基于cAMP/PKA/CREB信号通路独参汤对衰老模型大鼠认知功能障碍的影响

doi:10.13481/j.1671-587X.20210407

Abstract

Abstract: Objective

To explore the effect of Dushen Tang（DST） on the neuronal damage， the superoxide dismutase （SOD） and glutathione （GSH） activities in brain tissue， the malondialdehyde （MDA） and cyclic adenosine monophosphate （cAMP） levels in the D-galactose （D-gal）-induced aging model rats and the activation of cyclic adenosine monophosphate/protein kinase A/CAMP response element binding protein （cAMP/PKA/CREB） signal pathway， and to elucidate the improvement effect of DST on the cognitive dysfunction of the D-gal-induced aging model rats.

Methods

Forty SD rats were randomly divided into control group， model group， positive drug group， and DST group， with 10 rats in each group. Except for control group， the rats in other groups were given intraperitoneal injection of D-gal at a dose of 500 mg·kg^－1·d^－1for 40 d to establish the aging models. On the 5th day of the model construction， the rats in positive drug group was given vitamin E 0.027 g·kg^－1， and the rats in DST group were given DST 5mL （equivalent to 0.3 g·kg^－1·d^－1crude drug）， for 36 d. The states of the rats were observed and the growth curves were draw； the water maze was used to detect the learning and memory abilities of the rats； the biochemical and ELISA kits were used to detect the activities of SOD， GSH and the levels of MDA and cAMP in the rat brain tissue； the transmission electron microscope was used to observe the ultrastructures of the rat hippocampus neurons； Congo red staining was used to observe the age spots in hippocampus tissue of the rats； Western blotting was used to detect the expression levels of cAMP/PKA/CREB signaling pathway-related proteins in hippocampus tissue of the rats.

Results

Compared with model group， the body weights of rats in positive drug group and DST group were increased， the learning and memory abilities were increased （P<0.05）， the activities of SOD and GSH and the levels of cAMP in brain tissue of the rats were significantly increased（P<0.05），and the levels of MDA were decreased （P<0.05）. Compared with model group， the pathological changes of neuron ultrastructures of the rats in positive drug group and DST group were improved and the areas of orange-red sediments and age spots in hippocampus tissue of the aging model rats were significantly decreased（P<0.01）；the expression levels of PKA， cAMP， adenylate cyclase（ADCY），CREB，and brain-derived neurotrophic factor （BDNF） proteins in brain tissue of the rats were significantly increased（P<0.05），and the expression levels of guanine nucleotide-binding protein alpha inhibitor（GNAI） were decreased （P<0.05）.

Conclusion

DST can significantly improve the cognitive ability of the D-gal-induced aging model rats，and its mechanism may be related to scavenging free radicals and activating cAMP/PKA/CREB signaling pathway to improve the nerve cell damage.

Key words: Dushen Tang, aging, cognitive function, D-galactose, cyclic adenosine monophosphate, protein kinase A, response element binding protein

CLC Number:

R285.5

Jifeng WANG,Xiaoran LIU,Xin SUI,Mo KAN,Hui LI,Wenjun GUO,Qing YANG,Zhuang ZHANG,Sitong MING,Na LI,Xiaobo QU. Effect of Dushen Tang on cognitive dysfunction of aging model rats based on cAMP/PKA/CREB signal pathway[J].Journal of Jilin University(Medicine Edition), 2021, 47(4): 865-873.

