Advertisement

The Neuroprotective Effect of the HDAC2/3 Inhibitor MI192 on the Penumbra After Photothrombotic Stroke in the Mouse Brain

  • S. V. Demyanenko
  • V. V. Nikul
  • A. B. UzdenskyEmail author
Article
  • 47 Downloads

Abstract

Unilateral photothrombotic stroke caused tissue infarct in the mouse cerebral cortex. The injury of the cerebral cortex impaired the mouse motor activity, in particular the functional asymmetry in forelimb use. In the peri-infarct cortical tissue outside the infarct core cell apoptosis occurred at 4 and 7 days after PTS. The downregulation of acetylated α-tubulin, a marker of stable microtubules, showed the destruction of neurites, axons, and dendrites in injured neurons. However, the upregulation of GAP43 indicates the stimulation of neurite growth that was possibly aimed at the recovery of the cortical tissue in the damaged cerebral hemisphere. Application of MI-192, an inhibitor of histone deacetylases HDAC2 and HDAC3, demonstrated the neuroprotective activity in the mouse brain subjected to photothrombotic stroke. It reduced the volume of the PTS-induced infarction core in the mouse brain, partly restored the functional symmetry in the forelimb use, decreased the level of PTS-induced apoptosis and acetylation of α-tubulin characteristic for stable microtubules, and increased the expression of GAP-43 in the cerebral cortex of the damaged hemisphere. These data point to the involvement of HDAC2 and HDAC3 in the photothrombotic injury of the mouse brain not only in the infarction core but also outside it. The application of MI192 after PTS reduced or eliminated these negative effects and exerted the neuroprotective effect on the mouse brain. It may be a promising neuroprotector agent for anti-stroke therapy.

