Skip to main content

Advertisement

SpringerLink
Log in

The Emerging Role of Epigenetics in Cerebral Ischemia

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Despite great progresses in the treatment and prevention of ischemic stroke, it is still among the leading causes of death and serious long-term disability all over the world, indicating that innovative neural regenerative and neuroprotective agents are urgently needed for the development of therapeutic approaches with greater efficacy for ischemic stroke. More and more evidence suggests that a spectrum of epigenetic processes play an important role in the pathophysiology of cerebral ischemia. In the present review, we first discuss recent developments in epigenetic mechanisms, especially their roles in the pathophysiology of cerebral ischemia. Specifically, we focus on DNA methylation, histone deacetylase, histone methylation, and microRNAs (miRNAs) in the regulation of vascular and neuronal regeneration after cerebral ischemia. Additionally, we highlight epigenetic strategies for ischemic stroke treatments, including the inhibition of histone deacetylase enzyme and DNA methyltransferase activities, and miRNAs. These therapeutic strategies are far from clinic use, but preliminary data indicate that neuroprotective agents targeting these pathways can modulate neural cell regeneration and promote brain repair and functional recovery after cerebral ischemia. A better understanding of how epigenetics influences the process and progress of cerebral ischemia will pave the way for discovering more sensitive and specific biomarkers and new targets and therapeutics for ischemic stroke.

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.

Fig. 1

Similar content being viewed by others

Abbreviations

5-Aza:

5-aza-2’-deoxycytidine

5-aza-Dc:

5-Aza-deoxycytidine

ABL:

Acetylbritannilactone

ALA:

Alpha-lipoic acid

BBB:

Blood–brain barrier

BMSCs:

Bone-marrow-derived stromal stem cells

CBP:

cAMP-response element binding protein -binding protein

CECs:

Cerebral endothelial cells

CMPs:

Chromatin-modifying proteins

CNS:

Central nervous system

coREST:

Corepressors of the RE-1 silencing transcription factor

CpG:

Cytosine-phosphate-guanine

CREB:

cAMP-response element binding protein

CSD:

Cortical spreading depression

CYP:

Cytochrome P450

De-MSCs:

Dedifferentiated mesenchymal stem cells

DNMT:

DNA methyltransferase

DNMT3a:

DNA methyltransferase 3a

ECs:

Endothelial cells

ESR1:

Estrogen receptor alpha

GCI:

Global cerebral ischemia

GR:

Glucocorticoid receptor

H3-K4:

Lysine 4 of histone 3

H3-K9:

H3 at lysine 9

HBMECs:

Human brain microvessel endothelial cells

HDACs:

Histone deacetylases

HIE:

Hypoxic–ischemic encephalopathy

HPC:

Hypoxic pre-conditioning

IGF:

Insulin-like growth factor

IPC:

Ischemic pre-conditioning

IRF9:

Interferon regulatory factor 9

KSRP:

KH-type splicing regulatory protein

PIF:

Pre-implantation factor

REST:

Repressor element-1 silencing transcription factor

SNPs:

Single nucleotide-polymorphisms

lncRNAs:

Long non-coding RNAs

LSD1:

Lysine-specific histone demethylase 1

MCAO:

Middle cerebral artery occlusion

MMP9:

Matrix metallinoprotease-9

MRP1:

Multidrug-resistance-associated protein 1

MSCs:

Multipotent mesenchymal stromal cells

MT:

Metallothionein

MTase:

Methyltransferase

MyD88:

Myeloid differentiation primary response gene 88

NF-κB:

Nuclear factor κB

NKCC1:

Na(+)-K(+)-2Cl(-) co-transporter type 1

nNOS:

Neuronal nitric oxide synthase

NR3C1:

Nuclear receptor subfamily 3 group C member 1

NSCs:

Neural stem cells

OGD:

Oxygen–glucose deprivation

OLGs:

Oligodendrocytes

OPCs:

Oligodendrocyte progenitor cells

OPRM1:

Mu opioid receptor 1

PGC-1α:

Peroxisome proliferator-activated receptor-γ co-activator-1α

piRNA:

Piwi-interacting RNAs

PON1:

Paraoxonase 1

PPARdelta:

Peroxisome proliferator-activated receptor delta

PSD-95:

Postsynaptic density-95

SalB:

Salvianolic acid B

SDF-1:

Stromal-cell-derived factor-1

SIK1:

Salt-induced kinase 1

SIRT1:

Silent information regulator 1

SLC8A1:

Na(+)-Ca(2+) exchanger 1

SOCS1:

Suppressor of cytokine signaling 1

SRF:

Serum response factor

SVZ:

Subventricular zone

TCT:

Tocotrienol

TBP:

TATA-binding protein

TLR4:

Toll-like receptor 4

Tregs:

Regulatory T cells

TSA:

Trichostatin-A

TSP-1:

Thrombospondin-1

ULMs:

Ubiquitin-like modifiers

UTR:

Untranslated region

VEGF:

Vascular endothelial growth factor

VNS:

Vagus nerve stimulation

VPA:

Valproate

XIAP:

X-linked inhibitor of apoptosis

References

  1. Kohyama J, Kojima T, Takatsuka E, Yamashita T, Namiki J, Hsieh J, Gage FH, Namihira M et al (2008) Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. Proc Natl Acad Sci U S A 105(46):18012–18017. doi:10.1073/pnas.0808417105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zukin RS (2010) Eradicating the mediators of neuronal death with a fine-tooth comb. Sci Signal 3(125):pe20. doi:10.1126/scisignal.3125pe20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Stapels M, Piper C, Yang T, Li M, Stowell C, Xiong ZG, Saugstad J, Simon RP et al (2010) Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci Signal 3(111):ra15. doi:10.1126/scisignal.2000502

    Article  PubMed  CAS  Google Scholar 

  4. Yilmaz G, Alexander JS, Erkuran Yilmaz C, Granger DN (2010) Induction of neuro-protective/regenerative genes in stem cells infiltrating post-ischemic brain tissue. Experimental & translational stroke medicine 2(1):11. doi:10.1186/2040-7378-2-11

    Article  CAS  Google Scholar 

  5. Wang S, Kelly S (2013) Global cerebral ischemia induces increased expression of multiple retrotransposons. Biochem Biophys Res Commun 434(3):572–576. doi:10.1016/j.bbrc.2013.03.116

    Article  CAS  PubMed  Google Scholar 

  6. Lee HA, Hong SH, Kim JW, Jang IS (2010) Possible involvement of DNA methylation in NKCC1 gene expression during postnatal development and in response to ischemia. J Neurochem 114(2):520–529. doi:10.1111/j.1471-4159.2010.06772.x

    Article  CAS  PubMed  Google Scholar 

  7. Gonzalez-Rodriguez PJ, Xiong F, Li Y, Zhou J, Zhang L (2014) Fetal hypoxia increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of glucocorticoid receptors. Neurobiol Dis 65:172–179. doi:10.1016/j.nbd.2014.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kumral A, Tuzun F, Tugyan K, Ozbal S, Yilmaz O, Yesilirmak CD, Duman N, Ozkan H (2013) Role of epigenetic regulatory mechanisms in neonatal hypoxic-ischemic brain injury. Early Hum Dev 89(3):165–173. doi:10.1016/j.earlhumdev.2012.09.016

