, Volume 51, Issue 2, pp 88–96 | Cite as

Neuroprotective Effects of the Small-Molecule Enhancer of Rapamycin in the Cellular Model of Parkinson’s Disease

  • S. DarabiEmail author
  • A. Noori-Zadeh
  • F. Rajaei
  • H. A. Abbaszadeh
  • M.-A. Abdollahifar
  • S. Bakhtiyari

Parkinson’s disease (PD) is one of the most frequent neurodegenerative diseases. We investigated the protective effects of the small-molecule enhancer of rapamycin SMER28 in the SH-SY5Y cellular model of PD induced by 6-hydroxydopamine (6-OHDA). The cell viability and apoptosis estimations were performed using MTT and annexin V-FITC assays, respectively. The levels of intracellular reactive oxygen species (ROSs) and mitochondrial membrane potential were determined by the respective fluorescence detection. ELISA assays were performed to detect the levels of dopamine and α-synuclein. Additionally, mTOR signaling and the expression levels of autophagy-related proteins, including Beclin-1, p62, and LC3, were analyzed by Western blot. SMER28 increased the cell viability and mitochondrial membrane potential but decreased ɑ-synuclein and intracellular ROSs. SMER28 also reversed the decreased dopamine level and increased α-synuclein expression induced by 6-OHDA. The latter (100 μM) induced intense apoptosis, but 50 μM SMER28 prevented the latter via autophagy induction. We also noticed that SMER28 triggered autophagy and enhanced Beclin-1 expression, and LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in SH-SY5Y cells. Blocking of autophagy by a selective inhibitor, 3-methyladenosine, decreased the autophagy ratio in SMER28-treated SH-SY5Y cells, suggesting a considerable neuroprotective role of SMER28-induced autophagy. Taken together, it can be concluded that SMER28 exerts a protective effect against cellular damage induced by 6-OHDA via autophagy induction. Therefore, SMER28 may serve as a promising potential adjuvant therapy for PD treatment.


