党参-茯苓配伍调控ERα/PI3K/Akt信号通路改善单侧颈总动脉永久结扎痴呆大鼠的认知障碍

doi:10.12122/j.issn.1673-4254.2026.02.02

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (2): 247-258.doi: 10.12122/j.issn.1673-4254.2026.02.02

• • 上一篇

党参-茯苓配伍调控ERα/PI3K/Akt信号通路改善单侧颈总动脉永久结扎痴呆大鼠的认知障碍

杨佳瑶¹^,²(), 何玉莲¹^,², 郭延垒¹, 尚芳红¹^,²^,³, 花雷¹^,², 阳勇¹^,²^,⁴, 张小梅¹^,²^,³^,⁴(), 魏江平¹^,²^,³()

^1.中药新药创制川渝共建重点实验室//重庆市中药研究院，重庆 400065
^2.国家中医药管理局中药化学三级实验室//重庆市中药研究院重庆 400065
^3.重庆中医药学院中药学院，重庆 402760
^4.川渝共建慢病中药新药泸州市重点实验室，泸州 646000

收稿日期:2025-08-10 出版日期:2026-02-20 发布日期:2026-03-10
通讯作者: 张小梅,魏江平 E-mail:yangjiayao959@163.com;ZXM761@163.com;sichuanwjp@163.com
作者简介:杨佳瑶，在读硕士研究生，E-mail: yangjiayao959@163.com
基金资助:
国家自然科学基金青年科学基金(82104427);重庆市巴渝青年岐黄学者支持项目

Radix codonopsis combined with Poria improves cognitive impairment in rats with unilateral common carotid artery ligation by regulating the ERα/PI3K/Akt signaling pathway

Jiayao YANG¹^,²(), Yulian He¹^,², Yanlei GUO¹, Fanghong SHANG¹^,²^,³, Lei HUA¹^,², Yong YANG¹^,²^,⁴, Xiaomei ZHANG¹^,²^,³^,⁴(), Jiangping WEI¹^,²^,³()

^1.Sichuan -Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China
^2.Third Level Laboratory of Traditional Chinese Medicine Chemistry of the State Administration of Traditional Chinese Medicine, Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China
^3.College of Chinese Materia Medica, Chongqing University of Chinese Medicine, Chongqing 402760, China
^4.Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China

Received:2025-08-10 Online:2026-02-20 Published:2026-03-10
Contact: Xiaomei ZHANG, Jiangping WEI E-mail:yangjiayao959@163.com;ZXM761@163.com;sichuanwjp@163.com
Supported by:
Natural Science Foundation for the Youth (NSFY) of China(82104427)

摘要/Abstract

摘要：

目的基于UPLC-Q-TOF-MS/MS分析研究党参-茯苓配伍（CRP）治疗痴呆症的作用机制。方法采用于UPLC-Q-TOF-MS/MS分析单侧颈总动脉永久结扎（UCCA）模型大鼠的 CRP 的入血入脑成分，并对入血和入脑成分进行网络药理学分析。CRP灌胃UCCA 大鼠干预1个月后通过Morris水迷宫评价其学习记忆能力；苏木精-伊红染色观察海马和皮质的病理形态学变化；NeuN染色分析海马和皮层神经元数量变化；采用代谢组学分析 CRP 治疗UCCA大鼠前后脑内代谢物变化差异；酶联免疫吸附测定（ELISA）检测脑内谷氨酸和γ-氨基丁酸（GABA）的含量；免疫组化法考察雌激素受体α（ERα）的蛋白表达；Western blotting分析p-PI3K、PI3K、p-Akt、Akt的蛋白表达。结果在UCCA大鼠的脑组织和血液中分别鉴定出125种和126种成分，其中，脑组织中发现了89种党参成分和 36 种茯苓成分，血液中发现了85种党参成分和41种茯苓成分。网络药理学分析表明，CRP治疗痴呆主要与调节进入脑组织的成分所影响的PI3K/Akt等信号通路有关。与假手术组比较，模型大鼠的第5天的逃避潜伏期明显延长（P<0.01），平台象限活动时间、海马和皮质的神经元明显损伤且NeuN平均光密度明显下降（P<0.05）；脑内谷氨酸和GABA/谷氨酸含量明显升高（P<0.05），ERα、p-PI3K/PI3K、p-Akt/Akt蛋白表达下调（P<0.05）。与模型组比较，CRP干预大鼠的第5天的逃避潜伏期明显缩短（P<0.01），穿越平台次数、平台象限活动时间均明显增加（P<0.05），海马和皮质的神经元损伤好转且NeuN平均光密度明显升高（P<0.05）；代谢组学分析表明CRP治疗作用主要富集于雌激素信号通路和 GABA 能突触等信号通路。CRP组大鼠脑内的谷氨酸和GABA/谷氨酸含量明显降低（P<0.05），ERα、p-PI3K/PI3K和p-Akt/Akt蛋白表达上调（P<0.05）。结论 CRP 能够改善UCCA痴呆大鼠的学习和记忆缺陷，这与其对脑内ERα/PI3K/Akt信号通路的调节有关。

