Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-365 Knockdown Prevents Ischemic Neuronal Injury by Activating Oxidation Resistance 1-Mediated Antioxidant Signals

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

MicroRNA-365 (miR-365) is upregulated in the ischemic brain and is involved in oxidative damage in the diabetic rat. However, it is unclear whether miR-365 regulates oxidative stress (OS)-mediated neuronal damage after ischemia. Here, we used a transient middle cerebral artery occlusion model in rats and the hydrogen peroxide-induced OS model in primary cultured neurons to assess the roles of miR-365 in neuronal damage. We found that miR-365 exacerbated ischemic brain injury and OS-induced neuronal damage and was associated with a reduced expression of OXR1 (Oxidation Resistance 1). In contrast, miR-365 antagomir alleviated both the brain injury and OXR1 reduction. Luciferase assays indicated that miR-365 inhibited OXR1 expression by directly targeting the 3′-untranslated region of Oxr1. Furthermore, knockdown of OXR1 abolished the neuroprotective and antioxidant effects of the miR-365 antagomir. Our results suggest that miR-365 upregulation increases oxidative injury by inhibiting OXR1 expression, while its downregulation protects neurons from oxidative death by enhancing OXR1-mediated antioxidant signals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999, 79: 1431–1568.

    Article  CAS  PubMed  Google Scholar 

  2. Zhao H, Han Z, Ji X, Luo Y. Epigenetic regulation of oxidative stress in ischemic stroke. Aging Dis 2016, 7: 295–306.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Li XJ, Zhang LM, Gu J, Zhang AZ, Sun FY. Melatonin decreases production of hydroxyl radical during cerebral ischemia-reperfusion. Acta Pharmacol Sin 1997, 18: 394–396.

    CAS  Google Scholar 

  4. Davis SM, Pennypacker KR. Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke. Neurochem Int 2017, 107: 23–32.

    Article  CAS  PubMed  Google Scholar 

  5. Ramos E, Patino P, Reiter RJ, Gil-Martin E, Marco-Contelles J, Parada E, et al. Ischemic brain injury: new insights on the protective role of melatonin. Free Radic Biol Med 2017, 104: 32–53.

    Article  CAS  PubMed  Google Scholar 

  6. Chamorro A, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 2016, 15: 869–881.

    Article  CAS  PubMed  Google Scholar 

  7. Baker K, Marcus CB, Huffman K, Kruk H, Malfroy B, Doctrow SR. Synthetic combined superoxide dismutase catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury. J Pharmacol Exp Ther 1998, 284: 215–221.

    CAS  PubMed  Google Scholar 

  8. Gu WP, Zhao H, Yenari MA, Sapolsky RM, Steinberg GK. Catalase over-expression protects striatal neurons from transient focal cerebral ischemia. Neuroreport 2004, 15: 413–416.

    Article  CAS  PubMed  Google Scholar 

  9. Ishibashi N, Prokopenko O, Weisbrot-Lefkowitza M, Reuhl KR, Mirochnitchenko O. Glutathione peroxidase inhibits cell death and glial activation following experimental stroke. Brain Res Mol Brain Res 2002, 109: 34–44.

    Article  CAS  PubMed  Google Scholar 

  10. Volkert MR, Elliott NA, Housman DE. Functional genomics reveals a family of eukaryotic oxidation protection genes. Proc Natl Acad Sci U S A 2000, 97: 14530–14535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Durand M, Kolpak A, Farrell T, Elliott NA, Shao W, Brown M, et al. The OXR domain defines a conserved family of eukaryotic oxidation resistance proteins. BMC Cell Biol 2007, 8: 13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang M, Luna L, Sorbo JG, Alseth I, Johansen RF, Backe PH, et al. Human OXR1 maintains mitochondrial DNA integrity and counteracts hydrogen peroxide-induced oxidative stress by regulating antioxidant pathways involving p21. Free Radic Biol Med 2014, 77: 41–48.

    Article  CAS  PubMed  Google Scholar 

  13. Sanada Y, Asai S, Ikemoto A, Moriwaki T, Nakamura N, Miyaji M, et al. Oxidation resistance 1 is essential for protection against oxidative stress and participates in the regulation of aging in caenorhabditis elegans. Free Radic Res 2014, 48: 919–928.

    Article  CAS  PubMed  Google Scholar 

  14. Kobayashi N, Takahashi M, Kihara S, Niimi T, Yamashita O, Yaginuma T. Cloning of cDNA encoding a bombyx mori homolog of human oxidation resistance 1 (OXR1) protein from diapause eggs, and analyses of its expression and function. J Insect Physiol 2014, 68: 58–68.

    Article  CAS  PubMed  Google Scholar 

  15. Finelli MJ, Liu KX, Wu Y, Oliver PL, Davies KE. Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations. Hum Mol Genet 2015, 24: 3529–3544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu KX, Edwards B, Lee S, Finelli MJ, Davies B, Davies KE, et al. Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis. Brain 2015, 138: 1167–1181.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Oliver PL, Finelli MJ, Edwards B, Bitoun E, Butts DL, Becker EB, et al. Oxr1 is essential for protection against oxidative stress-induced neurodegeneration. PLoS Genet 2011, 7: e1002338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jaramillo-Gutierrez G, Molina-Cruz A, Kumar S, Barillas-Mury C. The anopheles gambiae oxidation resistance 1 (OXR1) gene regulates expression of enzymes that detoxify reactive oxygen species. PLoS One 2010, 5: e11168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004, 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  20. Zhou S, Ding F, Gu X. Non-coding RNAs as emerging regulators of neural injury responses and regeneration. Neurosci Bull 2016, 32: 253–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li WY, Zhang WT, Cheng YX, Liu YC, Zhai FG, Sun P, et al. Inhibition of KLF7-targeting microRNA 146b promotes sciatic nerve regeneration. Neurosci Bull 2018, 34: 419–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang Y, Yang Z, Le W. Tiny but mighty: promising roles of microRNAs in the diagnosis and treatment of Parkinson’s disease. Neurosci Bull 2017, 33: 543–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li G, Morris-Blanco KC, Lopez MS, Yang T, Zhao H, Vemuganti R, et al. Impact of microRNAs on ischemic stroke: from pre- to post-disease. Prog Neurobiol 2018, 163–164: 59–78.

