Downregulation of miR‑21 suppresses 1‑methyl‑4‑phenylpyridinium‑induced neuronal damage
in MES23.5 cells

Mao,Huawu; Ding,Lidong

doi:10.3892/etm.2019.7853

Downregulation of miR‑21 suppresses 1‑methyl‑4‑phenylpyridinium‑induced neuronal damage in MES23.5 cells

Authors:
- Huawu Mao
- Lidong Ding
View Affiliations

Affiliations: Department of Neurology, The Second People's Hospital of Taizhou, Taizhou, Jiangsu 225500, P.R. China
Published online on: August 5, 2019 https://doi.org/10.3892/etm.2019.7853
Pages: 2467-2474
Copyright: © Mao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Accumulating evidence suggests that overproduction of oxidative stress, increases neuroinflammation and activates apoptosis. These two processes are associated with the development of Parkinson's disease (PD). The present study aimed to investigate the role of miR‑21 in the development of PD. 1‑Methyl‑4‑phenylpyridinium (MPP+) was used to induce a PD‑like model in MES23.5 cells. The results of the reverse transcription‑quantitative PCR assays indicated that miR‑21 levels were markedly increased in MES23.5 cells following MPP+ treatment. Furthermore, MES23.5 cells were transfected with miR‑21 inhibitor, mimics and/or relevant negative control, following MPP+ administration. The results of the functional assays revealed that downregulation of miR‑21 significantly attenuated the induction of cell apoptosis and reactive oxygen species (ROS) production, while it enhanced the survival of MPP+‑induced MES23.5 cells. Furthermore, downregulation of miR‑21 increased the expression levels of tyrosine hydroxylase, whereas suppression of miR‑21 inhibited the production of pro‑inflammatory cytokines [interleukin (IL)‑6, IL‑1β and tumor necrosis factor‑α] in MES23.5 cells. Western blot analysis further indicated that the Bcl‑2/Bax protein expression ratio was significantly increased and double luciferase assay analysis confirmed that Bcl‑2 was a direct target of miR‑21. Taken collectively, the data demonstrated that downregulation of miR‑21 protected cells from MPP+‑mediated cytotoxicity by the inhibition of apoptosis induction, the reduction of the inflammatory response and the suppression of ROS production. The present findings may provide novel approaches for PD clinical treatment.

View Figures

View References

1	Kalia LV and Lang AE: Parkinson's disease. Lancet. 386:896–912. 2015. View Article : Google Scholar : PubMed/NCBI
2	Andican G, Konukoglu D, Bozluolcay M, Bayulkem K, Firtiina S and Burcak G: Plasma oxidative and inflammatory markers in patients with idiopathic Parkinson's disease. Acta Neurol Belg. 112:155–159. 2012. View Article : Google Scholar : PubMed/NCBI
3	Mullin S and Schapira AH: Pathogenic mechanisms of neurodegeneration in Parkinson disease. Neurol Clin. 33:1–17. 2015. View Article : Google Scholar : PubMed/NCBI
4	Maiti P, Manna J and Dunbar GL: Current understanding of the molecular mechanisms in Parkinson's disease: Targets for potential treatments. Transl Neurodegener. 6:282017. View Article : Google Scholar : PubMed/NCBI
5	Mohr AM and Mott JL: Overview of microRNA biology. Semin Liver Dis. 35:3–11. 2015. View Article : Google Scholar : PubMed/NCBI
6	Moss EG: MicroRNAs: Hidden in the genome. Curr Biol. 12:R138–R140. 2002. View Article : Google Scholar : PubMed/NCBI
7	Ma L, Wei L, Wu F, Hu Z, Liu Z and Yuan W: Advances with microRNAs in Parkinson's disease research. Drug Des Devel Ther. 7:1103–1113. 2013.PubMed/NCBI
8	Quinlan S, Kenny A, Medina M, Engel T and Jimenez-Mateos EM: MicroRNAs in neurodegenerative diseases. Int Rev Cell Mol Biol. 334:309–343. 2017. View Article : Google Scholar : PubMed/NCBI
9	Fu Y, Zhen J and Lu Z: Synergetic neuroprotective effect of docosahexaenoic acid and aspirin in SH-Y5Y by inhibiting miR-21 and activating RXRalpha and PPARalpha. DNA Cell Biol. 36:482–489. 2017. View Article : Google Scholar : PubMed/NCBI
10	Su C, Yang X and Lou J: Geniposide reduces alpha-synuclein by blocking microRNA-21/lysosome-associated membrane protein 2A interaction in Parkinson disease models. Brain Res 1644. 98–106. 2016. View Article : Google Scholar
11	Singer TP, Ramsay RR, McKeown K, Trevor A and Castagnoli NE Jr: Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Toxicology. 49:17–23. 1988. View Article : Google Scholar : PubMed/NCBI
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
13	Peng J, Liu Q, Rao MS and Zeng X: Using human pluripotent stem cell-derived dopaminergic neurons to evaluate candidate Parkinson's disease therapeutic agents in MPP+ and rotenone models. J Biomol Screen. 18:522–533. 2013. View Article : Google Scholar : PubMed/NCBI
14	Ge X, Li W, Huang S, Yin Z, Yang M, Han Z, Han Z, Chen F, Wang H, Lei P and Zhang J: Increased miR-21-3p in injured brain microvascular endothelial cells following traumatic brain injury aggravates blood-brain barrier damage by promoting cellular apoptosis and inflammation through targeting MAT2B. J Neurotrauma. 36:1291–1305. 2019. View Article : Google Scholar : PubMed/NCBI
15	Oh SE, Park HJ, He L, Skibiel C, Junn E and Mouradian MM: The Parkinson's disease gene product DJ-1 modulates miR-221 to promote neuronal survival against oxidative stress. Redox Biol. 19:62–73. 2018. View Article : Google Scholar : PubMed/NCBI
16	Li J, Sun Y and Chen J: Identification of critical genes and miRNAs associated with the development of parkinson's disease. J Mol Neurosci. 65:527–535. 2018. View Article : Google Scholar : PubMed/NCBI
17	Wong G and Nass R: miRNAs and their putative roles in the development and progression of Parkinson's disease. Front Genet. 3:3152013. View Article : Google Scholar : PubMed/NCBI
18	Titze-de-Almeida R and Titze-de-Almeida SS: miR-7 replacement therapy in parkinson's disease. Curr Gene Ther. 18:143–153. 2018. View Article : Google Scholar : PubMed/NCBI
19	Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI
20	Lotharius J, Dugan LL and O'Malley KL: Distinct mechanisms underlie neurotoxin-mediated cell death in cultured dopaminergic neurons. J Neurosci. 19:1284–1293. 1999. View Article : Google Scholar : PubMed/NCBI
21	Devathasan G, Chong PN, Puvanendran K, Lun KC and Wong PK: Low-dose bromocriptine therapy in severe Parkinson's disease. Clin Neuropharmacol. 7:231–237. 1984. View Article : Google Scholar : PubMed/NCBI
22	Yadava N and Nicholls DG: Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. J Neurosci. 27:7310–7317. 2007. View Article : Google Scholar : PubMed/NCBI