Figures/Tables 7

Fig. 1

Fig. 2

Fig. 3

Fig. 4

Tab. 1

Fig. 5

Fig. 6

References 27

1	宋承吉. 《十药神书》与独参汤［J］. 人参研究， 2005， 17（2）： 2-3.
2	YANG D W， YANG X F， YAN H， et al. UPLC-MS/MS determination of twelve ginsenosides in shenfu Tang and dushen Tang［J］. Int J Anal Chem， 2019， 2019： 6217125.
3	LI S L， LAI S F， SONG J Z， et al. Decocting-induced chemical transformations and global quality of Du-Shen-Tang， the decoction of ginseng evaluated by UPLC-Q-TOF-MS/MS based chemical profiling approach［J］. J Pharm Biomed Anal， 2010， 53（4）： 946-957.
4	CHOI S H， LEE R， NAM S M， et al. Ginseng gintonin， aging societies， and geriatric brain diseases［J］. Integr Med Res， 2021， 10（1）： 100450.
5	KIM H J， JUNG S W， KIM S Y， et al. Panax ginseng as an adjuvant treatment for Alzheimer’s disease［J］. J Ginseng Res， 2018， 42（4）： 401-411.
6	苏向东，陆启丽，高琴琴，等. 独参汤化学成分的研究［J］. 人参研究， 2013， 25（4）：12-16.
7	凌继祖. 氧化应激在间歇性低氧幼鼠认知障碍和海马损伤中的机制研究［D］.兰州：兰州大学， 2020.
8	AKHTER K F， MUMIN M A， LUI E M K， et al. Fabrication of fluorescent labeled ginseng polysaccharide nanoparticles for bioimaging and their immunomodulatory activity on macrophage cell lines［J］. Int J Biol Macromol， 2018， 109： 254-262.
9	ZHANG Y， YANG X M， WANG S， et al. Ginsenoside Rg3 prevents cognitive impairment by improving mitochondrial dysfunction in the rat model of Alzheimer’s disease［J］. J Agric Food Chem， 2019， 67（36）： 10048-10058.
10	BUDNI J， GARCEZ M L， MINA F， et al. The oral administration of D-galactose induces abnormalities within the mitochondrial respiratory chain in the brain of rats［J］. Metab Brain Dis， 2017， 32（3）： 811-817.
11	李红波，王小琴，熊飞，等.六味地黄丸对D-半乳糖致衰老大鼠抗氧化功能影响的实验研究［J］.中国中医药科技，2019，26（1）：31-33.
12	段懿涵，盛瑜，徐健，等. 姬松茸多糖对D-半乳糖诱导的衰老模型小鼠的抗衰老作用及其Keap1/Nrf2/ARE信号转导途径机制［J］. 吉林大学学报（医学版）， 2020， 46（2）： 346-351， 435.
13	刘颖，王宇瑄，陈勤，等. 健脑益智胶囊对衰老小鼠大脑学习记忆功能减退的作用机制研究［J］.中国医院药学杂志， 2020， 40（17）： 1840-1845.
14	梅健，王艳丽，雷莹，等. 衰老相关认知障碍的研究进展［J］.海南医学， 2020， 31（15）： 2014-2017.
15	许梦然，王迦琦，高婧雯，等. 北柴胡多糖对D-半乳糖致衰老模型小鼠的保护作用及其机制［J］. 吉林大学学报（医学版）， 2020， 46（6）： 1215-1220， 1350.
16	黄清松，李红枝，郑敏，等.姬松茸粗多糖提高脑老化小鼠学习记忆能力的作用及其机制［J］.吉林大学学报（医学版）， 2014， 40（1）：70-73.
17	MA C L， LI L， YANG G M， et al. Neuroprotective effect of gastrodin in methamphetamine-induced apoptosis through regulating cAMP/PKA/CREB pathway in cortical neuron［J］. Hum Exp Toxicol， 2020， 39（8）： 1118-1129.
18	郑彩霞. PKA/CREB信号通路在电针改善脑缺血大鼠学习记忆功能中作用机制的研究［D］.武汉：华中科技大学， 2017.
19	平鑫. 基于cAMP-PKA-CREB通路探讨化浊解毒疏肝方对癫痫大鼠学习记忆的影响［D］. 保定：河北大学， 2020.
20	赵凡，尚志远，瞿融. 黄芩含药血清对神经干细胞分化钠离子通道基因及cAMP/PKA信号通路的影响［J］.中医杂志， 2020， 61（16）： 1444-1448.
21	于琰同，张风霞. 复健片对大脑中动脉闭塞模型大鼠cAMP/PKA信号通路mRNA及神经营养因子表达的影响［J］.四川中医， 2020， 38（7）： 69-73.
22	尹传红，闫宇辉. 高压氧通过激活CREB/BDNF信号通路减轻阿尔茨海默病小鼠海马神经元突触损伤［J］.中国病理生理杂志， 2020， 36（6）： 1063-1070.
23	SANDERS O， RAJAGOPAL L. Phosphodiesterase inhibitors for Alzheimer’s disease： a systematic review of clinical trials and epidemiology with a mechanistic rationale［J］. J Alzheimers Dis Rep， 2020，4（1）： 185-215.
24	伍向民，王晓敏，黄开勇，等. 5-羟色胺转运体敲除小鼠行为学与其海马PKA/CREB/BDNF信号通路水平变化的研究［J］.广西医科大学学报， 2020， 37（5）： 827-831.
25	ZHOU L， MA S L， YEUNG P K， et al. Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor， Prozac［J］. Transl Psychiatry， 2016， 6（9）： e881.
26	郝继伟，李莺歌，王来，等. BDNF在APP/PS1转基因小鼠皮层和海马内的表达及其对学习记忆能力的影响［J］. 中国病理生理杂志， 2019， 35（5）： 858-864.
27	GONG J J， ZHOU F， WANG S X X， et al. Caveolin-3 protects diabetic hearts from acute myocardial infarction/reperfusion injury through β2AR， cAMP/PKA， and BDNF/TrkB signaling pathways［J］. Aging （Albany NY）， 2020， 12（14）： 14300-14313.

