Glycyrrhizic Acid Alleviates 6-Hydroxydopamine and Corticosterone-Induced Neurotoxicity in SH-SY5Y Cells Through Modulating Autophagy
Recent researches have shown that autophagy is associated with the pathogenesis of neurodegenerative disorders, but there is no paper to investigate the effects of autophagy modulation on Parkinson’s disease depression (PDD). In addition, glycyrrhizic acid (GA), the major bioactive ingredient of Radix glycyrrhizae, can induce autophagy and ease rotenone-induced Parkinson’s disease (PD). However, there is also no paper to study the action and molecular mechanisms of GA on PDD. In this research, we built the injury model of SH-SY5Y cells through 6-hydroxydopamine (6-OHDA) and corticosterone (CORT). Then, our results showed that GA markedly increased the viability and decreased the apoptosis in SH-SY5Y cells after pre-treating with 6-OHDA and CORT. Moreover, GA notably decreased the expressions of α-Syn and p-S1292-LRRK2 proteins, and significantly increased the levels of CREB and BDNF proteins. Previous papers have suggested that CORT contributed to dopaminergic neurodegeneration via the glucocorticoid (GC)/glucocorticoid receptor (GR) interaction, and our results showed that GA reduced GC level and hypothalamic–pituitary–adrenal (HPA) activity in SH-SY5Y cells by regulating GR signaling pathway. Furthermore, mechanism investigations also showed that GA had the ability to up-regulate the conversion of LC3B II/I and the expression of Beclin-1, and induce autophagy in SH-SY5Y cells, which were reversed by the autophagy inhibitor 3-methyladenine (3-MA). Collectively, these findings proved that GA exerted efficient activity against neurotoxicity in SH-SY5Y cells induced by 6-OHDA and CORT via activation of autophagy, which should be developed as an efficient candidate for treating PDD in the future.
KeywordsAutophagy Glycyrrhizic acid Neurotoxicity Parkinson’s disease depression SH-SY5Y cells
This work was supported by National Natural Science foundation of China (No. 81573922), Hubei province technical innovation project (No. 2017ACA176), Natural Science Foundation of Guangdong Province (No. 2017ZC0135) and Elite Youth Education Program of Guangzhou University of Chinese Medicine (No. QNYC20140104).
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 6.Dobkin RD, Menza M, Bienfait KL, Gara M, Marin H, Mark MH, Dicke A, Friedman J (2011) Depression in Parkinson’s disease: symptom improvement and residual symptoms after acute pharmacologic management. Am J Geriatr Psychiatry 19(3):222–229. https://doi.org/10.1097/JGP.0b013e3181e448f7 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Dobkin RD, Menza M, Bienfait KL, Gara M, Marin H, Mark MH, Dicke A, Troster A (2010) The impact of antidepressant treatment on cognitive functioning in depressed patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 22(2):188–195. https://doi.org/10.1176/appi.neuropsych.22.2.188 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884. https://doi.org/10.1038/nature04723 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Ann Rev Neurosci 28:57–87. https://doi.org/10.1146/annurev.neuro.28.061604.135718 CrossRefPubMedGoogle Scholar
- 12.Jiang TF, Zhang YJ, Zhou HY, Wang HM, Tian LP, Liu J, Ding JQ, Chen SD (2013) Curcumin ameliorates the neurodegenerative pathology in A53T alpha-synuclein cell model of Parkinson’s disease through the downregulation of mTOR/p70S6K signaling and the recovery of macroautophagy. J Neuroimmune Pharmacol 8(1):356–369. https://doi.org/10.1007/s11481-012-9431-7 CrossRefPubMedGoogle Scholar
- 23.Qiu G, Spangler EL, Wan R, Miller M, Mattson MP, So KF, de Cabo R, Zou S, Ingram DK (2012) Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids. Neurobiol Aging 33(10):2398–2410. https://doi.org/10.1016/j.neurobiolaging.2011.11.025 CrossRefPubMedGoogle Scholar
- 25.Wang S, Ge W, Harns C, Meng X, Zhang Y, Ren J (2018) Ablation of toll-like receptor 4 attenuates aging-induced myocardial remodeling and contractile dysfunction through NCoRI-HDAC1-mediated regulation of autophagy. J Mol Cell Cardiol 119:40–50. https://doi.org/10.1016/j.yjmcc.2018.04.009 CrossRefPubMedGoogle Scholar
- 26.Schneider L, Giordano S, Zelickson BR, M SJ, Ouyang GAB, Fineberg X, Darley-Usmar N, Zhang VM J (2011) Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress. Free Radic Biol Med 51(11):2007–2017. https://doi.org/10.1016/j.freeradbiomed.2011.08.030 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Fan Y, Howden AJM, Sarhan AR, Lis P, Ito G, Martinez TN, Brockmann K, Gasser T, Alessi DR, Sammler EM (2018) Interrogating Parkinson’s disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochem J 475(1):23–44. https://doi.org/10.1042/bcj20170803 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607. https://doi.org/10.1016/j.neuron.2004.11.005 CrossRefPubMedGoogle Scholar
- 33.Qi G, Mi Y, Wang Y, Li R, Huang S, Li X, Liu X (2017) Neuroprotective action of tea polyphenols on oxidative stress-induced apoptosis through the activation of the TrkB/CREB/BDNF pathway and Keap1/Nrf2 signaling pathway in SH-SY5Y cells and mice brain. Food Funct 8(12):4421–4432. https://doi.org/10.1039/c7fo00991g CrossRefPubMedGoogle Scholar
- 36.West DC, Kocherginsky M, Tonsing-Carter EY, Dolcen DN, Hosfield DJ, Lastra RR, Sinnwell JP, Thompson KJ, Bowie KR, Harkless RV, Skor MN, Pierce CF, Styke SC, Kim CR, de Wet L, Greene GL (2018) Discovery of a glucocorticoid receptor (GR) activity signature using selective GR antagonism in ER-negative breast cancer. Clin Cancer Res. https://doi.org/10.1158/1078-0432.ccr-17-2793 CrossRefPubMedGoogle Scholar