Asiaticoside reduces autophagy and improves memory in a rat model of dementia through mTOR signaling pathway regulation

Guo,Min; Xu,Jianmeng; Wang,Shiwei; Dong,Baohua

doi:10.3892/mmr.2021.12284

Asiaticoside reduces autophagy and improves memory in a rat model of dementia through mTOR signaling pathway regulation

Authors:
- Min Guo
- Jianmeng Xu
- Shiwei Wang
- Baohua Dong
View Affiliations

Affiliations: Department of Neurology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, P.R. China, Department of Neurosurgery, Dongying District People's Hospital of Dongying City, Dongying, Shandong 257000, P.R. China, Department of Traditional Chinese Medicine, Dongying District People's Hospital of Dongying City, Dongying, Shandong 257000, P.R. China, Department of Neurology, Dongying District People's Hospital of Dongying City, Dongying, Shandong 257000, P.R. China
Published online on: July 12, 2021 https://doi.org/10.3892/mmr.2021.12284
Article Number: 645

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vascular dementia (VD) is one of the leading causes of neurological disorder following Alzheimer's disease. The present study evaluated the possible role of asiaticoside in the treatment of rats with VD and its inhibitory effects on autophagy in hippocampal tissues. Double ligation was used for permanent occlusion of the arteries, and spatial memory was assessed using the T‑maze test. Western blotting was used for determination of protein expression levels and H&E staining for histological analysis. Treatment of rats with VD with asiaticoside significantly alleviated the impairment in spontaneously altered behaviors and significantly reduced escape latency. VD mediated a decrease in distance travelled, swim time and number of platform crossings, whereas this was alleviated by asiaticoside. Furthermore, VD‑mediated hippocampal tissue damage was significantly alleviated by asiaticoside treatment (P<0.05), and asiaticoside alleviated formation of autophagosomes and markedly suppressed the number of primary lysosomes. In asiaticoside‑treated rats, VD‑mediated increases in Beclin 1 and microtubule‑associated protein light chain 3 (LC3) II expression in the hippocampal tissues were alleviated. Asiaticoside treatment also prevented suppression of mammalian target of rapamycin (mTOR) phosphorylation in VD rat hippocampal tissues. Notably, the rapamycin‑mediated suppression of phosphorylated‑mTOR, and elevation of Beclin 1 and LC3II expression in the rat hippocampus could not be alleviated by asiaticoside treatment. In conclusion, asiaticoside effectively prevented cerebral ischemia‑mediated cognitive impairment and neuronal damage in the rats. Moreover, autophagy was inhibited and the mTOR pathway was activated in rats with cerebral ischemia by asiaticoside treatment. Therefore, asiaticoside may warrant further study as a therapeutic agent for the treatment of dementia.