    Article  CAS  PubMed  Google Scholar 

  9. Hu CJ, Chen SD, Yang DI, Lin TN, Chen CM, Huang TH, Hsu CY (2006) Promoter region methylation and reduced expression of thrombospondin-1 after oxygen-glucose deprivation in murine cerebral endothelial cells. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 26(12):1519–1526. doi:10.1038/sj.jcbfm.9600304

    Article  CAS  Google Scholar 

  10. Westberry JM, Prewitt AK, Wilson ME (2008) Epigenetic regulation of the estrogen receptor alpha promoter in the cerebral cortex following ischemia in male and female rats. Neuroscience 152(4):982–989. doi:10.1016/j.neuroscience.2008.01.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li Y, Xiao D, Dasgupta C, Xiong F, Tong W, Yang S, Zhang L (2012) Perinatal nicotine exposure increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of angiotensin II receptors. Stroke; a journal of cerebral circulation 43(9):2483–2490. doi:10.1161/STROKEAHA.112.664698

    Article  CAS  PubMed Central  Google Scholar 

  12. Li Y, Xiao D, Yang S, Zhang L (2013) Promoter methylation represses AT2R gene and increases brain hypoxic-ischemic injury in neonatal rats. Neurobiol Dis 60:32–38. doi:10.1016/j.nbd.2013.08.011

    Article  CAS  PubMed  Google Scholar 

  13. Lee JC, Park JH, Yan BC, Kim IH, Cho GS, Jeoung D, Kwon YG, Kim YM et al (2013) Effects of transient cerebral ischemia on the expression of DNA methyltransferase 1 in the gerbil hippocampal CA1 region. Neurochem Res 38(1):74–81. doi:10.1007/s11064-012-0890-2

    Article  CAS  PubMed  Google Scholar 

  14. Endres M, Fan G, Meisel A, Dirnagl U, Jaenisch R (2001) Effects of cerebral ischemia in mice lacking DNA methyltransferase 1 in post-mitotic neurons. Neuroreport 12(17):3763–3766

    Article  CAS  PubMed  Google Scholar 

  15. Pandi G, Nakka VP, Dharap A, Roopra A, Vemuganti R (2013) MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage. PLoS One 8(3):e58039. doi:10.1371/journal.pone.0058039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Singh V, Sharma P, Capalash N (2013) DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer. Curr Cancer Drug Targets 13(4):379–399

    Article  CAS  PubMed  Google Scholar 

  17. Endres M, Meisel A, Biniszkiewicz D, Namura S, Prass K, Ruscher K, Lipski A, Jaenisch R et al (2000) DNA methyltransferase contributes to delayed ischemic brain injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 20(9):3175–3181

    CAS  Google Scholar 

  18. Dock H, Theodorsson A, Theodorsson E (2015) DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats. Transl Stroke Res. doi:10.1007/s12975-015-0397-7

  19. Park YH, Lee YM, Kim DS, Park J, Suk K, Kim JK, Han HS (2013) Hypothermia enhances induction of protective protein metallothionein under ischemia. J Neuroinflammation 10:21. doi:10.1186/1742-2094-10-21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Baltan S, Bachleda A, Morrison RS, Murphy SP (2011) Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia. Translational stroke research 2(3):411–423. doi:10.1007/s12975-011-0087-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kassis H, Chopp M, Liu XS, Shehadah A, Roberts C, Zhang ZG (2014) Histone deacetylase expression in white matter oligodendrocytes after stroke. Neurochem Int 77:17–23. doi:10.1016/j.neuint.2014.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kassis H, Shehadah A, Chopp M, Roberts C, Zhang ZG (2015) Stroke Induces Nuclear Shuttling of Histone Deacetylase 4. Stroke; a journal of cerebral circulation. doi:10.1161/STROKEAHA.115.009046

  23. Yildirim F, Ji S, Kronenberg G, Barco A, Olivares R, Benito E, Dirnagl U, Gertz K et al (2014) Histone acetylation and CREB binding protein are required for neuronal resistance against ischemic injury. PLoS One 9(4):e95465. doi:10.1371/journal.pone.0095465

    Article  PubMed  PubMed Central  Google Scholar 

  24. Markus HS, Makela KM, Bevan S, Raitoharju E, Oksala N, Bis JC, O’Donnell C, Hainsworth A et al (2013) Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke; a journal of cerebral circulation 44(5):1220–1225. doi:10.1161/STROKEAHA.111.000217

    Article  CAS  PubMed Central  Google Scholar 

  25. Peng S, Zhao S, Yan F, Cheng J, Huang L, Chen H, Liu Q, Ji X et al (2015) HDAC2 selectively regulates FOXO3a-mediated gene transcription during oxidative stress-induced neuronal cell death. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(3):1250–1259. doi:10.1523/JNEUROSCI.2444-14.2015

    Article  CAS  Google Scholar 

  26. Luo CX, Lin YH, Qian XD, Tang Y, Zhou HH, Jin X, Ni HY, Zhang FY et al (2014) Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke. The Journal of neuroscience : the official journal of the Society for Neuroscience 34(40):13535–13548. doi:10.1523/JNEUROSCI.1305-14.2014

    Article  CAS  Google Scholar 

  27. Formisano L, Guida N, Valsecchi V, Cantile M, Cuomo O, Vinciguerra A, Laudati G, Pignataro G et al (2015) Sp3/REST/HDAC1/HDAC2 Complex Represses and Sp1/HIF-1/p300 Complex Activates ncx1 Gene Transcription, in Brain Ischemia and in Ischemic Brain Preconditioning, by Epigenetic Mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(19):7332–7348. doi:10.1523/JNEUROSCI.2174-14.2015

    Article  CAS  Google Scholar 

  28. Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS (2012) Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci U S A 109(16):E962–E971. doi:10.1073/pnas.1121568109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Formisano L, Noh KM, Miyawaki T, Mashiko T, Bennett MV, Zukin RS (2007) Ischemic insults promote epigenetic reprogramming of mu opioid receptor expression in hippocampal neurons. Proc Natl Acad Sci U S A 104(10):4170–4175. doi:10.1073/pnas.0611704104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Langley B, Brochier C, Rivieccio MA (2009) Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke; a journal of cerebral circulation 40(8):2899–2905. doi:10.1161/strokeaha.108.540229

    Article  CAS  Google Scholar 

  31. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35(4):870–880. doi:10.1038/npp.2009.197

    Article  CAS  Google Scholar 

  32. Murphy SP, Lee RJ, McClean ME, Pemberton HE, Uo T, Morrison RS, Bastian C, Baltan S (2014) MS-275, a class I histone deacetylase inhibitor, protects the p53-deficient mouse against ischemic injury. J Neurochem 129(3):509–515. doi:10.1111/jnc.12498

    Article  CAS  PubMed  Google Scholar 

  33. Faraco G, Pancani T, Formentini L, Mascagni P, Fossati G, Leoni F, Moroni F, Chiarugi A (2006) Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol 70(6):1876–1884. doi:10.1124/mol.106.027912