关键词: 党参-茯苓配伍, 痴呆, 单侧颈总动脉永久结扎大鼠, γ-氨基丁酸, ERα/PI3K/Akt信号通路

Abstract:

Objective To investigate the mechanism of Radix codonopsis combined with Poria (CRP) for improving cognitive impairment induced by permanent unilateral common carotid artery ligation (UCCA) in rats. Methods UPLC-Q-TOF-MS/MS and network pharmacology analysis were used to analyze the components of CRP in the blood and brain of rats medicated with CRP. Rat models of UCCA were treated with CRP gavage for 1 month, and Morris water maze, HE staining, and NeuN staining were used to assess the therapeutic efficacy. Metabolomics analysis, ELISA, immunohistochemistry, and Western blotting were employed to explore and validate the therapeutic mechanism of CRP. Results A total of 125 chemical constituents were identified in the brain tissue (89 Radix codonopsis components and 36 Poria components) and 126 in blood samples (85 Radix codonopsis components and 41 Poria components) of medicated rats. Network pharmacology analysis revealed that the therapeutic mechanism of CRP on dementia involved primarily the PI3K/Akt signaling pathway, regulated by the brain-targeting constituents of CRP. In UCCA rats, CRP treatment significantly improved their performance in Morris water maze test, alleviated neuronal damage in the hippocampus and cortex, and increased expression level of NeuN. Metabolomics analysis revealed significant enrichment of the estrogen and GABAergic synapse signaling pathways in CRP-treated rats. CRP obviously reduced the brain levels of glutamate and GABA/glutamate in UCCA rats, and downregulated the proteins expressions of ERα, p-PI3K/PI3K and p-Akt/Akt. Conclusion CRP improves learning and memory impairment in UCCA rats possibly by modulating the ERα/PI3K/Akt signaling pathway in the brain.

Key words: compatibility of Radix codonopsis and Poria, dementia, permanent unilateral common carotid artery ligation, GABA, ERα/PI3K/Akt signaling pathway

杨佳瑶, 何玉莲, 郭延垒, 尚芳红, 花雷, 阳勇, 张小梅, 魏江平. 党参-茯苓配伍调控ERα/PI3K/Akt信号通路改善单侧颈总动脉永久结扎痴呆大鼠的认知障碍[J]. 南方医科大学学报, 2026, 46(2): 247-258.

Jiayao YANG, Yulian He, Yanlei GUO, Fanghong SHANG, Lei HUA, Yong YANG, Xiaomei ZHANG, Jiangping WEI. Radix codonopsis combined with Poria improves cognitive impairment in rats with unilateral common carotid artery ligation by regulating the ERα/PI3K/Akt signaling pathway[J]. Journal of Southern Medical University, 2026, 46(2): 247-258.