View Figures

View References

1	O'Brien JT and Thomas A: Vascular dementia. Lancet. 386:1698–1706. 2015. View Article : Google Scholar
2	Smith EE: Clinical presentations and epidemiology of vascular dementia. Clin Sci (Lond). 131:1059–1068. 2017. View Article : Google Scholar : PubMed/NCBI
3	Jayant S and Sharma B: Selective modulator of cannabinoid receptor type 2 reduces memory impairment and infarct size during cerebral hypoperfusion and vascular dementia. Curr Neurovasc Res. 13:289–302. 2016. View Article : Google Scholar : PubMed/NCBI
4	Levine DA and Langa KM: Vascular cognitive impairment: Disease mechanisms and therapeutic implications. Neurotherapeutics. 8:361–373. 2011. View Article : Google Scholar : PubMed/NCBI
5	Voigt O and Pöggeler S: Self-eating to grow and kill: Autophagy in filamentous ascomycetes. Appl Microbiol Biotechnol. 97:9277–9290. 2013. View Article : Google Scholar : PubMed/NCBI
6	Bharadwaj PR, Verdile G, Barr RK, Gupta V, Steele JW, Lachenmayer ML, Yue Z, Ehrlich ME, Petsko G, Ju S, et al: Latrepirdine (dimebon) enhances autophagy and reduces intra-cellular GFP-Aβ42 levels in yeast. J Alzheimers Dis. 32:949–967. 2012. View Article : Google Scholar : PubMed/NCBI
7	Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B and Bao JK: Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45:487–498. 2012. View Article : Google Scholar : PubMed/NCBI
8	Lu J, Qian HY, Liu LJ, Zhou BC, Xiao Y, Mao JN, An GY, Rui MZ, Wang T and Zhu CL: Mild hypothermia alleviates excessive autophagy and mitophagy in a rat model of asphyxial cardiac arrest. Neurol Sci. 35:1691–1699. 2014. View Article : Google Scholar : PubMed/NCBI
9	Fujita S, Sakurai M, Baba H, Abe K and Tominaga R: Autophagy-mediated stress response in motor neurons after hypothermic spinal cord ischemia in rabbits. J Vasc Surg. 62:1312–1319. 2015. View Article : Google Scholar : PubMed/NCBI
10	Hwang JY, Gertner M, Pontarelli F, Court-Vazquez B, Bennett MV, Ofengeim D and Zukin RS: Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagyin hippocampal neurons destined to die. Cell Death Differ. 24:317–329. 2017. View Article : Google Scholar : PubMed/NCBI
11	Chang H, Li X, Cai Q, Li C, Tian L, Chen J, Xing X, Gan Y, Ouyang W and Yang Z: The PI3K/Akt/mTOR pathway is involved in CVB3-induced autophagy of HeLa cells. Int J Mol Med. 40:182–192. 2017. View Article : Google Scholar : PubMed/NCBI
12	Schaaf MB, Keulers TG, Vooijs MA and Rouschop KM: LC3/GABARAP family proteins: Autophagy-(un)related functions. FASEB J. 30:3961–3978. 2016. View Article : Google Scholar : PubMed/NCBI
13	Dong MS, Jung SH, Kim HJ, Kim JR, Zhao LX, Lee ES, Lee EJ, Yi JB, Lee N, Cho YB, et al: Structure-related cytotoxicity and anti-hepatofibric effect of asiatic acid derivatives in rat hepatic stellate cell-line, HSC-T6. Arch Pharm Res. 27:512–517. 2004. View Article : Google Scholar : PubMed/NCBI
14	Guo JS, Cheng CL and Koo MW: Inhibitory effects of Centella asiatica water extract and asiaticoside on inducible nitric oxide synthase during gastric ulcer healing in rats. Planta Med. 70:1150–1154. 2004. View Article : Google Scholar : PubMed/NCBI
15	Chen S, Yin ZJ, Jiang C, Ma ZQ, Fu Q, Qu R and Ma SP: Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism. Pharmacol Biochem Behav. 122:7–15. 2014. View Article : Google Scholar : PubMed/NCBI
16	Yun KJ, Kim JY, Kim JB, Lee KW, Jeong SY, Park HJ, Jung HJ, Cho YW, Yun K and Lee KT: Inhibition of LPS-induced NO and PGE2 production by asiatic acid via NF-kappa B inactivation in RAW 264.7 macrophages: Possible involvement of the IKK and MAPK pathways. Int Immunopharmacol. 8:431–441. 2008. View Article : Google Scholar : PubMed/NCBI
17	Xing M, Sun Q, Wang Y, Cheng Y and Zhang N: Hydroxysafflor yellow A increases BDNF and NMDARs in the hippocampus in A vascular dementia rat model. Brain Res. 1642:419–425. 2016. View Article : Google Scholar : PubMed/NCBI