    Article  CAS  PubMed  Google Scholar 

  34. Kim HJ, Leeds P, Chuang DM (2009) The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem 110(4):1226–1240. doi:10.1111/j.1471-4159.2009.06212.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liesz A, Zhou W, Na SY, Hammerling GJ, Garbi N, Karcher S, Mracsko E, Backs J et al (2013) Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. The Journal of neuroscience : the official journal of the Society for Neuroscience 33(44):17350–17362. doi:10.1523/JNEUROSCI.4901-12.2013

    Article  CAS  Google Scholar 

  36. Wang B, Zhu X, Kim Y, Li J, Huang S, Saleem S, Li RC, Xu Y et al (2012) Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. Free Radic Biol Med 52(5):928–936. doi:10.1016/j.freeradbiomed.2011.12.006

    Article  CAS  PubMed  Google Scholar 

  37. Kim HJ, Chuang DM (2014) HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res 6(3):206–223

    PubMed  PubMed Central  Google Scholar 

  38. Baltan S, Murphy SP, Danilov CA, Bachleda A, Morrison RS (2011) Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(11):3990–3999. doi:10.1523/JNEUROSCI.5379-10.2011

    Article  CAS  Google Scholar 

  39. Baltan S (2012) Histone deacetylase inhibitors preserve function in aging axons. J Neurochem 123(Suppl 2):108–115. doi:10.1111/j.1471-4159.2012.07949.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ma XH, Gao Q, Jia Z, Zhang ZW (2015) Neuroprotective capabilities of TSA against cerebral ischemia/reperfusion injury via PI3K/Akt signaling pathway in rats. Int J Neurosci 125(2):140–146. doi:10.3109/00207454.2014.912217

    Article  CAS  PubMed  Google Scholar 

  41. Fleiss B, Nilsson MK, Blomgren K, Mallard C (2012) Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury. J Neuroinflammation 9:70. doi:10.1186/1742-2094-9-70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yildirim F, Gertz K, Kronenberg G, Harms C, Fink KB, Meisel A, Endres M (2008) Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury. Exp Neurol 210(2):531–542. doi:10.1016/j.expneurol.2007.11.031

    Article  CAS  PubMed  Google Scholar 

  43. Hasan MR, Kim JH, Kim YJ, Kwon KJ, Shin CY, Kim HY, Han SH, Choi DH et al (2013) Effect of HDAC inhibitors on neuroprotection and neurite outgrowth in primary rat cortical neurons following ischemic insult. Neurochem Res 38(9):1921–1934. doi:10.1007/s11064-013-1098-9

    Article  CAS  PubMed  Google Scholar 

  44. Liu XS, Chopp M, Kassis H, Jia LF, Hozeska-Solgot A, Zhang RL, Chen C, Cui YS et al (2012) Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience 220:313–321. doi:10.1016/j.neuroscience.2012.06.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang Z, Tsai LK, Munasinghe J, Leng Y, Fessler EB, Chibane F, Leeds P, Chuang DM (2012) Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke. Stroke; a journal of cerebral circulation 43(9):2430–2436. doi:10.1161/STROKEAHA.112.652545

    Article  CAS  PubMed Central  Google Scholar 

  46. Xuan A, Long D, Li J, Ji W, Hong L, Zhang M, Zhang W (2012) Neuroprotective effects of valproic acid following transient global ischemia in rats. Life Sci 90(11-12):463–468. doi:10.1016/j.lfs.2012.01.001

    Article  CAS  PubMed  Google Scholar 

  47. Wang Z, Leng Y, Tsai LK, Leeds P, Chuang DM (2011) Valproic acid attenuates blood-brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 31(1):52–57. doi:10.1038/jcbfm.2010.195

    Article  CAS  Google Scholar 

  48. Hernandez-Jimenez M, Hurtado O, Cuartero MI, Ballesteros I, Moraga A, Pradillo JM, McBurney MW, Lizasoain I et al (2013) Silent information regulator 1 protects the brain against cerebral ischemic damage. Stroke; a journal of cerebral circulation 44(8):2333–2337. doi:10.1161/STROKEAHA.113.001715

    Article  CAS  Google Scholar 

  49. Lanzillotta A, Sarnico I, Ingrassia R, Boroni F, Branca C, Benarese M, Faraco G, Blasi F et al (2010) The acetylation of RelA in Lys310 dictates the NF-kappaB-dependent response in post-ischemic injury. Cell death & disease 1:e96. doi:10.1038/cddis.2010.76

    Article  CAS  Google Scholar 

  50. Lanzillotta A, Pignataro G, Branca C, Cuomo O, Sarnico I, Benarese M, Annunziato L, Spano P et al (2013) Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window. Neurobiol Dis 49:177–189. doi:10.1016/j.nbd.2012.08.018

    Article  CAS  PubMed  Google Scholar 

  51. Ingrassia R, Lanzillotta A, Sarnico I, Benarese M, Blasi F, Borgese L, Bilo F, Depero L et al (2012) 1B/(-)IRE DMT1 expression during brain ischemia contributes to cell death mediated by NF-kappaB/RelA acetylation at Lys310. PLoS One 7(5):e38019. doi:10.1371/journal.pone.0038019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fu B, Zhang J, Zhang X, Zhang C, Li Y, Zhang Y, He T, Li P et al (2014) Alpha-lipoic acid upregulates SIRT1-dependent PGC-1alpha expression and protects mouse brain against focal ischemia. Neuroscience 281C:251–257. doi:10.1016/j.neuroscience.2014.09.058

    Article  CAS  Google Scholar 

  53. Lv H, Wang L, Shen J, Hao S, Ming A, Wang X, Su F, Zhang Z (2015) Salvianolic acid B attenuates apoptosis and inflammation via SIRT1 activation in experimental stroke rats. Brain Res Bull 115:30–36. doi:10.1016/j.brainresbull.2015.05.002

    Article  CAS  PubMed  Google Scholar 

  54. Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Yang X, Li J, Di S et al (2015) Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res 58(1):61–70. doi:10.1111/jpi.12193

    Article  CAS  PubMed  Google Scholar 

  55. Chen HZ, Guo S, Li ZZ, Lu Y, Jiang DS, Zhang R, Lei H, Gao L et al (2014) A critical role for interferon regulatory factor 9 in cerebral ischemic stroke. The Journal of neuroscience : the official journal of the Society for Neuroscience 34(36):11897–11912. doi:10.1523/JNEUROSCI.1545-14.2014

    Article  Google Scholar 

  56. Cheng J, Uchida M, Zhang W, Grafe MR, Herson PS, Hurn PD (2011) Role of salt-induced kinase 1 in androgen neuroprotection against cerebral ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 31(1):339–350. doi:10.1038/jcbfm.2010.98

    Article  CAS  Google Scholar 

  57. Kaur H, Kumar A, Jaggi AS, Singh N (2015) Pharmacologic investigations on the role of Sirt-1 in neuroprotective mechanism of postconditioning in mice. J Surg Res 197(1):191–200. doi:10.1016/j.jss.2015.03.010