图/表 9

参考文献 34

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NO.	Retain time (min)	Ion peak assignment	Theoretical value mass (m/z)	Measured value mass (m/z)	Deviation (ppm)	Chemical formula	Name
1	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	6,7-dehydroporicoic acid H
2	6.96	[M-H]-	466.30831	465.30019	-1.8	C30H42O4	daedaleanic acid E
3	7.98	[M+H]+	444.32396	445.33071	-1.2	C28H44O4	3β,5a,9a-trihydroxyergosta-7,22-dien-6-one
4	1.87	[M+H]+	162.05282	163.06008	-0.1	C6H10O5	Dimethyl L-malate
5	2.78	[M-H]-	244.06954	243.06212	-0.6	C9H12N2O6	L-uridine
6	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	Poricoic acid A
7	5.75	[M-H]-	484.31887	483.31188	0.6	C30H44O5	Poricoic acid B
8	9.91	[M-H]-	200.17763	199.1705	0.7	C12H24O2	lauric acid
9	8.83	[M-H]-/[M+H]+	256.24023	255.23296	0	C16H32O2	palmitic acid
10	19.07	[M+H]+	512.35018	513.35749	0.1	C32H48O5	Poricoic acid AM
11	6.68	[M-H]-	584.40769	583.40041	0	C36H56O6	Tumulosic acid methy ester
12	5.8	[M-H]-	514.32944	513.32202	-0.3	C31H46O6	Poricoic acid A(F)
13	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	Poricoic acid BM
14	6.4	[M-H]-	486.33453	485.32735	0.2	C30H46O5	Poricoic acid G
15	5.34	[M-H]-	470.33961	469.33272	0.8	C30H46O4	3β,16α-Dihydroxy-lanosta-7,9(11),24-trien-21-oic acid
16	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	25-Hydroxyporicoic acid H
17	6.62	[M-H]-	468.32396	467.31682	0.3	C30H44O4	16-Deoxyporicoic acid B
18	11.03	[M+H]+	528.34509	529.3529	1	C32H48O6	Poricoic acid DM
19	5.75	[M-H]-	484.31887	483.31188	0.6	C30H44O5	Poriacosone A
20	5.75	[M-H]-	484.31887	483.31188	0.6	C30H44O5	Poriacosone B
21	6.11	[M-H]-	496.31887	495.31138	-0.4	C31H44O5	6α-Hydroxy-polyporenic acid C
22	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	16α,25-Dihydroxyeburiciconic acid
23	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	16α,29-Dihydroxyeburiconic acid
24	19.07	[M+H]+	512.35018	513.35749	0.1	C32H48O5	Pachymenin D
25	8.09	[M+H]+	540.34509	541.35241	0.1	C33H48O6	6α-Hydroxydehydropachymic acid
26	5.28	[M-H]-/[M+H]+	204.08988	203.08279	1	C11H12N2O2	tryptophan
27	2.73	[M+H]+	112.02728	113.03426	-2.6	C4H4N2O2	uracil
28	2.78	[M-H]-	244.06954	243.06212	-0.6	C9H12N2O6	uridine
29	5.92	[M+H]+	187.06333	188.0706	0	C11H9NO2	6-Methoxy-4-quinolinecarbaldehyde
30	4.32	[M+H]+	165.07898	166.08625	0	C9H11NO2	phenylalanine(L-Phenylalanine)
31	5.38	[M-H]-	372.14203	371.13537	1.6	C17H24O9	tangshenoside Ⅱ
32	8.14	[M-H]-	262.12051	261.11355	1.2	C15H18O4	nervolan C
33	5.38	[M-H]-	372.14203	371.13537	1.6	C17H24O9	Eleutheroside B(syringin)
34	7.61	[M-H]-	222.08921	221.08202	0.4	C12H14O4	dillapiole
35	7.61	[M-H]-	222.08921	221.08202	0.4	C12H14O4	1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene
36	11.43	[M+H]+	418.16277	419.16949	-1.3	C22H26O8	syringaresinol
37	10.18	[M+H]+	362.17294	363.17942	-2.2	C20H26O6	secoisolariciresinol
38	5.88	[M-H]-	498.29814	497.29218	2.6	C30H42O6	pseudolarolide E
39	8.68	[M-H]-	270.05282	269.04523	-1.2	C15H10O5	apigenin
40	11.9	[M-H]-/[M+H]+	280.24023	279.23241	-1.9	C18H32O2	linoleic acid
41	11.34	[M-H]-	228.20893	227.20169	0.2	C14H28O2	myristic acid
42	8.33	[M-H]-	284.27153	283.26384	-1.5	C18H36O2	stearic acid
43	6.52	[M-H]-	188.10486	187.09787	1.5	C9H16O4	azelaic acid
44	8.83	[M-H]-/[M+H]+	256.24023	255.23296	0	C16H32O2	Palmitic Acid (n-hexadecanoic acid)
45	5.8	[M-H]-	182.05791	181.05037	-1.5	C9H10O4	syringaldehyde
46	1.9	[M+H]+	96.02113	97.02847	0.7	C5H4O2	Furfural(2-furaldehyde)
47	8.68	[M-H]-	270.05282	269.04523	-1.2	C15H10O5	emodin
48	7.24	[M-H]-	542.23633	541.23118	3.9	C26H38O12	codonopilodiynoside F
49	7.24	[M-H]-	542.23633	541.23118	3.9	C26H38O12	codonopilodiynoside G
50	7.24	[M-H]-	542.23633	541.23118	3.9	C26H38O12	codonopilodiynoside K
51	7.75	[M-H]-/[M+H]+	250.12051	249.11329	0.2	C14H18O4	pilosulyne B
52	7.46	[M-H]-/[M+H]+	254.15181	253.14441	-0.5	C14H22O4	pilosulyne F
53	7.46	[M-H]-/[M+H]+	254.15181	253.14441	-0.5	C14H22O4	pilosulyne G
54	5.8	[M-H]-	514.32944	513.32202	-0.3	C31H46O6	pseudolarolide U
55	1.97	[M+H]+	255.11067	256.11797	0.1	C12H17NO5	radicamine A
56	5.92	[M+H]+	187.06333	188.0706	0	C11H9NO2	6-methoxy-4-formylquinoline
57	5.91	[M-H]-	486.18496	485.1766	-2.2	C21H30N2O11	tatarine C-4′-O-β-D-glucopyranoside
58	10.18	[M+H]+	362.17294	363.17942	-2.2	C20H26O6	1,6-Hexanediol-3,4-di (4-hydroxy-3-methoxyphenyl)
59	5.9	[M-H]-	540.23593	539.22752	-2.1	C30H36O9	sesquimarocanol B