Parkinson’s disease cellular model 6-OHDA apoptosis autophagy 3-methyladenosine dopaminergic neurons SH-SY5Y cells SMER28 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A. Kulkarni, J. Chen, and S. Maday, “Neuronal autophagy and intercellular regulation of homeostasis in the brain,” Curr. Opin. Neurobiol., 51, 29–36 (2018).CrossRefGoogle Scholar
  2. 2.
    M. Xilouri and L. Stefanis, “Autophagy in the central nervous system: implications for neurodegenerative disorders,” CNS Neurol. Disord. Drug Targets, 9, No. 6, 701–719 (2010).CrossRefGoogle Scholar
  3. 3.
    M. Xilouri and L. Stefanis, “Autophagic pathways in Parkinson disease and related disorders,” Expert Rev. Mol. Med., 13, e8 (2011), doi:
  4. 4.
    S. Darabi, A. Noori-Zadeh, F. Rajaei, et al., “SMER28 attenuates dopaminergic toxicity mediated by 6-hydroxydopamine in the rats via modulating oxidative burdens and autophagy-related parameters”, Neurochem. Res., 43, No. 12, 2313–2323 (2018).CrossRefGoogle Scholar
  5. 5.
    S. Darabi, A. Noori-Zadeh, H. A. Abbaszadeh, and F. Rajaei, “Trehalose activates autophagy and prevents hydrogen peroxide-induced apoptosis in the bone marrow stromal cells”, Iran J. Pharm. Res., 17, No. 3, 1141–1149 (2018).Google Scholar
  6. 6.
    H. A. Abbaszadeh, S. Niknazar, S. Darabi, et al., “Stem cell transplantation and functional recovery after spinal cord injury: a systematic review and meta-analysis”, Anat. Cell Biol., 51, No 3, 180–188 (2018).CrossRefGoogle Scholar
  7. 7.
    S. Darabi, T. Tiraihi, A. Delshad, et al., “Creatine enhances transdifferentiation of bone marrow stromal cell-derived neural stem cell into GABAergic neuron-like cells characterized with differential gene expression,” Mol. Neurobiol., 54, No. 3, 1978–1991 (2017).CrossRefGoogle Scholar
  8. 8.
    S. Darabi, T. Tiraihi, A. Delshad, et al., “In vitro nonviral murine pro-neurotrophin 3 gene transfer into rat bone marrow stromal cells,” J. Neurol. Sci., 375, 137–145 (2017).CrossRefGoogle Scholar
  9. 9.
    N. Sefati, H. A. Abbaszadeh, F. F. Fathabady, et al., “The combined effects of mesenchymal stem cell conditioned media and low-level laser on stereological and biomechanical parameter in hypothyroidism rat model”, J. Lasers Med. Sci., 9, No.4, 243–248 (2018).CrossRefGoogle Scholar
  10. 10.
    S. Darabi, T. Tiraihi, A. Noori-Zadeh, et al., “Creatine and retinoic acid effects on the induction of autophagy and differentiation of adipose tissue-derived stem cells into GABAergic-like neurons,” J. Babol Univ. Med. Sci., 19, No. 8, 41–49 (2017).Google Scholar
  11. 11.
    M. H. Karimfar, S. Rostami, K. Haghani, et al., “Melatonin alleviates bleomycin-induced pulmonary fibrosis in mice,” J. Biol. Regul. Homeost. Agents, 29, No. 2, 327–334 (2015).Google Scholar
  12. 12.
    H. Kazemi, A. Noori-Zadeh, S. Darabi, and F. Rajaei, “Lithium prevents cell apoptosis through autophagy induction,” Bratisl. Lek. Listy, 119, No. 4, 234–239 (2018).Google Scholar
  13. 13.
    S. Sarkar, E. O. Perlstein, S. Imarisio, et al., “Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models,” Nat. Chem. Boil., 3, No. 6, 331–338 (2007).CrossRefGoogle Scholar
  14. 14.
    H.-R. Xie, L.-S. Hu, and G.-Y. Li, “SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease,’ Chin. Med. J. (Engl.), 123, No. 8, 1086–1092 (2010).Google Scholar
  15. 15.
    M. Shams Nooraei, A. Noori-Zadeh, S. Darabi, et al., “Low level of autophagy-related gene 10 (ATG10) expression in the 6-hydroxydopamine rat model of Parkinson’s disease,” Iran Biomed. J., 22, No. 1, 15–21 (2018).Google Scholar
  16. 16.
    J. J. Palacino, D. Sagi, M. S. Goldberg, et al., “Mitochondrial dysfunction and oxidative damage in parkin-deficient mice,” J. Biol. Chem., 279, No. 18, 18614–18622 (2004).CrossRefGoogle Scholar
  17. 17.
    X. L. Liu, Y. D. Wang, X. M. Yu, et al., “Mitochondria-mediated damage to dopaminergic neurons in Parkinson’s disease,” Int. J. Mol. Med., 41, No. 2, 615–623 (2018).Google Scholar
  18. 18.
    J. D. Guo, X. Zhao, Y. Li, et al., “Damage to dop-aminergic neurons by oxidative stress in Parkinson’s disease,” Int. J. Mol. Med., 41, No. 4, 1817–1825 (2018).Google Scholar
  19. 19.
    J. M. Gump and A. Thorburn, “Autophagy and apoptosis: what is the connection?” Trends Cell Biol., 21, No. 7, 387–392 (2011).CrossRefGoogle Scholar
  20. 20.
    B. Levine and J. Yuan, “Autophagy in cell death: an innocent convict?” J. Clin. Invest., 115, No. 10, 2679–2688 (2005).CrossRefGoogle Scholar
  21. 21.
    S. Ghavami, S. Shojaei, B. Yeganeh, et al., “Autophagy and apoptosis dysfunction in neurodegenerative disorders,” Prog. Neurobiol., 112, 24–49 (2014).CrossRefGoogle Scholar
  22. 22.
    L. Scott, V. L. Dawson, and T. M. Dawson, “Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson’s disease genes,” Exp. Neurol., 298, Pt. B, 191–201 (2017).Google Scholar
  23. 23.
    R. Kang, H. J. Zeh, M. T. Lotze, and D. Tang. “The Beclin 1 network regulates autophagy and apoptosis,” Cell Death Differ., 18, No. 4, 571–580 (2011).CrossRefGoogle Scholar
  24. 24.
    Z. Y. Shi, J. X. Deng, S. Fu, et al., “Protective effect of autophagy in neural ischemia and hypoxia: Negative regulation of the Wnt/β-catenin pathway,” Int. J. Mol. Med., 40, No. 6, 1699–1708 (2017).Google Scholar
  25. 25.
    G. G. Chiang and R. T. Abraham, “Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase,” J. Biol. Chem., 280, No. 27, 25485–25490 (2005).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • S. Darabi
    • 1
    Email author
  • A. Noori-Zadeh
    • 2
  • F. Rajaei
    • 1
  • H. A. Abbaszadeh
    • 3
  • M.-A. Abdollahifar
    • 4
  • S. Bakhtiyari
    • 5
  1. 1.Cellular and Molecular Research CenterQazvin University of Medical SciencesQazvinIran
  2. 2.Department of Clinical Biochemistry, Faculty of Allied Medical SciencesIlam University of Medical SciencesIlamIran
  3. 3.Hearing Disorders Research Center, Loghman Hakim Medical Center, and Department of Biology and Anatomical Sciences, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
  4. 4.Department of Anatomical Sciences and Biology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
  5. 5.Department of Clinical Biochemistry, Faculty of MedicineIlam University of Medical SciencesIlamIran

Personalised recommendations