3 Biotech

, 9:386 | Cite as

Elevated serum levels of brain-derived neurotrophic factor and miR-124 in acute ischemic stroke patients and the molecular mechanism

  • Jie Wang
  • Qiong Huang
  • Ji Ding
  • Xiaoping WangEmail author
Original Article


Brain-derived neurotrophic factor (BDNF) and microRNAs (miRNAs) play a significant role in the pathogenesis of acute ischemic stroke (AIS). The present study investigates the elevated expression of BDNF and miR-124 in AIS patients. In the present study, serum samples from AIS patients and healthy controls were collected to determine the regulatory role and mechanism of operation of BDNF and to determine the regulatory miRNAs involved in AIS. Using bioinformatics analysis, we identified putative and regulatory miR-124. The effect of miR-124 on BDNF expression was examined in human neuronal cell lines. Moreover, the function of miR-124 in regulating BDNF was analyzed by assessing the serum level of BDNF in both AIS patients and healthy controls. The results indicate that the BDNF level of AIS patients is very low compared with that of controls. In contrast, real-time polymerase chain reaction (RT-PCR) data revealed a very high serum level of miR-124 in AIS patients relative to healthy individuals. The associations of the National Institutes of Health (NIH) stroke scale (NIHSS) score with BDNF and BDNF-related miR-124 serum levels were calculated using Pearson’s/Spearman’s correlation coefficient. The findings revealed a negative correlation between NIHSS score and BDNF level, whereas a positive correlation was observed between NIHSS score and miR-124. In addition, the relationship between serum BDNF and miR-124 was negative in AIS patients. In conclusion, this study provides strong evidence that serum BDNF and the BDNF-regulatory miR-124 may serve as molecular markers for AIS.


Brain-derived neurotrophic factor Acute ischemic stroke miR-124 Human neuronal cell lines NIH NIHSS 



The authors acknowledge the Institution, Institutional Review Board and Ethics Committee for providing support and funding to carrying out this research.

Authors contribution

XPW is the corresponding of the manuscript, who planned and designed the experiments for the project. In addition, first draft of the manuscript was written by corresponding author along with JD Research work was carried out and executed equally by JW and QH In addition, part of the research experiments such as statistical analysis was carried out by JD.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Human and animal rights

This article includes human study and it was approved by the Institutional Ethical Review Board, Ethical Committee, and Research Advisory Committees of the affiliated hospital and research institute. Also, proper written consent was acquired from both the patients and the spectators before collecting samples.


