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Adv Pharm Bull. 2020;10(3): 452-457.
doi: 10.34172/apb.2020.055
PMID: 32665905
PMCID: PMC7335986
Scopus ID: 85088617195
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Research Article

Contribution of Lysosome and Sigma Receptors to Neuroprotective Effects of Memantine Against Beta-Amyloid in the SH-SY5Y Cells

Mojtaba Keshavarz 1* ORCID logo, Majid Reza Farrokhi 1 ORCID logo, Elahe Amirinezhad Fard 1 ORCID logo, Mohammad Mehdipour 2 ORCID logo

1 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
2 Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
*Corresponding Author: Mojtaba Keshavarz, Tel/Fax: +9871 3623 4508, Email: Mkeshavar@sums.ac.ir

Abstract

Purpose: Memantine is an approved drug for the treatment of Alzheimer’s disease (AD). Autophagy, lysosome dysfunction, and sigma receptors have possible roles in the pathophysiology of AD. Therefore, we aimed to investigate the contribution of sigma receptors and lysosome inhibition to the neuroprotective effects of memantine against amyloid-beta (Aβ)-induced neurotoxicity in SH-SY5Y cells.

Methods: We determined the neuroprotective effects of memantine (2.5 µM), dizocilpine (MK801, as a selective N-methyl-D-aspartate (NMDA) receptor antagonist) (5 μM) against Aβ25– 35 (2 μg/μL)-induced neurotoxicity. We used chloroquine (10, 20, and 40 μM) as a lysosome inhibitor and BD-1063 (1, 10, and 30 μM) as a selective sigma receptor antagonist. The MTT assay was used to measure the neurotoxicity in the SH-SY5Y cells. Data were analyzed using the one-way ANOVA.

Results: Memantine (2.5 µM), dizocilpine (5 µM), chloroquine (10 and 20 µM) and BD-1063 (1, 10 and 30 µM) decreased the neurotoxic effects of Aβ on the SH-SY5Y cells. However, chloroquine (40 µM) increased the neurotoxic effects of Aβ. Cell viability in the cells treated with memantine + Aβ + chloroquine (10, 20, and 40 μM) was significantly lower than the memantine + Aβ-treated group. Moreover, cell viability in the memantine + Aβ group was higher than the memantine + Aβ + BD-1063 (10 and 30 μM) groups.

Conclusion: The lysosomal and sigma receptors may contribute to the neuroprotective mechanism of memantine and other NMDA receptor antagonists. Moreover, the restoration of lysosomes function and the modulation of sigma receptors are potential targets in the treatment of AD.

Keywords: Amyloid beta-Peptides, Lysosomes, Memantine, Neuroprotection, Sigma receptors
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Submitted: 26 Sep 2018
Revision: 27 Aug 2019
Accepted: 14 Nov 2019
ePublished: 11 May 2020
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