    Article  CAS  PubMed  Google Scholar 

  24. Fang X, Sun D, Wang Z, Yu Z, Liu W, Pu Y, et al. MiR-30a positively regulates the inflammatory response of microglia in experimental autoimmune encephalomyelitis. Neurosci Bull 2017, 33: 603–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mo JL, Liu Q, Kou ZW, Wu KW, Yang P, Chen XH, et al. MicroRNA-365 modulates astrocyte conversion into neuron in adult rat brain after stroke by targeting Pax6. Glia 2018, 66:1263–1532.

    Article  Google Scholar 

  26. Zheng K, Wang N, Shen Y, Zhang Z, Gu Q, Xu X, et al. Pro-apoptotic effects of microRNA-365 on retinal neurons by targeting IGF-1 in diabetic rats: an in vivo and in vitro study. J Diabetes Investig 2018, 9:1041–1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang J, Zhang J, Chen X, Yang Y, Wang F, Li W, et al. MiR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. Exp Eye Res 2018, 168: 89–99.

    Article  CAS  PubMed  Google Scholar 

  28. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral-artery occlusion without craniectomy in rats. Stroke 1989, 20: 84–91.

    Article  CAS  PubMed  Google Scholar 

  29. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 1990, 10: 290–293.

    Article  CAS  PubMed  Google Scholar 

  30. Wu KW, Kou ZW, Mo JL, Deng XX, Sun FY. Neurovascular coupling protects neurons against hypoxic injury via inhibition of potassium currents by generation of nitric oxide in direct neuron and endothelium cocultures. Neuroscience 2016, 334: 275–282.

    Article  CAS  PubMed  Google Scholar 

  31. Ma Q, Zhao H, Tao Z, Wang R, Liu P, Han Z, et al. MicroRNA-181c exacerbates brain injury in acute ischemic stroke. Aging Dis 2016, 7: 705–714.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Redon CE, Dickey JS, Bonner WM, Sedelnikova OA. Gamma-H2AX as a biomarker of DNA damage induced by ionizing radiation in human peripheral blood lymphocytes and artificial skin. Adv Space Res 2009, 43: 1171–1178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Downs JA, Lowndes NF, Jackson SP. A role for saccharomyces cerevisiae histone H2A in DNA repair. Nature 2000, 408: 1001–1004.

    Article  CAS  PubMed  Google Scholar 

  34. Kuo LJ, Yang LX. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In Vivo 2008, 22: 305–309.

    CAS  Google Scholar 

  35. He L, He T, Farrar S, Ji L, Liu T, Ma X. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem 2017, 44: 532–553.

    Article  PubMed  Google Scholar 

  36. Sun X, Zhang QW, Xu M, Guo JJ, Shen SW, Wang YQ, et al. New striatal neurons form projections to substantia nigra in adult rat brain after stroke. Neurobiol Dis 2012, 45: 601–609.

    Article  PubMed  Google Scholar 

  37. Hou SW, Wang YQ, Xu M, Shen DH, Wang JJ, Huang F, et al. Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke 2008, 39: 2837–2844.

    Article  CAS  PubMed  Google Scholar 

  38. Duan CL, Liu CW, Shen SW, Yu Z, Mo JL, Chen XH, et al. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. Glia 2015, 63: 1660–1670.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Darsalia V, Heldmann U, Lindvall O, Kokaia Z. Stroke-induced neurogenesis in aged brain. Stroke 2005, 36: 1790–1795.

    Article  PubMed  Google Scholar 

  40. Zhang QW, Deng XX, Sun X, Xu JX, Sun FY. Exercise promotes axon regeneration of newborn striatonigral and corticonigral projection neurons in rats after ischemic stroke. PLoS One 2013, 8: e80139.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81030020, 81571197, and 81771268) and the National Education Program of China (J0730860).

Author information

Authors and Affiliations

  1. Department of Neurobiology and Institute for Basic Research on Aging and Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Jia-Lin Mo, Xiao Chen, Yu Lei, Ling-Ling Lv, Cheng Qian & Feng-Yan Sun

  2. Department of Neurosurgery, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Zhi-Guang Pan & Feng-Yan Sun

  3. State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Jia-Lin Mo, Zhi-Guang Pan, Xiao Chen, Yu Lei, Ling-Ling Lv, Cheng Qian & Feng-Yan Sun

  4. Shanghai Key Laboratory of Clinical Geriatric Medicine, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Feng-Yan Sun

Authors
  1. Jia-Lin Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Guang Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling-Ling Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feng-Yan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feng-Yan Sun.

Ethics declarations

Conflict of interest

The authors claim that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 43 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mo, JL., Pan, ZG., Chen, X. et al. MicroRNA-365 Knockdown Prevents Ischemic Neuronal Injury by Activating Oxidation Resistance 1-Mediated Antioxidant Signals. Neurosci. Bull. 35, 815–825 (2019). https://doi.org/10.1007/s12264-019-00371-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-019-00371-y

Keywords

Search

Navigation