NO.	Retain time (min)	Ion peak assignment	Theoretical value mass (m/z)	Measured value mass (m/z)	Deviation (ppm)	Chemical formula	Name
1	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	6,7-dehydroporicoic acid H
2	6.96	[M-H]-	466.30831	465.30019	-1.8	C30H42O4	daedaleanic acid E
3	7.98	[M+H]+	444.32396	445.33071	-1.2	C28H44O4	3β,5a,9a-trihydroxyergosta-7,22-dien-6-one
4	1.87	[M+H]+	162.05282	163.06008	-0.1	C6H10O5	Dimethyl L-malate
5	2.78	[M-H]-	244.06954	243.06212	-0.6	C9H12N2O6	L-uridine
6	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	Poricoic acid A
7	5.75	[M-H]-	484.31887	483.31188	0.6	C30H44O5	Poricoic acid B
8	9.91	[M-H]-	200.17763	199.1705	0.7	C12H24O2	lauric acid
9	8.83	[M-H]-/[M+H]+	256.24023	255.23296	0	C16H32O2	palmitic acid
10	19.07	[M+H]+	512.35018	513.35749	0.1	C32H48O5	Poricoic acid AM
11	6.68	[M-H]-	584.40769	583.40041	0	C36H56O6	Tumulosic acid methy ester
12	5.8	[M-H]-	514.32944	513.32202	-0.3	C31H46O6	Poricoic acid A(F)
13	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	Poricoic acid BM
14	6.4	[M-H]-	486.33453	485.32735	0.2	C30H46O5	Poricoic acid G
15	5.34	[M-H]-	470.33961	469.33272	0.8	C30H46O4	3β,16α-Dihydroxy-lanosta-7,9(11),24-trien-21-oic acid
16	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	25-Hydroxyporicoic acid H
17	6.62	[M-H]-	468.32396	467.31682	0.3	C30H44O4	16-Deoxyporicoic acid B
18	11.03	[M+H]+	528.34509	529.3529	1	C32H48O6	Poricoic acid DM
19	5.75	[M-H]-	484.31887	483.31188	0.6	C30H44O5	Poriacosone A
20	5.75	[M-H]-	484.31887	483.31188	0.6	C30H44O5	Poriacosone B
21	6.11	[M-H]-	496.31887	495.31138	-0.4	C31H44O5	6α-Hydroxy-polyporenic acid C
22	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	16α,25-Dihydroxyeburiciconic acid
23	5.83	[M-H]-	498.33453	497.32724	0	C31H46O5	16α,29-Dihydroxyeburiconic acid
24	19.07	[M+H]+	512.35018	513.35749	0.1	C32H48O5	Pachymenin D
25	8.09	[M+H]+	540.34509	541.35241	0.1	C33H48O6	6α-Hydroxydehydropachymic acid
26	5.28	[M-H]-/[M+H]+	204.08988	203.08279	1	C11H12N2O2	tryptophan
27	2.73	[M+H]+	112.02728	113.03426	-2.6	C4H4N2O2	uracil
28	2.78	[M-H]-	244.06954	243.06212	-0.6	C9H12N2O6	uridine