Keywords

Photothrombotic stroke Epigenetics Histone deacetylase HDAC inhibitor MI192 

Notes

Funding Information

This study was funded by the Russian Science Foundation (grant no. 18-15-00110).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198.  https://doi.org/10.1016/j.neuron.2010.07.002 CrossRefGoogle Scholar
  2. 2.
    Manning NW, Campbell BC, Oxley TJ, Chapot R (2014) Acute ischemic stroke: time, penumbra, and reperfusion. Stroke 45:640–644.  https://doi.org/10.1161/STROKEAHA.113.003798 CrossRefGoogle Scholar
  3. 3.
    Hankey GJ (2017) Stroke. Lancet 389:641–654.  https://doi.org/10.1016/S0140-6736(16)30962-X CrossRefGoogle Scholar
  4. 4.
    Majid A (2014) Neuroprotection in stroke: past, present, and future. ISRN Neurol 2014:515716.  https://doi.org/10.1155/2014/515716 CrossRefGoogle Scholar
  5. 5.
    Rajah GB, Ding Y (2017) Experimental neuroprotection in ischemic stroke: a concise review. Neurosurg Focus 42(4):E2.  https://doi.org/10.3171/2017.1.FOCUS16497 CrossRefGoogle Scholar
  6. 6.
    Patel Rajan AG, McMullen PW (2017) Neuroprotection in the treatment of acute ischemic stroke. Prog Cardiovasc Dis 59:542–548.  https://doi.org/10.1016/j.pcad.2017.04.005 CrossRefGoogle Scholar
  7. 7.
    Karsy M, Brock A, Guan J, Taussky P, Kalani MY, Park MS (2017) Neuroprotective strategies and the underlying molecular basis of cerebrovascular stroke. Neurosurg Focus 42:E3.  https://doi.org/10.3171/2017.1.FOCUS16522 CrossRefGoogle Scholar
  8. 8.
    Zhou Z, Lu J, Liu WW, Manaenko A, Hou X, Mei Q, Huang JL, Tang J et al (2018) Advances in stroke pharmacology. Pharmacol Ther 191:23–42.  https://doi.org/10.1016/j.pharmthera.2018.05.012 CrossRefGoogle Scholar
  9. 9.
    Luo Y, Tang H, Li H, Zhao R, Huang Q, Liu J (2019) Recent advances in the development of neuroprotective agents and therapeutic targets in the treatment of cerebral ischemia. Eur J Med Chem 162:132–146.  https://doi.org/10.1016/j.ejmech.2018.11.014 CrossRefGoogle Scholar
  10. 10.
    Demyanenko SV, Panchenko SN, Uzdensky AB (2015) Expression of neuronal and signaling proteins in penumbra around a photothrombotic infarction core in rat cerebral cortex. Biochem Mosc 80:790–799.  https://doi.org/10.1134/S0006297915060152 CrossRefGoogle Scholar
  11. 11.
    Demyanenko S, Uzdensky A (2017) Profiling of signaling proteins in penumbra after focal photothrombotic infarct in the rat brain cortex. Mol Neurobiol 54:6839–6856.  https://doi.org/10.1007/s12035-017-0736-7. CrossRefGoogle Scholar
  12. 12.
    Uzdensky A, Demyanenko S, Fedorenko G, Lapteva T, Fedorenko A (2017) Photothrombotic infarct in the rat brain cortex: protein profile and morphological changes in penumbra. Mol Neurobiol 54:4172–4188.  https://doi.org/10.1007/s12035-016-9964-5. CrossRefGoogle Scholar
  13. 13.
    Kouzarides T, Berger SL (2006) Chromatin modifications and mechanisms. In: Allis CD, Jenuwein T, Reinberg D (eds) Epigenetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp. 191–209Google Scholar
  14. 14.
    Konsoula Z, Barile FA (2012) Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders. J Pharmacol Toxicol Methods 66:215–220.  https://doi.org/10.1016/j.vascn.2012.08.001 CrossRefGoogle Scholar
  15. 15.
    Schweizer S, Meisel A, Märschenz S (2013) Epigenetic mechanisms in cerebral ischemia. J Cereb Blood Flow Metab 33:1335–1346.  https://doi.org/10.1038/jcbfm.2013.93 CrossRefGoogle Scholar
  16. 16.
    Volmar CH, Wahlestedt C (2015) Histone deacetylases (HDACs) and brain functions. Neuroepigenetics 1:20–27.  https://doi.org/10.1016/j.nepig.2014.10.002 CrossRefGoogle Scholar
  17. 17.
    Hu Z, Zhong B, Tan J, Chen C, Lei Q, Zeng L (2017) The emerging role of epigenetics in cerebral ischemia. Mol Neurobiol 54:1887–1905.  https://doi.org/10.1007/s12035-016-9788-3 CrossRefGoogle Scholar
  18. 18.
    Demyanenko SV, Dzreyan VA, Neginskaya MA, Uzdensky AB (2019) Expression of histone deacetylases HDAC1 and HDAC2 and their role in apoptosis in the penumbra induced by photothrombotic stroke. Mol Neurobiol (in press)Google Scholar
  19. 19.
    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 90:463–468CrossRefGoogle Scholar
  20. 20.
    Ganai SA, Ramadoss M, Mahadevan V (2016) Histone deacetylase (HDAC) inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. Curr Neuropharmacol 14:55–71CrossRefGoogle Scholar
  21. 21.
    Wang ZY, Qin W, Yi F (2015) Targeting histone deacetylases: perspectives for epigenetic-based therapy in cardio-cerebrovascular disease. J Geriatr Cardiol 12:153–164.  https://doi.org/10.11909/j.issn.1671-5411.2015.02.010. Google Scholar
  22. 22.
    Schmidt A, Hoppen M, Strecker JK, Diederich K, Schabitz WR, Schilling M, Minnerup J (2012) Photochemically induced ischemic stroke in rats. Exp Transl Stroke Med 4:13.  https://doi.org/10.1186/2040-7378-4-13 CrossRefGoogle Scholar
  23. 23.
    Uzdensky AB (2018) Photothrombotic stroke as a model of ischemic stroke. Transl Stroke Res 9:437–451.  https://doi.org/10.1007/s12975-017-0593-8 CrossRefGoogle Scholar
  24. 24.
    Demyanenko S, Neginskaya M, Berezhnaya E (2018) Expression of class I histone deacetylases in ipsilateral and contralateral hemispheres after the focal photothrombotic infarction in the mouse brain. Transl Stroke Res 9:471–483.  https://doi.org/10.1007/s12975-017-0595-6 CrossRefGoogle Scholar
  25. 25.
    Paxinos G, Franklin KBJ (2013) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. Academic Press, AmsterdamGoogle Scholar
