Apelin-13 Protects PC12 Cells Against Methamphetamine-Induced Oxidative Stress, Autophagy and Apoptosis
- 126 Downloads
Methamphetamine (METH) is a potent psychomotor stimulant that has a high potential for abuse in humans. In addition, it is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to METH causes psychosis and increases the risk of Parkinson’s disease. Apelin-13 is a novel endogenous ligand which studies have shown that may have a neuroprotective effect. Therefore, we hypothesized that Apelin-13 might adequately prevent METH-induced neurotoxicity via the inhibition of apoptotic, autophagy, and ROS responses. In this study, PC12 cells were exposed to both METH (0.5, 1, 2, 3, 4, 6 mmol/L) and Apelin-13 (0.5, 1.0, 2.0, 4.0, 8.0 μmol/L) in vitro for 24 h to measure determined dose, and then downstream pathways were measured to investigate apoptosis, autophagy, and ROS responses. The results have indicated that Apelin-13 decreased the apoptotic response post-METH exposure in PC12 cells by increasing cell viability, reducing apoptotic rates. In addition, the study has revealed Apelin-13 decreased gene expression of Beclin-1 by Real-Time PCR and LC3-II by western blotting in METH-induced PC12 cells, which demonstrated autophagy is reduced. In addition, this study has shown that Apelin-13 reduces intracellular ROS of METH-induced PC12 cells. These results support Apelin-13 to be investigated as a potential drug for treatment of neurodegenerative diseases. It is suggested that Apelin-13 is beneficial in reducing oxidative stress, which may also play an important role in the regulation of METH-triggered apoptotic response. Hence, these data indicate that Apelin-13 could potentially alleviate METH-induced neurotoxicity via the reduction of oxidative damages, apoptotic, and autophagy cell death.
KeywordsMethamphetamine Apelin-13 Neurotoxicity Apoptosis Autophagy Reactive oxygen species
The present study was supported by Shahroud University of medical sciences as an MSc Thesis. We hereby acknowledge the research deputy for grant No 9667.
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflict of interests related to this work.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Research Involving Human and Animal Participants
This article does not contain any studies with human participants performed by any of the authors.
- 4.UNODC I (2009) World drug report. United Nations, New York, NYGoogle Scholar
- 5.Shin EJ, Dang DK, Tran TV, Tran HQ, Jeong JH, Nah SY, Jang CG, Yamada K, Nabeshima T, Kim HC (2017) Current understanding of methamphetamine-associated dopaminergic neurodegeneration and psychotoxic behaviors. Arch Pharmacal Res 40(4):403–428. https://doi.org/10.1007/s12272-017-0897-y CrossRefGoogle Scholar
- 11.Jang EY, Yang CH, Hedges DM, Kim SP, Lee JY, Ekins TG, Garcia BT, Kim HY, Nelson AC, Kim NJ, Steffensen SC (2016) The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens. Addict Biol 22:1304. https://doi.org/10.1111/adb.12419 CrossRefGoogle Scholar
- 13.Ghanbari F, Khaksari M, Vaezi G, Hojati V, Shiravi A (2018) Hydrogen sulfide protects hippocampal neurons against methamphetamine neurotoxicity via inhibition of apoptosis and neuroinflammation. J Mol Neurosci 67:133Google Scholar
- 14.Xu X, Huang E, Tai Y, Zhao X, Chen X, Chen C, Chen R, Liu C, Lin Z, Wang H, Xie W-B (2017) Nupr1 modulates methamphetamine-induced dopaminergic neuronal apoptosis and autophagy through CHOP-Trib3-mediated endoplasmic reticulum stress signaling pathway. Front Mol Neurosci 10:203CrossRefGoogle Scholar
- 15.Li Y, Hu Z, Chen B, Bu Q, Lu W, Deng Y, Zhu R, Shao X, Hou J, Zhao J, Li H, Zhang B, Huang Y, Lv L, Zhao Y, Cen X (2012) Taurine attenuates methamphetamine-induced autophagy and apoptosis in PC12 cells through mTOR signaling pathway. Toxicol Lett 215(1):1–7. https://doi.org/10.1016/j.toxlet.2012.09.019 CrossRefGoogle Scholar
- 16.Malyszko J, Malyszko JS, Pawlak K, Wolczynski S, Mysliwiec M (2008) Apelin, a novel adipocytokine, in relation to endothelial function and inflammation in kidney allograft recipients. Transpl Proc 40(10):3466–3469. https://doi.org/10.1016/j.transproceed.2008.06.059 CrossRefGoogle Scholar
- 25.Daviaud D, Boucher J, Gesta S, Dray C, Guigne C, Quilliot D, Ayav A, Ziegler O, Carpene C, Saulnier-Blache JS, Valet P, Castan-Laurell I (2006) TNFalpha up-regulates apelin expression in human and mouse adipose tissue. FASEB J 20(9):1528–1530. https://doi.org/10.1096/fj.05-5243fje CrossRefGoogle Scholar
- 28.Huang Y-N, Yang L-Y, Wang J-Y, Lai C-C, Chiu C-T, Wang J-Y (2017) L-Ascorbate protects against methamphetamine-induced neurotoxicity of cortical cells via inhibiting oxidative stress, autophagy, and apoptosis. Mol Neurobiol 54(1):125–136. https://doi.org/10.1007/s12035-015-9561-z CrossRefGoogle Scholar
- 39.Pitaksalee R, Sanvarinda Y, Sinchai T, Sanvarinda P, Thampithak A, Jantaratnotai N, Jariyawat S, Tuchinda P, Govitrapong P, Sanvarinda P (2015) Autophagy inhibition by caffeine increases toxicity of methamphetamine in SH-SY5Y neuroblastoma cell line. Neurotox Res 27(4):421–429. https://doi.org/10.1007/s12640-014-9513-9 CrossRefGoogle Scholar
- 44.Lau JWS, Senok S, Stadlin A (2000) Methamphetamine-induced oxidative stress in cultured mouse astrocytes. Ann N Y Acad Sci 914(1):146–156. https://doi.org/10.1111/j.1749-6632.2000.tb05192.x CrossRefGoogle Scholar