    Article  CAS  PubMed  Google Scholar 

  58. Zhang YZ, Zhang QH, Ye H, Zhang Y, Luo YM, Ji XM, Su YY (2010) Distribution of lysine-specific demethylase 1 in the brain of rat and its response in transient global cerebral ischemia. Neurosci Res 68(1):66–72. doi:10.1016/j.neures.2010.06.002

    Article  CAS  PubMed  Google Scholar 

  59. Chisholm NC, Henderson ML, Selvamani A, Park MJ, Dindot S, Miranda RC, Sohrabji F (2015) Histone methylation patterns in astrocytes are influenced by age following ischemia. Epigenetics : official journal of the DNA Methylation Society 10(2):142–152. doi:10.1080/15592294.2014.1001219

    Article  Google Scholar 

  60. Schweizer S, Harms C, Lerch H, Flynn J, Hecht J, Yildirim F, Meisel A, Marschenz S (2015) Inhibition of histone methyltransferases SUV39H1 and G9a leads to neuroprotection in an in vitro model of cerebral ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. doi:10.1038/jcbfm.2015.99

  61. Passaro D, Rana G, Piscopo M, Viggiano E, De Luca B, Fucci L (2010) Epigenetic chromatin modifications in the cortical spreading depression. Brain Res 1329:1–9. doi:10.1016/j.brainres.2010.03.001

    Article  CAS  PubMed  Google Scholar 

  62. Rana G, Donizetti A, Virelli G, Piscopo M, Viggiano E, De Luca B, Fucci L (2012) Cortical spreading depression differentially affects lysine methylation of H3 histone at neuroprotective genes and retrotransposon sequences. Brain Res 1467:113–119. doi:10.1016/j.brainres.2012.05.043

    Article  CAS  PubMed  Google Scholar 

  63. Jeyaseelan K, Lim KY, Armugam A (2008) MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke; a journal of cerebral circulation 39(3):959–966. doi:10.1161/STROKEAHA.107.500736

    Article  CAS  Google Scholar 

  64. Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, Turner RJ, Jickling G et al (2010) Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 30(1):92–101. doi:10.1038/jcbfm.2009.186

    Article  CAS  Google Scholar 

  65. Dharap A, Bowen K, Place R, Li LC, Vemuganti R (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 29(4):675–687. doi:10.1038/jcbfm.2008.157

    Article  CAS  Google Scholar 

  66. Ziu M, Fletcher L, Rana S, Jimenez DF, Digicaylioglu M (2011) Temporal differences in microRNA expression patterns in astrocytes and neurons after ischemic injury. PLoS One 6(2):e14724. doi:10.1371/journal.pone.0014724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yuan Y, Wang JY, Xu LY, Cai R, Chen Z, Luo BY (2010) MicroRNA expression changes in the hippocampi of rats subjected to global ischemia. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 17(6):774–778. doi:10.1016/j.jocn.2009.10.009

    Article  CAS  Google Scholar 

  68. Deng X, Zhong Y, Gu L, Shen W, Guo J (2013) MiR-21 involve in ERK-mediated upregulation of MMP9 in the rat hippocampus following cerebral ischemia. Brain Res Bull 94:56–62. doi:10.1016/j.brainresbull.2013.02.007

    Article  CAS  PubMed  Google Scholar 

  69. Murphy SJ, Lusardi TA, Phillips JI, Saugstad JA (2014) Sex differences in microRNA expression during developmentin rat cortex. Neurochem Int 77:24–32. doi:10.1016/j.neuint.2014.06.007

    Article  CAS  PubMed  Google Scholar 

  70. Dhiraj DK, Chrysanthou E, Mallucci GR, Bushell M (2013) miRNAs-19b, -29b-2* and -339-5p show an early and sustained up-regulation in ischemic models of stroke. PLoS One 8(12):e83717. doi:10.1371/journal.pone.0083717

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Hwang JY, Kaneko N, Noh KM, Pontarelli F, Zukin RS (2014) The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J Mol Biol 426(20):3454–3466. doi:10.1016/j.jmb.2014.07.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cui H, Yang L (2013) Analysis of microRNA expression detected by microarray of the cerebral cortex after hypoxic-ischemic brain injury. J Craniofac Surg 24(6):2147–2152. doi:10.1097/SCS.0b013e3182a243f3

    Article  PubMed  Google Scholar 

  73. Tan KS, Armugam A, Sepramaniam S, Lim KY, Setyowati KD, Wang CW, Jeyaseelan K (2009) Expression profile of MicroRNAs in young stroke patients. PLoS One 4(11):e7689. doi:10.1371/journal.pone.0007689

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Sepramaniam S, Tan JR, Tan KS, DeSilva DA, Tavintharan S, Woon FP, Wang CW, Yong FL et al (2014) Circulating microRNAs as biomarkers of acute stroke. Int J Mol Sci 15(1):1418–1432. doi:10.3390/ijms15011418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Tsai PC, Liao YC, Wang YS, Lin HF, Lin RT, Juo SH (2013) Serum microRNA-21 and microRNA-221 as potential biomarkers for cerebrovascular disease. J Vasc Res 50(4):346–354. doi:10.1159/000351767

    Article  CAS  PubMed  Google Scholar 

  76. Zhou J, Zhang J (2014) Identification of miRNA-21 and miRNA-24 in plasma as potential early stage markers of acute cerebral infarction. Mol Med Rep 10(2):971–976. doi:10.3892/mmr.2014.2245

    CAS  PubMed  Google Scholar 

  77. Leung LY, Chan CP, Leung YK, Jiang HL, Abrigo JM, Wang De F, Chung JS, Rainer TH et al (2014) Comparison of miR-124-3p and miR-16 for early diagnosis of hemorrhagic and ischemic stroke. Clinica chimica acta; international journal of clinical chemistry 433:139–144. doi:10.1016/j.cca.2014.03.007

    Article  CAS  PubMed  Google Scholar 

  78. Gan CS, Wang CW, Tan KS (2012) Circulatory microRNA-145 expression is increased in cerebral ischemia. Genetics and molecular research : GMR 11(1):147–152. doi:10.4238/2012.January.27.1

    Article  CAS  PubMed  Google Scholar 

  79. Long G, Wang F, Li H, Yin Z, Sandip C, Lou Y, Wang Y, Chen C et al (2013) Circulating miR-30a, miR-126 and let-7b as biomarker for ischemic stroke in humans. BMC Neurol 13:178. doi:10.1186/1471-2377-13-178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Zeng L, Liu J, Wang Y, Wang L, Weng S, Tang Y, Zheng C, Cheng Q et al (2011) MicroRNA-210 as a novel blood biomarker in acute cerebral ischemia. Front Biosci 3:1265–1272

    Google Scholar 

  81. Zeng L, Liu J, Wang Y, Wang L, Weng S, Chen S, Yang GY (2013) Cocktail blood biomarkers: prediction of clinical outcomes in patients with acute ischemic stroke. Eur Neurol 69(2):68–75. doi:10.1159/000342896

    Article  CAS  PubMed  Google Scholar 

  82. Kim JM, Jung KH, Chu K, Lee ST, Ban J, Moon J, Kim M, Lee SK et al (2015) Atherosclerosis-Related Circulating MicroRNAs as a Predictor of Stroke Recurrence. Translational stroke research 6(3):191–197. doi:10.1007/s12975-015-0390-1

