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

doi:10.12122/j.issn.1673-4254.2026.02.02

Abstract

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

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.

Figures/Tables 9

References 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