Group	Area of age spots
Control	0.00±0.00
Model	1 885.00±100.13^*
Positive drug	380.00±27.22^△
DST	546.33±16.62^△

[1]	Qian LI,Jingyi YUAN,Jiaqi ZHOU,Min ZHAO,Ke WANG. Pulmonary imaging changes as first manifestation of angioimmunoblastic T-cell lymphoma: A case report and literature review [J]. Journal of Jilin University(Medicine Edition), 2022, 48(3): 796-800.
[2]	Ping HU,Nan JIANG,Yinghua LI,Hongguang ZHAO. Analysis on characteristics of ¹⁸F-FDG PET/CT imaging of patient with primary small cell osteosarcoma of coccyx:A case report and literature review [J]. Journal of Jilin University(Medicine Edition), 2022, 48(1): 216-221.
[3]	Jiayi LI,Xiaojing JIA,Shaojie JIA,Yan MA,Yuxiu SHEN,Xin LIU,Hongyan QU,Ge BAI,Na CHENG. Effect of dual anti-platelet therapy with aspirin and clopidogrel on bleeding regression and prognosis of acute ischemic stroke patients complicated with cerebral microbleeds [J]. Journal of Jilin University(Medicine Edition), 2021, 47(6): 1531-1537.
[4]	Qian LI,Jiaqi ZHOU,Jingyi YUAN,Min ZHAO,Xin DI,Ke WANG. Spindle cell carcinoma of lung: A case report and literature review [J]. Journal of Jilin University(Medicine Edition), 2021, 47(6): 1557-1561.
[5]	Tianyi WANG,Yufeng ZHU,Miao SUN,Wei WANG. Application of three-dimensional reconstruction combined with indocyanine green intraoperative navigation in diagnosis and treatment of liver cancer [J]. Journal of Jilin University(Medicine Edition), 2021, 47(4): 1014-1021.
[6]	Yu WANG, Lan ZHAO, Bohong KAN, Huiyan SHI. Improvement effect of Sanjiao acupuncture on learning and memory abilities of rapid aging model mice by activating SDF-1α/CXCR4 pathway [J]. Journal of Jilin University(Medicine Edition), 2021, 47(3): 545-550.
[7]	Dong CHEN, Zhiyao LI, Haitao CHEN, Zhirui CHUAN, Yingxian ZHANG, Xin JIN, Shicong TANG, Xiaomao LUO. Diagnostic values of three-dimensional transrectal ultrasound and MRI in diagnosis of T substages and circumferential resection margin of patients with middle and lower rectal cancer [J]. Journal of Jilin University(Medicine Edition), 2021, 47(3): 753-760.
[8]	Dong CHEN,Zhiyao LI,Haitao CHEN,Zhirui CHUAN,Yingxian ZHANG,Xin JIN,Shicong TANG,Xiaomao LUO. Diagnostic value of three-dimensional transrectal ultrasound in preoperative N-staging of middle and lower rectal cancer [J]. Journal of Jilin University(Medicine Edition), 2021, 47(2): 497-504.
[9]	Dong CHEN,Haitao CHEN,Zhiyao LI,Fengming RANG,Xi ZHANG,Zhirui CHUAN,Shicong TANG,Xiaomao LUO. Effects of three-dimensional transrectal ultrasound and MRI in evaluation of extramural vascular invasion degrees of middle and lower rectal cancer [J]. Journal of Jilin University(Medicine Edition), 2021, 47(1): 203-209.
[10]	Meijuan LU,Xiande MA,Lu REN. Effect of acupuncture combined with medicine-induced autophagy on cognitive function of mice with ApoE gene knockout [J]. Journal of Jilin University(Medicine Edition), 2020, 46(6): 1124-1130.
[11]	Lingxue SHI,Shuo LIU,Xuewei ZHENG,Xiaoliang CHENG,Zhaohui CHEN,Baolin MA,Hongguo ZHANG,Jun DING. Application of magnetic resonance diffusion weighted imaging ADC and rADC in differential diagnosis of benign and malignant parotid gland tumors [J]. Journal of Jilin University(Medicine Edition), 2020, 46(6): 1309-1314.
[12]	ZHOU Dongkui, LU Mingqian, FENG Xuesong, LIU Yufei, SONG Hao, XU Liang. Follicular dendritic cell sarcoma of small intestine and ileocecal region: A case report and literature review [J]. Journal of Jilin University(Medicine Edition), 2020, 46(04): 858-862.
[13]	ZHAO Min, JIN Xin, DI Xin, TIAN Chang, LIU Jiaying, CONG Shan, WANG Ke. Invasive mucinous adenocarcinoma of lung: A case report and literature review [J]. Journal of Jilin University(Medicine Edition), 2020, 46(03): 634-638.
[14]	DUAN Yihan, SHENG Yu, XU Jian, LU Xuechun, DU Peige, AN Liping. Anti-aging effects of Agaricus blazei polysaccharide in D-galactose-induced aging model mice and Keap1/Nrf2/ARE signal transduction pathway mechanism [J]. Journal of Jilin University(Medicine Edition), 2020, 46(02): 346-351.
[15]	ZHAO Miao, WANG Yi, ZHANG Ying, FENG Yumei, CAO Yawen, JIANG Haisen, LI Wei. Improvement effect of curcumin on cognitive function in mice with sleep deprivation and its mechanism [J]. Journal of Jilin University(Medicine Edition), 2019, 45(06): 1373-1378.

Effect of Dushen Tang on cognitive dysfunction of aging model rats based on cAMP/PKA/CREB signal pathway

RichHTML

PDF (PC)

Like

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 7

References 27

Related Articles 15

Metrics

Comments

Recommended 10