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SMER28 Attenuates Dopaminergic Toxicity Mediated by 6-Hydroxydopamine in the Rats via Modulating Oxidative Burdens and Autophagy-Related Parameters

  • Shahram Darabi
  • Ali Noori-Zadeh
  • Farzad Rajaei
  • Hojjat Allah Abbaszadeh
  • Salar Bakhtiyari
  • Navid Ahmady Roozbahany
Original Paper

Abstract

Parkinson’s disease is the second most common neurodegenerative disease that occurs due to cellular autophagy deficiency and the accumulation of alpha-synuclein in the dopaminergic neurons of the substantia nigra pars compacta (SNc) of the brainstem. The SMER28 (also known as 6-Bromo-N-prop-2-enylquinazolin-4-amine) is an autophagy inducer. In this study, the neuroprotective effects of SMER28 were evaluated on autophagy induction, antioxidant system activation, and microgliosis attenuation. The Parkinson’s disease model was developed in the male Wistar rats by injection of 6-OHDA into the left striatum. Apomorphine-induced behavior assessment test and SNc cell counting were performed to investigate the neuroprotective effects of SMER28. This study examined the pharmacological roles of SMER28, especially by focusing on the autophagy (p62/ SQSTM1 and LC3II/LC3I ratio where LC3 is microtubule-associated protein 1A/1B-light chain 3), inhibiting free radicals, and activating the antioxidant system. The levels of malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), GSH/glutathione peroxidase (GPX), superoxide dismutase (SOD) activity and nuclear factor-erythroid 2-related factor-2 (Nrf2) were measured to evaluate the antioxidant activity of SMER28. Moreover, Iba-1 (ionized calcium binding adaptor molecule, indicating microgliosis) and tyrosine hydroxylase immunoreactivities were evaluated in the SNc. In the behavioral assessment, SMER28 (50 µg/kg) attenuated damages to the SNc dopaminergic neurons, characterized by improved motor function. The tissue observations revealed that SMER28 prevented the destruction of SNc neurons and attenuated microgliosis as well. It also reduced MDA and ROS production and increased GSH, GPX, SOD, and Nrf2 activities by inducing autophagy (decreasing p62 and increasing LC3II/LC3I ratio). Consequently, possibly with further studies, it can be considered as a drug for neurodegenerative diseases with proteinopathy etiology.

Keywords

Dopaminergic neurons Nrf2 Parkinson’s disease SMER28 SOD 

Notes

Acknowledgements

We are grateful for the financial (Grant Number: 880) supports of Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study was conducted in accordance with the guidelines for working with experimental animals set by the ethics committee (ethic code: IR.QUMS.REC.1396.149) of Qazvin University of Medical Sciences and the Guide for the Care and Use of Laboratory Animals, 8th Edition (National Academies Press, Washington, DC, 2011).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cellular and Molecular Research CenterQazvin University of Medical SciencesQazvinIran
  2. 2.Department of Clinical Biochemistry, Faculty of ParamedicineIlam University of Medical SciencesIlamIran
  3. 3.Hearing Disorders Research Center, Loghman Hakim HospitalShahid Beheshti University of Medical SciencesTehranIran
  4. 4.Department of Clinical Biochemistry, Faculty of MedicineIlam University of Medical SciencesIlamIran
  5. 5.Raymond Chang SchoolRyerson UniversityTorontoCanada

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