    Article  CAS  PubMed  Google Scholar 

  83. Liu ME, Liao YC, Lin RT, Wang YS, Hsi E, Lin HF, Chen KC, Juo SH (2013) A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis. Atherosclerosis 228(1):161–167. doi:10.1016/j.atherosclerosis.2013.01.036

    Article  CAS  PubMed  Google Scholar 

  84. Jeon YJ, Kim OJ, Kim SY, Oh SH, Oh D, Kim OJ, Shin BS, Kim NK (2013) Association of the miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with ischemic stroke and silent brain infarction risk. Arterioscler, Thromb, Vasc Biol 33(2):420–430. doi:10.1161/ATVBAHA.112.300251

    Article  CAS  Google Scholar 

  85. Liu Y, Ma Y, Zhang B, Wang SX, Wang XM, Yu JM (2014) Genetic polymorphisms in pre-microRNAs and risk of ischemic stroke in a Chinese population. Journal of molecular neuroscience : MN 52(4):473–480. doi:10.1007/s12031-013-0152-z

    Article  CAS  PubMed  Google Scholar 

  86. Buller B, Liu X, Wang X, Zhang RL, Zhang L, Hozeska-Solgot A, Chopp M, Zhang ZG (2010) MicroRNA-21 protects neurons from ischemic death. FEBS J 277(20):4299–4307. doi:10.1111/j.1742-4658.2010.07818.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang L, Dong LY, Li YJ, Hong Z, Wei WS (2012) miR-21 represses FasL in microglia and protects against microglia-mediated neuronal cell death following hypoxia/ischemia. Glia 60(12):1888–1895. doi:10.1002/glia.22404

    Article  PubMed  Google Scholar 

  88. Siegel C, Li J, Liu F, Benashski SE, McCullough LD (2011) miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc Natl Acad Sci U S A 108(28):11662–11667. doi:10.1073/pnas.1102635108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sun Y, Gui H, Li Q, Luo ZM, Zheng MJ, Duan JL, Liu X (2013) MicroRNA-124 protects neurons against apoptosis in cerebral ischemic stroke. CNS Neurosci Ther 19(10):813–819. doi:10.1111/cns.12142

    CAS  PubMed  Google Scholar 

  90. Liu X, Li F, Zhao S, Luo Y, Kang J, Zhao H, Yan F, Li S et al (2013) MicroRNA-124-mediated regulation of inhibitory member of apoptosis-stimulating protein of p53 family in experimental stroke. Stroke; a journal of cerebral circulation 44(7):1973–1980. doi:10.1161/STROKEAHA.111.000613

    Article  CAS  Google Scholar 

  91. Irmady K, Jackman KA, Padow VA, Shahani N, Martin LA, Cerchietti L, Unsicker K, Iadecola C et al (2014) Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 34(9):3419–3428. doi:10.1523/JNEUROSCI.1982-13.2014

    Article  CAS  Google Scholar 

  92. Gubern C, Camos S, Ballesteros I, Rodriguez R, Romera VG, Canadas R, Lizasoain I, Moro MA et al (2013) miRNA expression is modulated over time after focal ischaemia: up-regulation of miR-347 promotes neuronal apoptosis. FEBS J 280(23):6233–6246. doi:10.1111/febs.12546

    Article  CAS  PubMed  Google Scholar 

  93. Yin KJ, Deng Z, Huang H, Hamblin M, Xie C, Zhang J, Chen YE (2010) miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis 38(1):17–26. doi:10.1016/j.nbd.2009.12.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chang CY, Lui TN, Lin JW, Lin YL, Hsing CH, Wang JJ, Chen RM (2014) Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells. Arch toxicol. doi:10.1007/s00204-014-1364-x

  95. Qiu J, Zhou XY, Zhou XG, Cheng R, Liu HY, Li Y (2013) Neuroprotective effects of microRNA-210 against oxygen-glucose deprivation through inhibition of apoptosis in PC12 cells. Mol Med Rep 7(6):1955–1959. doi:10.3892/mmr.2013.1431

    CAS  PubMed  Google Scholar 

  96. Qiu J, Zhou XY, Zhou XG, Cheng R, Liu HY, Li Y (2013) Neuroprotective effects of microRNA-210 on hypoxic-ischemic encephalopathy. BioMed research international 2013:350419. doi:10.1155/2013/350419

    PubMed  PubMed Central  Google Scholar 

  97. Qu Y, Wu J, Chen D, Zhao F, Liu J, Yang C, Wei D, Ferriero DM et al (2014) MiR-139-5p inhibits HGTD-P and regulates neuronal apoptosis induced by hypoxia-ischemia in neonatal rats. Neurobiol Dis 63:184–193. doi:10.1016/j.nbd.2013.11.023

    Article  PubMed  CAS  Google Scholar 

  98. Ouyang YB, Xu L, Lu Y, Sun X, Yue S, Xiong XX, Giffard RG (2013) Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia 61(11):1784–1794. doi:10.1002/glia.22556

    Article  PubMed  Google Scholar 

  99. Shi G, Liu Y, Liu T, Yan W, Liu X, Wang Y, Shi J, Jia L (2012) Upregulated miR-29b promotes neuronal cell death by inhibiting Bcl2L2 after ischemic brain injury. Exp Brain Res 216(2):225–230. doi:10.1007/s00221-011-2925-3

    Article  CAS  PubMed  Google Scholar 

  100. Lee YJ, Johnson KR, Hallenbeck JM (2012) Global protein conjugation by ubiquitin-like-modifiers during ischemic stress is regulated by microRNAs and confers robust tolerance to ischemia. PLoS One 7(10):e47787. doi:10.1371/journal.pone.0047787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Doeppner TR, Doehring M, Bretschneider E, Zechariah A, Kaltwasser B, Muller B, Koch JC, Bahr M et al (2013) MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation. Acta Neuropathol 126(2):251–265. doi:10.1007/s00401-013-1142-5

    Article  CAS  PubMed  Google Scholar 

  102. Zhu F, Liu JL, Li JP, Xiao F, Zhang ZX, Zhang L (2014) MicroRNA-124 (miR-124) regulates Ku70 expression and is correlated with neuronal death induced by ischemia/reperfusion. Journal of molecular neuroscience : MN 52(1):148–155. doi:10.1007/s12031-013-0155-9

    Article  CAS  PubMed  Google Scholar 

  103. Peng Z, Li J, Li Y, Yang X, Feng S, Han S, Li J (2013) Downregulation of miR-181b in mouse brain following ischemic stroke induces neuroprotection against ischemic injury through targeting heat shock protein A5 and ubiquitin carboxyl-terminal hydrolase isozyme L1. J Neurosci Res 91(10):1349–1362. doi:10.1002/jnr.23255

    Article  CAS  PubMed  Google Scholar 

  104. Wang P, Liang J, Li Y, Li J, Yang X, Zhang X, Han S, Li S et al (2014) Down-regulation of miRNA-30a alleviates cerebral ischemic injury through enhancing beclin 1-mediated autophagy. Neurochem Res 39(7):1279–1291. doi:10.1007/s11064-014-1310-6