  26. 26.
    McCloy RA, Rogers S, Caldon CE, Lorca T, Castro A, Burgess A (2014) Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle 13:1400–1412.  https://doi.org/10.4161/cc.28401 CrossRefGoogle Scholar
  27. 27.
    Chelluboina B, Klopfenstein JD, Gujrati M, Rao JS, Veeravalli KK (2014) Temporal regulation of apoptotic and anti-apoptotic molecules after middle cerebral artery occlusion followed by reperfusion. Mol Neurobiol 49:50–65.  https://doi.org/10.1007/s12035-013-8486-7 CrossRefGoogle Scholar
  28. 28.
    Demyanenko S, Berezhnaya E, Neginskaya M, Rodkin S, Dzreyan V, Pitinova M (2019, 2019) Сlass II histone deacetylases in the post-stroke recovery period-expression, cellular, and subcellular localization-promising targets for neuroprotection. J Cell Biochem.  https://doi.org/10.1002/jcb.29266
  29. 29.
    Chen W, Qiao D, Liu X, Shi K (2017) Treadmill exercise improves motor dysfunction and hyperactivity of the corticostriatal glutamatergic pathway in rats with 6-OHDA-induced Parkinson’s disease. Neural Plast 2017:2583910–2583911.  https://doi.org/10.1155/2017/2583910 Google Scholar
  30. 30.
    Barth TM, Jones TA, Schallert T (1990) Functional subdivisions of the rat somatic sensorimotor cortex. Behav Brain Res 39:73–95CrossRefGoogle Scholar
  31. 31.
    Carmichael ST, Archibeque I, Luke L, Nolan T, Momiy J, Li S (2005) Growth-associated gene expression after stroke: Evidence for a growth-promoting region in peri-infarct cortex. Exp Neurol 193:291–311CrossRefGoogle Scholar
  32. 32.
    Westermann S, Weber K (2003) Post-translational modifications regulate microtubule function. Nat Rev Mol Cell Biol 42:938–947.  https://doi.org/10.1038/nrm1260. CrossRefGoogle Scholar
  33. 33.
    Boissinot M, Inman M, Hempshall A, James SR, Gill JH, Selby P, Bowen DT, Grigg R et al (2012) Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192. Leuk Res 36:1304–1310.  https://doi.org/10.1016/j.leukres.2012.07.002 CrossRefGoogle Scholar
  34. 34.
    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. Transl Stroke Res 2:411–423.  https://doi.org/10.1007/s12975-011-0087-z CrossRefGoogle Scholar
  35. 35.
    Broide RS, Redwine JM, Aftahi N, Young W, Bloom FE, Winrow CJ (2007) Distribution of histone deacetylases 1-11 in the rat brain. J Mol Neurosci 31:47–58.  https://doi.org/10.1007/BF02686117 CrossRefGoogle Scholar
  36. 36.
    Wagner FF, Weїwer M, Lewis MC, Holson EB (2013) Small molecule inhibitors of zinc-dependent histone deacetylases. Neurotherapeutics 10:589–604.  https://doi.org/10.1007/s13311-013-0226-1 CrossRefGoogle Scholar
  37. 37.
    Krämer OH (2009) HDAC2: a critical factor in health and disease. Trends Pharmacol Sci 30:647–655.  https://doi.org/10.1016/j.tips.2009.09.007 CrossRefGoogle Scholar
  38. 38.
    Lin YH, Dong J, Tang Y, Ni HY, Zhang Y, Su P, Liang HY, Yao MC et al (2017) Opening a new time window for treatment of stroke by targeting HDAC2. J Neurosci 37:6712–6728.  https://doi.org/10.1523/JNEUROSCI.0341-17.2017 CrossRefGoogle Scholar
  39. 39.
    Zhao B, Yuan Q, Hou JB, Xia ZY, Zhan LY, Li M, Jiang M, Gao WW et al (2019) Inhibition of HDAC3 ameliorates cerebral ischemia reperfusion injury in diabetic mice in vivo and in vitro. J Diabetes Res 2019:8520856–8520812.  https://doi.org/10.1155/2019/8520856 CrossRefGoogle Scholar
  40. 40.
    Gibson CL, Murphy SP (2010) Benefits of histone deacetylase inhibitors for acute brain injury: A systematic review of animal studies. J Neurochem 115:806–813.  https://doi.org/10.1111/j.1471-4159.2010.06993.x CrossRefGoogle Scholar
  41. 41.
    Fessler EB, Chibane FL, Wang Z, Chuang DM (2013) Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. Curr Pharm Des 19:5105–5120CrossRefGoogle Scholar
  42. 42.
    Yusoff SI, Roman M, Lai FY, Eagle-Hemming B, Murphy GJ, Kumar T, Wozniak M (2019) Systematic review and meta-analysis of experimental studies evaluating the organ protective effects of histone deacetylase inhibitors. Transl Res 205:1–16.  https://doi.org/10.1016/j.trsl.2018.11.002 CrossRefGoogle Scholar
  43. 43.
    Seo YJ, Kang Y, Muench L, Reid A, Caesar S, Jean L, Wagner F, Holson E et al (2014) Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors. ACS Chem Neurosci 5:588–596.  https://doi.org/10.1021/cn500021p CrossRefGoogle Scholar
  44. 44.
    Bacon T, Seiler C, Wolny M, Hughes R, Watson P, Schwabe J, Grigg R, Peckham M (2015) Histone deacetylase 3 indirectly modulates tubulin acetylation. Biochem J 472:367–377.  https://doi.org/10.1042/BJ20150660 CrossRefGoogle Scholar
  45. 45.
    Li X, Liu X, Gao M, Han L, Qiu D, Wang H, Xiong B, Sun SC et al (2017) HDAC3 promotes meiotic apparatus assembly in mouse oocytes by modulating tubulin acetylation. Development 144:3789–3797.  https://doi.org/10.1242/dev.153353 CrossRefGoogle Scholar
  46. 46.
    Yang X, Wu Q, Zhang L, Feng L (2016) Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in rats. Front Mol Neurosci 9:131. eCollection 2016.  https://doi.org/10.3389/fnmol.2016.00131 Google Scholar
  47. 47.
    Skene JH (1989) Axonal growth-associated proteins. Annu Rev Neurosci 12:127–156CrossRefGoogle Scholar
  48. 48.
    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 38:1921–1934.  https://doi.org/10.1007/s11064-013-1098-9 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratory of Molecular Neurobiology, Academy of Biology and BiotechnologySouthern Federal UniversityRostov-on-DonRussia

Personalised recommendations