  1. Ambros V (2004) The functions of animal microRNAs Nature 431: 350–355. Proc Natl Acad Sci USA 103:3687–3692Google Scholar
  2. Anacker C, Zunszain PA, Carvalho LA, Pariante CM (2011) The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 36:415–425CrossRefGoogle Scholar
  3. Arumugam TV, Granger DN, Mattson MP (2005) Stroke and T-cells. Neuromolecular Med 7:229–242CrossRefGoogle Scholar
  4. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefGoogle Scholar
  5. Bathina S, Srinivas N, Das UN (2016) BDNF protects pancreatic β cells (RIN5F) against cytotoxic action of alloxan, streptozotocin, doxorubicin and benzo(a)pyrene in vitro. Metabolism 65:667–684CrossRefGoogle Scholar
  6. Bathina S, Srinivas N, Das UN (2017) Streptozotocin produces oxidative stress, inflammation and decreases BDNF concentrations to induce apoptosis of RIN5F cells and type 2 diabetes mellitus in Wistar rats. Biochem Biophys Res Commun 486:406–413CrossRefGoogle Scholar
  7. Bonita R, Mendis S, Truelsen T, Bogousslavsky J, Toole J, Yatsu F (2004) The global stroke initiative. Lancet Neurol 3:391–393CrossRefGoogle Scholar
  8. Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331–e339CrossRefGoogle Scholar
  9. Cook DJ, Nguyen C, Chun HN (2017) Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke. J Cereb Blood Flow Metab 37:1030–1045CrossRefGoogle Scholar
  10. Coolen M, Katz S, Bally-Cuif L (2013) miR-9: a versatile regulator of neurogenesis. Front Cell Neurosci 7:220CrossRefGoogle Scholar
  11. Cooper-Kuhn CM (2007) Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38:2165–2172CrossRefGoogle Scholar
  12. Harris NM, Ritzel R, Mancini NS (2016) Nano-particle delivery of brain derived neurotrophic factor after focal cerebral ischemia reduces tissue injury and enhances behavioral recovery. Pharmacol Biochem Behav 150:48–56CrossRefGoogle Scholar
  13. Ikeda Y, Yahata N, Ito I (2008) Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia. Schizophr Res 101:58–66CrossRefGoogle Scholar
  14. Ji Q, Ji Y, Peng J (2016) Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients. PLoS One 11:e0163645CrossRefGoogle Scholar
  15. Jiang Y, Wei N, Zhu J (2017) Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat. Mediators Inflamm. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Jickling GC, Sharp FR (2015) Biomarker panels in ischemic stroke. Stroke 46:915–920CrossRefGoogle Scholar
  17. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735–739CrossRefGoogle Scholar
  18. Laterza OF, Lim L, Garrett-Engele PW (2009) Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury. Clin Chem 55:1977–1983CrossRefGoogle Scholar
  19. Lee Y, Ahn C, Han J (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419CrossRefGoogle Scholar
  20. Legos JJ, Barone FC (2003) Update on pharmacological strategies for stroke: prevention, acute intervention and regeneration. Curr Opin Investig Drugs 4:847–858PubMedGoogle Scholar
  21. Long G, Wang F, Li H (2013) Circulating miR-30a, miR-126 and let-7b as biomarker for ischemic stroke in humans. BMC Neurol 13:178CrossRefGoogle Scholar
  22. Maddahi A, Edvinsson L (2010) Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway. J Neuroinflammation 7:14CrossRefGoogle Scholar
  23. Majno G, Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146:3PubMedPubMedCentralGoogle Scholar
  24. Mattson M, Duan W, Pedersen W, Culmsee C (2001) Neurodegenerative disorders and ischemic brain diseases. Apoptosis 6:69–81CrossRefGoogle Scholar
  25. Meng WD, Sun SJ, Yang J, Chu RX, Tu W, Liu Q (2017) Elevated serum brain-derived neurotrophic factor (BDNF) but not BDNF gene Val66Met polymorphism is associated with autism spectrum disorders. Mol Neurobiol 54:1167–1172CrossRefGoogle Scholar
  26. Muir KW, Tyrrell P, Sattar N, Warburton E (2007) Inflammation and ischaemic stroke. Curr Opin Neurol 20:334–342CrossRefGoogle Scholar
  27. Peng G, Yuan Y, Wu S, He F, Hu Y, Luo B (2015) MicroRNA let-7e is a potential circulating biomarker of acute stage ischemic stroke. Transl Stroke Res 6:437–445CrossRefGoogle Scholar
  28. Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG (2005) Regulation of miRNA expression during neural cell specification. Eur J Neurosci 21:1469–1477CrossRefGoogle Scholar
  29. Tu WJ, Dong X, Zhao SJ, Yang DG, Chen H (2013) Prognostic value of plasma neuroendocrine biomarkers in patients with acute ischaemic stroke. J Neuroendocrinol 25:771–778CrossRefGoogle Scholar
  30. Tuttolomondo A, Di Raimondo D, di Sciacca R, Pinto A, Licata G (2008) Inflammatory cytokines in acute ischemic stroke. Curr Pharm Des 14:3574–3589CrossRefGoogle Scholar
  31. Vila N, Castillo J, Davalos A, Esteve A, Planas AM, Chamorro A (2003) Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke 34:671–675CrossRefGoogle Scholar
  32. Wang J, Gao L, Yang YL (2017) Low serum levels of brain-derived neurotrophic factor were associated with poor short-term functional outcome and mortality in acute ischemic stroke. Mol Neurobiol 54:7335–7342CrossRefGoogle Scholar
  33. Witwer KW, Sisk JM, Gama L, Clements JE (2010) MicroRNA regulation of IFN-β protein expression: rapid and sensitive modulation of the innate immune response. J Immunol 184:2369–2376CrossRefGoogle Scholar
  34. Yasutake C, Kuroda K, Yanagawa T, Okamura T, Yoneda H (2006) Serum BDNF, TNF-α and IL-1β levels in dementia patients. Eur Arch Psychiatry Clin Neurosci 256:402–406CrossRefGoogle Scholar
  35. Yekta S, Shih IH, Bartel DP (2004) MicroRNA-directed cleavage of HOXB8 mRNA. Science 304:594–596CrossRefGoogle Scholar
  36. Yi R, Qin Y, Macara IG, Cullen BR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011–3016CrossRefGoogle Scholar

Copyright information

© King Abdulaziz City for Science and Technology 2019

Authors and Affiliations

  1. 1.Department of Neurology, Tong Ren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Personalised recommendations