    Article  CAS  PubMed  Google Scholar 

  105. Buller B, Chopp M, Ueno Y, Zhang L, Zhang RL, Morris D, Zhang Y, Zhang ZG (2012) Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation. Glia 60(12):1906–1914. doi:10.1002/glia.22406

    Article  PubMed  PubMed Central  Google Scholar 

  106. Sepramaniam S, Ying LK, Armugam A, Wintour EM, Jeyaseelan K (2012) MicroRNA-130a represses transcriptional activity of aquaporin 4 M1 promoter. J Biol Chem 287(15):12006–12015. doi:10.1074/jbc.M111.280701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sepramaniam S, Armugam A, Lim KY, Karolina DS, Swaminathan P, Tan JR, Jeyaseelan K (2010) MicroRNA 320a functions as a novel endogenous modulator of aquaporins 1 and 4 as well as a potential therapeutic target in cerebral ischemia. J Biol Chem 285(38):29223–29230. doi:10.1074/jbc.M110.144576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bake S, Selvamani A, Cherry J, Sohrabji F (2014) Blood brain barrier and neuroinflammation are critical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats. PLoS One 9(3):e91427. doi:10.1371/journal.pone.0091427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Selvamani A, Sathyan P, Miranda RC, Sohrabji F (2012) An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS One 7(2):e32662. doi:10.1371/journal.pone.0032662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang Y, Zhang Y, Huang J, Chen X, Gu X, Wang Y, Zeng L, Yang GY (2014) Increase of circulating miR-223 and insulin-like growth factor-1 is associated with the pathogenesis of acute ischemic stroke in patients. BMC Neurol 14:77. doi:10.1186/1471-2377-14-77

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Harraz MM, Eacker SM, Wang X, Dawson TM, Dawson VL (2012) MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc Natl Acad Sci U S A 109(46):18962–18967. doi:10.1073/pnas.1121288109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Xu LJ, Ouyang YB, Xiong X, Stary CM, Giffard RG (2015) Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Exp Neurol 264:1–7. doi:10.1016/j.expneurol.2014.11.007

    Article  CAS  PubMed  Google Scholar 

  113. Moon JM, Xu L, Giffard RG (2013) Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33(12):1976–1982. doi:10.1038/jcbfm.2013.157

    Article  CAS  Google Scholar 

  114. Ouyang YB, Lu Y, Yue S, Xu LJ, Xiong XX, White RE, Sun X, Giffard RG (2012) miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobiol Dis 45(1):555–563. doi:10.1016/j.nbd.2011.09.012

    Article  CAS  PubMed  Google Scholar 

  115. Huang W, Liu X, Cao J, Meng F, Li M, Chen B, Zhang J (2015) miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling. Journal of molecular neuroscience : MN 55(4):821–829. doi:10.1007/s12031-014-0434-0

    Article  CAS  PubMed  Google Scholar 

  116. Chi W, Meng F, Li Y, Li P, Wang G, Cheng H, Han S, Li J (2014) Impact of microRNA-134 on neural cell survival against ischemic injury in primary cultured neuronal cells and mouse brain with ischemic stroke by targeting HSPA12B. Brain Res 1592:22–33. doi:10.1016/j.brainres.2014.09.072

    Article  CAS  PubMed  Google Scholar 

  117. Chi W, Meng F, Li Y, Wang Q, Wang G, Han S, Wang P, Li J (2014) Downregulation of miRNA-134 protects neural cells against ischemic injury in N2A cells and mouse brain with ischemic stroke by targeting HSPA12B. Neuroscience 277:111–122. doi:10.1016/j.neuroscience.2014.06.062

    Article  CAS  PubMed  Google Scholar 

  118. Liu P, Zhao H, Wang R, Wang P, Tao Z, Gao L, Yan F, Liu X et al (2015) MicroRNA-424 protects against focal cerebral ischemia and reperfusion injury in mice by suppressing oxidative stress. Stroke; a journal of cerebral circulation 46(2):513–519. doi:10.1161/STROKEAHA.114.007482

    Article  CAS  Google Scholar 

  119. Zhao H, Tao Z, Wang R, Liu P, Yan F, Li J, Zhang C, Ji X et al (2014) MicroRNA-23a-3p attenuates oxidative stress injury in a mouse model of focal cerebral ischemia-reperfusion. Brain Res 1592:65–72. doi:10.1016/j.brainres.2014.09.055

    Article  CAS  PubMed  Google Scholar 

  120. Khanna S, Rink C, Ghoorkhanian R, Gnyawali S, Heigel M, Wijesinghe DS, Chalfant CE, Chan YC et al (2013) Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33(8):1197–1206. doi:10.1038/jcbfm.2013.68

    Article  CAS  Google Scholar 

  121. Xu WH, Yao XY, Yu HJ, Huang JW, Cui LY (2012) Downregulation of miR-199a may play a role in 3-nitropropionic acid induced ischemic tolerance in rat brain. Brain Res 1429:116–123. doi:10.1016/j.brainres.2011.10.007

    Article  CAS  PubMed  Google Scholar 

  122. Yang ZB, Zhang Z, Li TB, Lou Z, Li SY, Yang H, Yang J, Luo XJ et al (2014) Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke. Clin Sci 127(12):679–689. doi:10.1042/CS20140084

    Article  CAS  PubMed  Google Scholar 

  123. Vinciguerra A, Formisano L, Cerullo P, Guida N, Cuomo O, Esposito A, Di Renzo G, Annunziato L et al (2014) MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits. Molecular therapy : the journal of the American Society of Gene Therapy 22(10):1829–1838. doi:10.1038/mt.2014.113

    Article  CAS  Google Scholar 

  124. Liu Y, Zhang J, Han R, Liu H, Sun D, Liu X (2015) Downregulation of serum brain specific microRNA is associated with inflammation and infarct volume in acute ischemic stroke. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 22(2):291–295. doi:10.1016/j.jocn.2014.05.042

    Article  CAS  Google Scholar 

  125. Yu H, Wu M, Zhao P, Huang Y, Wang W, Yin W (2015) Neuroprotective effects of viral overexpression of microRNA-22 in rat and cell models of cerebral ischemia-reperfusion injury. J Cell Biochem 116(2):233–241. doi:10.1002/jcb.24960

    Article  CAS  PubMed  Google Scholar 

  126. Hutchison ER, Kawamoto EM, Taub DD, Lal A, Abdelmohsen K, Zhang Y, Wood WH 3rd, Lehrmann E et al (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61(7):1018–1028. doi:10.1002/glia.22483

    Article  PubMed  PubMed Central  Google Scholar 

  127. Su W, Hopkins S, Nesser NK, Sopher B, Silvestroni A, Ammanuel S, Jayadev S, Moller T et al (2014) The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf. J Immunol 192(1):358–366. doi:10.4049/jimmunol.1301397

    Article  CAS  PubMed  Google Scholar 

  128. Zhang L, Li YJ, Wu XY, Hong Z, Wei WS (2015) MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose-deprived microglia by targeting Toll-like receptor 4. J Neurochem 132(6):713–723. doi:10.1111/jnc.13021