29	5.92	[M+H]+	187.06333	188.0706	0	C11H9NO2	6-Methoxy-4-quinolinecarbaldehyde
30	4.32	[M+H]+	165.07898	166.08625	0	C9H11NO2	phenylalanine(L-Phenylalanine)
31	5.38	[M-H]-	372.14203	371.13537	1.6	C17H24O9	tangshenoside Ⅱ
32	8.14	[M-H]-	262.12051	261.11355	1.2	C15H18O4	nervolan C
33	5.38	[M-H]-	372.14203	371.13537	1.6	C17H24O9	Eleutheroside B(syringin)
34	7.61	[M-H]-	222.08921	221.08202	0.4	C12H14O4	dillapiole
35	7.61	[M-H]-	222.08921	221.08202	0.4	C12H14O4	1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene
36	11.43	[M+H]+	418.16277	419.16949	-1.3	C22H26O8	syringaresinol
37	10.18	[M+H]+	362.17294	363.17942	-2.2	C20H26O6	secoisolariciresinol
38	5.88	[M-H]-	498.29814	497.29218	2.6	C30H42O6	pseudolarolide E
39	8.68	[M-H]-	270.05282	269.04523	-1.2	C15H10O5	apigenin
40	11.9	[M-H]-/[M+H]+	280.24023	279.23241	-1.9	C18H32O2	linoleic acid
41	11.34	[M-H]-	228.20893	227.20169	0.2	C14H28O2	myristic acid
42	8.33	[M-H]-	284.27153	283.26384	-1.5	C18H36O2	stearic acid
43	6.52	[M-H]-	188.10486	187.09787	1.5	C9H16O4	azelaic acid
44	8.83	[M-H]-/[M+H]+	256.24023	255.23296	0	C16H32O2	Palmitic Acid (n-hexadecanoic acid)
45	5.8	[M-H]-	182.05791	181.05037	-1.5	C9H10O4	syringaldehyde
46	1.9	[M+H]+	96.02113	97.02847	0.7	C5H4O2	Furfural(2-furaldehyde)
47	8.68	[M-H]-	270.05282	269.04523	-1.2	C15H10O5	emodin
48	7.24	[M-H]-	542.23633	541.23118	3.9	C26H38O12	codonopilodiynoside F
49	7.24	[M-H]-	542.23633	541.23118	3.9	C26H38O12	codonopilodiynoside G
50	7.24	[M-H]-	542.23633	541.23118	3.9	C26H38O12	codonopilodiynoside K
51	7.75	[M-H]-/[M+H]+	250.12051	249.11329	0.2	C14H18O4	pilosulyne B
52	7.46	[M-H]-/[M+H]+	254.15181	253.14441	-0.5	C14H22O4	pilosulyne F
53	7.46	[M-H]-/[M+H]+	254.15181	253.14441	-0.5	C14H22O4	pilosulyne G
54	5.8	[M-H]-	514.32944	513.32202	-0.3	C31H46O6	pseudolarolide U
55	1.97	[M+H]+	255.11067	256.11797	0.1	C12H17NO5	radicamine A
56	5.92	[M+H]+	187.06333	188.0706	0	C11H9NO2	6-methoxy-4-formylquinoline
57	5.91	[M-H]-	486.18496	485.1766	-2.2	C21H30N2O11	tatarine C-4′-O-β-D-glucopyranoside
58	10.18	[M+H]+	362.17294	363.17942	-2.2	C20H26O6	1,6-Hexanediol-3,4-di (4-hydroxy-3-methoxyphenyl)
59	5.9	[M-H]-	540.23593	539.22752	-2.1	C30H36O9	sesquimarocanol B