18	Deacon RM and Rawlins JN: T-maze alternation in the rodent. Nat Protoc. 1:7–12. 2006. View Article : Google Scholar : PubMed/NCBI
19	Pulsinelli WA, Brierley JB and Plum F: Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 11:491–498. 1982. View Article : Google Scholar : PubMed/NCBI
20	Levine B, Mizushima N and Virgin HW: Autophagy inimmunity and inflammation. Nature. 469:323–335. 2011. View Article : Google Scholar : PubMed/NCBI
21	Zhao Y, Huang G, Chen S, Gou Y, Dong Z and Zhang X: Homocysteine aggravates cortical neural cell injury through neuronal autophagy overactivation following rat cerebral ischemia-reperfusion. Int J Mol Sci. 17:11962016. View Article : Google Scholar : PubMed/NCBI
22	Zou W, Song Y, Li Y, Du Y, Zhang X and Fu J: The role of autophagy in the correlation between neuron damage and cognitive impairmentin ratchronic cerebral hypoperfusion. Mol Neurobiol. 55:776–791. 2018. View Article : Google Scholar : PubMed/NCBI
23	Li L, Chen J, Sun S, Zhao J, Dong X and Wang J: Effects of estradiol on autophagy and Nrf-2/ARE signals after cerebral ischemia. Cell Physiol Biochem. 41:2027–2036. 2017. View Article : Google Scholar : PubMed/NCBI
24	Kim YC and Guan KL: mTOR: A pharmacologic target for autophagy regulation. J Clin Invest. 125:25–32. 2015. View Article : Google Scholar : PubMed/NCBI
25	Wang D, Lin Q, Su S, Liu K, Wu Y and Hai J: URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy. Neuroscience. 344:293–304. 2017. View Article : Google Scholar : PubMed/NCBI
26	Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, Agholme L, Agnello M, Agostinis P, Aguirre-Ghiso JA, et al: Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 8:445–544. 2012. View Article : Google Scholar : PubMed/NCBI
27	Wang J, Meng F, Cottrell JE, Sacktor TC and Kass IS: Metabotropic actions of the volatile anaesthetic sevoflurane increase protein kinase M synthesis and induce immediate preconditioning protection of rat hippocampal slices. J Physiol. 590:4093–4107. 2012. View Article : Google Scholar : PubMed/NCBI
28	Dai S, Xu Q, Liu S, Yu B, Liu J and Tang J: Role of autophagy and its signaling pathways in ischemia/reperfusion injury. Am J Transl Res. 9:4470–4480. 2017.PubMed/NCBI
29	Zhao P, Zhang BL, Liu K, Qin B and Li ZH: Overexpression of miR-638 attenuated the effects of hypoxia/reoxygenation treatment on cell viability, cell apoptosis and autophagy by targeting ATG5 in the human cardiomyocytes. Eur Rev Med Pharmacol Sci. 22:8462–8471. 2018.PubMed/NCBI
30	Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, et al: Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 90:1383–1435. 2010. View Article : Google Scholar : PubMed/NCBI
31	Yang SS, Liu YB, Yu JB, Fan Y, Tang SY, Duan WT, Wang Z, Gan RT and Yu B: Rapamycin protects heart from ischemia/reperfusion injury independent of autophagy by activating PI3 kinase-Akt pathway and mitochondria K(ATP) channel. Pharmazie. 65:760–765. 2010.PubMed/NCBI
32	Kiriyama Y and Nochi H: The function of autophagy in neurode- generative diseases. Int J Mol Sci. 16:26797–26812. 2015. View Article : Google Scholar : PubMed/NCBI
33	Che H, Yan Y, Kang XH, Guo F, Yan ML, Liu HL, Hou X, Liu T, Zong DK, Sun LL, et al: MicroRNA-27a promotes inefficient lysosomal clearance in the hippocampi of rats following chronic brain hypoperfusion. Mol Neurobiol. 54:2595–2610. 2017. View Article : Google Scholar : PubMed/NCBI
34	Jia Y, Jin W, Xiao Y, Dong Y, Wang T, Fan M, Xu J, Meng N, Li L and Lv P: Lipoxin A4 methyl ester alleviates vascular cognition impairment by regulating the expression of proteins related to autophagy and ER stress in the rat hippocampus. Cell Mol Biol Lett. 20:475–487. 2015. View Article : Google Scholar : PubMed/NCBI
35	Yang X, He C, Liu P, Song X, Thomas T, Tshimanga S, Wang F, Niu J, Sun T and Li PA: Inhibition of mTOR pathway by rapamycin reduces brain damage in rats subjected to transient forebrain ischemia. Int J Biol Sci. 11:1424–1435. 2015. View Article : Google Scholar : PubMed/NCBI