    Article  CAS  PubMed  Google Scholar 

  129. Zhang L, Dong LY, Li YJ, Hong Z, Wei WS (2012) The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor. J Neuroinflammation 9:211. doi:10.1186/1742-2094-9-211

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Yang Z, Zhong L, Zhong S, Xian R, Yuan B (2015) miR-203 protects microglia mediated brain injury by regulating inflammatory responses via feedback to MyD88 in ischemia. Mol Immunol 65(2):293–301. doi:10.1016/j.molimm.2015.01.019

    Article  CAS  PubMed  Google Scholar 

  131. Zhao H, Wang J, Gao L, Wang R, Liu X, Gao Z, Tao Z, Xu C et al (2013) MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involving suppressing microglia activation. Stroke; a journal of cerebral circulation 44(6):1706–1713. doi:10.1161/STROKEAHA.111.000504

    Article  CAS  Google Scholar 

  132. Ni J, Wang X, Chen S, Liu H, Wang Y, Xu X, Cheng J, Jia J, Zhen X (2015) MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. Brain Behav Immun. doi:10.1016/j.bbi.2015.04.014

  133. Mueller M, Zhou J, Yang L, Gao Y, Wu F, Schoeberlein A, Surbek D, Barnea ER et al (2014) PreImplantation factor promotes neuroprotection by targeting microRNA let-7. Proc Natl Acad Sci U S A 111(38):13882–13887. doi:10.1073/pnas.1411674111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wen Y, Zhang X, Dong L, Zhao J, Zhang C, Zhu C (2015) Acetylbritannilactone Modulates microRNA-155-Mediated Inflammatory Response in Ischemic Cerebral Tissues. Mol Med. doi:10.2119/molmed.2014.00199

  135. Wang Y, Dong X, Li Z, Wang W, Tian J, Chen J (2014) Downregulated RASD1 and upregulated miR-375 are involved in protective effects of calycosin on cerebral ischemia/reperfusion rats. J Neurol Sci 339(1-2):144–148. doi:10.1016/j.jns.2014.02.002

    Article  CAS  PubMed  Google Scholar 

  136. Vartanian KB, Mitchell HD, Stevens SL, Conrad VK, McDermott JE, Stenzel-Poore MP (2015) CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 35(2):257–266. doi:10.1038/jcbfm.2014.193

    Article  CAS  Google Scholar 

  137. Benoit ME, Tenner AJ (2011) Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(9):3459–3469. doi:10.1523/JNEUROSCI.3932-10.2011

    Article  CAS  Google Scholar 

  138. Tripathi AK, Dwivedi A, Pal MK, Rastogi N, Gupta P, Ali S, Prabhu MB, Kushwaha HN et al (2014) Attenuated neuroprotective effect of riboflavin under UV-B irradiation via miR-203/c-Jun signaling pathway in vivo and in vitro. J Biomed Sci 21:39. doi:10.1186/1423-0127-21-39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Park HA, Kubicki N, Gnyawali S, Chan YC, Roy S, Khanna S, Sen CK (2011) Natural vitamin E alpha-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1. Stroke; a journal of cerebral circulation 42(8):2308–2314. doi:10.1161/STROKEAHA.110.608547

    Article  CAS  PubMed Central  Google Scholar 

  140. Liu XS, Chopp M, Zhang RL, Tao T, Wang XL, Kassis H, Hozeska-Solgot A, Zhang L et al (2011) MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 6(8):e23461. doi:10.1371/journal.pone.0023461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Stary CM, Xu L, Sun X, Ouyang YB, White RE, Leong J, Li J, Xiong X et al (2015) MicroRNA-200c contributes to injury from transient focal cerebral ischemia by targeting Reelin. Stroke; a journal of cerebral circulation 46(2):551–556. doi:10.1161/STROKEAHA.114.007041

    Article  CAS  PubMed Central  Google Scholar 

  142. Birch D, Britt BC, Dukes SC, Kessler JA, Dizon ML (2014) MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia. Pediatr Res 76(4):334–340. doi:10.1038/pr.2014.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG et al (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30(7):1556–1564. doi:10.1002/stem.1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, Zhang ZG, Chopp M (2013) MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 31(12):2737–2746. doi:10.1002/stem.1409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Liu Y, Jiang X, Zhang X, Chen R, Sun T, Fok KL, Dong J, Tsang LL et al (2011) Dedifferentiation-reprogrammed mesenchymal stem cells with improved therapeutic potential. Stem Cells 29(12):2077–2089. doi:10.1002/stem.764

    Article  CAS  PubMed  Google Scholar 

  146. Liu FJ, Kaur P, Karolina DS, Sepramaniam S, Armugam A, Wong PT, Jeyaseelan K (2015) MiR-335 Regulates Hif-1alpha to Reduce Cell Death in Both Mouse Cell Line and Rat Ischemic Models. PLoS One 10(6):e0128432. doi:10.1371/journal.pone.0128432

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Hunsberger JG, Fessler EB, Wang Z, Elkahloun AG, Chuang DM (2012) Post-insult valproic acid-regulated microRNAs: potential targets for cerebral ischemia. Am J Transl Res 4(3):316–332

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Liu Y, Pan Q, Zhao Y, He C, Bi K, Chen Y, Zhao B, Chen Y, Ma X (2015) MicroRNA-155 Regulates ROS Production, NO Generation, Apoptosis and Multiple Functions of Human Brain Microvessel Endothelial Cells Under Physiological and Pathological Conditions. Journal of cellular biochemistry. doi:10.1002/jcb.25234

  149. Yin KJ, Deng Z, Hamblin M, Xiang Y, Huang H, Zhang J, Jiang X, Wang Y et al (2010) Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 30(18):6398–6408. doi:10.1523/JNEUROSCI.0780-10.2010

    Article  CAS  Google Scholar 

  150. Lou YL, Guo F, Liu F, Gao FL, Zhang PQ, Niu X, Guo SC, Yin JH et al (2012) miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia. Mol Cell Biochem 370(1-2):45–51. doi:10.1007/s11010-012-1396-6

    Article  CAS  PubMed  Google Scholar 

  151. Zeng L, He X, Wang Y, Tang Y, Zheng C, Cai H, Liu J, Wang Y et al (2014) MicroRNA-210 overexpression induces angiogenesis and neurogenesis in the normal adult mouse brain. Gene Ther 21(1):37–43. doi:10.1038/gt.2013.55

    Article  CAS  PubMed  Google Scholar 

  152. Li LJ, Huang Q, Zhang N, Wang GB, Liu YH (2014) miR-376b-5p regulates angiogenesis in cerebral ischemia. Mol Med Rep 10(1):527–535. doi:10.3892/mmr.2014.2172

    CAS  PubMed  Google Scholar 

  153. Chen J, Yang T, Yu H, Sun K, Shi Y, Song W, Bai Y, Wang X et al (2010) A functional variant in the 3’-UTR of angiopoietin-1 might reduce stroke risk by interfering with the binding efficiency of microRNA 211. Hum Mol Genet 19(12):2524–2533. doi:10.1093/hmg/ddq131