Group	Dose (g/kg)	First day (s)	Second day (s)	Third day (s)	Fourth day (s)	Fifth day (s)
Sham	-	106.00±31.81	70.36±22.25	54.49±17.23^{^^}	22.33±7.06^{^^^##}	16.39±5.18^{^^^##}
Model	-	111.55±35.28	73.46±23.23	57.63±18.23	70.05±22.15**	57.67±18.24^{^^}**
Aricept	1.17×10^-3	93.94±29.71	78.36±24.80	43.53±13.77^{^^}	29.67±9.38^{^^^#}	26.05±8.24^{^^^#}
CRP-L	3.5	92.78±29.34	85.58±27.02	59.17±18.71	33.98±10.75^{^^^#}	23.75±7.51^{^^^##}
CRP-H	7	98.54±31.16	98.89±31.27	69.63±22.02	50.43±15.95^{^^^}	22.81±7.21^{^^^##}

Group	Dose (g/kg)	First day (s)	Second day (s)	Third day (s)	Fourth day (s)	Fifth day (s)
Sham	-	106.00±31.81	70.36±22.25	54.49±17.23^{^^}	22.33±7.06^{^^^##}	16.39±5.18^{^^^##}
Model	-	111.55±35.28	73.46±23.23	57.63±18.23	70.05±22.15**	57.67±18.24^{^^}**
Aricept	1.17×10^-3	93.94±29.71	78.36±24.80	43.53±13.77^{^^}	29.67±9.38^{^^^#}	26.05±8.24^{^^^#}
CRP-L	3.5	92.78±29.34	85.58±27.02	59.17±18.71	33.98±10.75^{^^^#}	23.75±7.51^{^^^##}
CRP-H	7	98.54±31.16	98.89±31.27	69.63±22.02	50.43±15.95^{^^^}	22.81±7.21^{^^^##}

Group	Dose (g/kg)	Platform quadrant cumulative Time (s)	Times of platform crossing time (time)	Average swimming speed (cm/s)
Sham	-	32.37±10.24^#	4.22±1.34	14.74±4.66
Model	-	21.33±6.75*	2.50±0.79	12.44±3.94
Aricept	1.17×10^-3	34.68±10.97^##	4.20±1.33	13.69±4.33
CRP-L	3.5	33.94±10.73^#	5.80±1.83^##	13.58±4.29
CRP-H	7	29.22±9.24	3.20±1.01	13.87±4.39

党参-茯苓配伍调控ERα/PI3K/Akt信号通路改善单侧颈总动脉永久结扎痴呆大鼠的认知障碍

Radix codonopsis combined with Poria improves cognitive impairment in rats with unilateral common carotid artery ligation by regulating the ERα/PI3K/Akt signaling pathway

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