isoleucine biosynthesis	1	1
10	alpha-Linolenic acid metabolism	1	0
11	Arginine biosynthesis	1	1
12	Alanine, aspartate, and glutamate metabolism	1	1
13	Glyoxylate and dicarboxylate metabolism	1	1
14	Biosynthesis of unsaturated fatty acids	1	0
15	Pyrimidine metabolism	1	1
16	Valine, leucine, and isoleucine degradation	1	1
17	Fatty acid biosynthesis	1	1
18	Aminoacyl-tRNA biosynthesis	1	1
19	Purine metabolism	1	1

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Evaluation of the pharmacological effects and exploration of the mechanism of traditional Chinese medicine preparation Ciwujia tablets in treating insomnia based on ethology, energy metabolism, and urine metabolomic approaches.

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