    Article  CAS  PubMed  Google Scholar 

  154. Dharap A, Vemuganti R (2010) Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways. J Neurochem 113(6):1685–1691. doi:10.1111/j.1471-4159.2010.06735.x

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Lusardi TA, Farr CD, Faulkner CL, Pignataro G, Yang T, Lan J, Simon RP, Saugstad JA (2010) Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 30(4):744–756. doi:10.1038/jcbfm.2009.253

    Article  CAS  Google Scholar 

  156. Lee ST, Chu K, Jung KH, Yoon HJ, Jeon D, Kang KM, Park KH, Bae EK et al (2010) MicroRNAs induced during ischemic preconditioning. Stroke; a journal of cerebral circulation 41(8):1646–1651. doi:10.1161/STROKEAHA.110.579649

    Article  CAS  Google Scholar 

  157. Sun M, Yamashita T, Shang J, Liu N, Deguchi K, Feng J, Abe K (2015) Time-Dependent Profiles of MicroRNA Expression Induced by Ischemic Preconditioning in the Gerbil Hippocampus. Cell Transplant 24(3):367–376. doi:10.3727/096368915X686869

    Article  PubMed  Google Scholar 

  158. Shin JH, Park YM, Kim DH, Moon GJ, Bang OY, Ohn T, Kim HH (2014) Ischemic brain extract increases SDF-1 expression in astrocytes through the CXCR2/miR-223/miR-27b pathway. Biochim Biophys Acta 1839(9):826–836. doi:10.1016/j.bbagrm.2014.06.019

    Article  CAS  PubMed  Google Scholar 

  159. Liu C, Peng Z, Zhang N, Yu L, Han S, Li D, Li J (2012) Identification of differentially expressed microRNAs and their PKC-isoform specific gene network prediction during hypoxic pre-conditioning and focal cerebral ischemia of mice. J Neurochem 120(5):830–841. doi:10.1111/j.1471-4159.2011.07624.x

    Article  CAS  PubMed  Google Scholar 

  160. Cao L, Feng C, Li L, Zuo Z (2012) Contribution of microRNA-203 to the isoflurane preconditioning-induced neuroprotection. Brain Res Bull 88(5):525–528. doi:10.1016/j.brainresbull.2012.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Sun Y, Li Y, Liu L, Wang Y, Xia Y, Zhang L, Ji X (2015) Identification of miRNAs Involved in the Protective Effect of Sevoflurane Preconditioning Against Hypoxic Injury in PC12 Cells. Cell Mol Neurobiol. doi:10.1007/s10571-015-0205-7

  162. Shi H, Sun BL, Zhang J, Lu S, Zhang P, Wang H, Yu Q, Stetler RA et al (2013) miR-15b suppression of Bcl-2 contributes to cerebral ischemic injury and is reversed by sevoflurane preconditioning. CNS Neurol Disord: Drug Targets 12(3):381–391

    Article  CAS  Google Scholar 

  163. Zhao YY, Wang WA, Hu H (2015) Treatment with recombinant tissue plasminogen activator alters the microRNA expression profiles in mouse brain after acute ischemic stroke. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. doi:10.1007/s10072-015-2149-6

  164. Zhang L, Chopp M, Liu X, Teng H, Tang T, Kassis H, Zhang ZG (2012) Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway. Arterioscler, Thromb, Vasc Biol 32(8):1856–1864. doi:10.1161/ATVBAHA.112.252619

    Article  CAS  Google Scholar 

  165. Yang J, Gao F, Zhang Y, Liu Y, Zhang D (2015) Buyang Huanwu Decoction (BYHWD) Enhances Angiogenic Effect of Mesenchymal Stem Cell by Upregulating VEGF Expression After Focal Cerebral Ischemia. J Mol Neurosci: MN. doi:10.1007/s12031-015-0539-0

  166. Jiang Y, Li L, Tan X, Liu B, Zhang Y, Li C (2015) miR-210 mediates vagus nerve stimulation-induced antioxidant stress and anti-apoptosis reactions following cerebral ischemia/reperfusion injury in rats. Journal of neurochemistry. doi:10.1111/jnc.13097

  167. Guo F, Han X, Zhang J, Zhao X, Lou J, Chen H, Huang X (2014) Repetitive transcranial magnetic stimulation promotes neural stem cell proliferation via the regulation of MiR-25 in a rat model of focal cerebral ischemia. PLoS One 9(10):e109267. doi:10.1371/journal.pone.0109267

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Pang XM, Liu JL, Li JP, Huang LG, Zhang L, Xiang HY, Feng LB, Chen CY, Li SH, Su SY (2015) Fastigial nucleus stimulation regulates neuroprotection via induction of a novel microRNA, rno-miR-676-1, in middle cerebral artery occlusion rats. J Neurochem. doi:10.1111/jnc.13094

  169. Huang LG, Li JP, Pang XM, Chen CY, Xiang HY, Feng LB, Su SY, Li SH et al (2015) MicroRNA-29c Correlates with Neuroprotection Induced by FNS by Targeting Both Birc2 and Bak1 in Rat Brain after Stroke. CNS Neurosci Ther 21(6):496–503. doi:10.1111/cns.12383

    Article  CAS  PubMed  Google Scholar 

  170. Dharap A, Nakka VP, Vemuganti R (2011) Altered expression of PIWI RNA in the rat brain after transient focal ischemia. Stroke; a journal of cerebral circulation 42(4):1105–1109. doi:10.1161/STROKEAHA.110.598391

    Article  CAS  PubMed Central  Google Scholar 

  171. Dharap A, Nakka VP, Vemuganti R (2012) Effect of focal ischemia on long noncoding RNAs. Stroke; a journal of cerebral circulation 43(10):2800–2802. doi:10.1161/STROKEAHA.112.669465

    Article  CAS  PubMed Central  Google Scholar 

  172. Dharap A, Pokrzywa C, Vemuganti R (2013) Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST. ASN Neuro 5(4):283–289. doi:10.1042/AN20130029

    Article  CAS  PubMed  Google Scholar 

  173. Seripa D, Panza F, Daragjati J, Paroni G, Pilotto A (2015) Measuring pharmacogenetics in special groups: geriatrics. Expert Opin Drug Metab Toxicol 11(7):1073–1088. doi:10.1517/17425255.2015.1041919

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This article has been supported by National Natural Science Foundation of China (grant no. 81201019 and 81171239).

Author information

Authors and Affiliations

  1. Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

    Zhiping Hu, Bingwu Zhong, Chunli Chen, Qiang Lei & Liuwang Zeng

  2. Department of Traditional Chinese Medicine, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

    Bingwu Zhong

  3. National Key Laboratory of Medical Genetics, Central South University, Changsha, 410078, Hunan, China

    Jieqiong Tan

Authors
  1. Zhiping Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bingwu Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jieqiong Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chunli Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiang Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liuwang Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liuwang Zeng.

Ethics declarations

Conflict of interest

The authors confirm that this article content has no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Z., Zhong, B., Tan, J. et al. The Emerging Role of Epigenetics in Cerebral Ischemia. Mol Neurobiol 54, 1887–1905 (2017). https://doi.org/10.1007/s12035-016-9788-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-9788-3

Keywords

Search

Navigation