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HDAC1 Expression, Histone Deacetylation, and Protective Role of Sodium Valproate in the Rat Dorsal Root Ganglia After Sciatic Nerve Transection

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Abstract

Nerve injury is an important reason of human disability and death. We studied the role of histone deacetylation in the response of the dorsal root ganglion (DRG) cells to sciatic nerve transection. Sciatic nerve transection in the rat thigh induced overexpression of histone deacetylase 1 (HDAC1) in the ipsilateral DRG at 1–4 h after axotomy. In the DRG neurons, HDAC1 initially upregulated at 1 h but then redistributed from the nuclei to the cytoplasm at 4 h after axotomy. Histone H3 was deacetylated at 24 h after axotomy. Deacetylation of histone H4, accumulation of amyloid precursor protein, a nerve injury marker, and GAP-43, an axon regeneration marker, were observed in the axotomized DRG on day 7. Neuronal injury occurred on day 7 after axotomy along with apoptosis of DRG cells, which were mostly the satellite glial cells remote from the site of sciatic nerve transection. Administration of sodium valproate significantly reduced apoptosis not only in the injured ipsilateral DRG but also in the contralateral ganglion. It also reduced the deacetylation of histones H3 and H4, prevented axotomy-induced accumulation of amyloid precursor protein, which indicated nerve injury, and overexpressed GAP-43, a nerve regeneration marker, in the axotomized DRG. Therefore, HDAC1 was involved in the axotomy-induced injury of DRG neurons and glial cells. HDAC inhibitor sodium valproate demonstrated the neuroprotective activity in the axotomized DRG.

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References

  1. Furlan JC, Gulasingam S, Craven BC (2019) Epidemiology of war-related spinal cord injury among combatants: a systematic review. Global Spine J 9:545–558. https://doi.org/10.1177/2192568218776914

    Article  PubMed  Google Scholar 

  2. Laskowitz D, Grant G (eds) (2016) Translational research in traumatic brain injury. CRC Press/Taylor and Francis Group, Boca Raton

    Google Scholar 

  3. Hill CS (2016) Traumatic axon injury: mechanisms and translational opportunities. Trends Neurosci 39:311–324. https://doi.org/10.1016/j.tins.2016.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Witiw CD, Fehlings MG (2015) Acute spinal cord injury. J Spinal Disord Tech 28:202–210. https://doi.org/10.1097/BSD.0000000000000287

    Article  PubMed  Google Scholar 

  5. Rishal I, Fainzilber M (2014) Axon-soma communication in neuronal injury. Nat Rev Neurosci 15:З2-42. https://doi.org/10.1038/nrn3609.

  6. Demyanenko S, Dzreyan V, Uzdensky A (2019) Axotomy-induced changes of the protein profile in the crayfish ventral cord ganglia. J Mol Neurosci 68:667–678. https://doi.org/10.1007/s12031-019-01329-5

    Article  CAS  PubMed  Google Scholar 

  7. 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, pp. 191–209

    Google Scholar 

  8. Lebrun-Julien F, Suter U (2015) Combined HDAC1 and HDAC2 depletion promotes retinal ganglion cell survival after injury through reduction of p53 target gene expression. ASN Neuro 7(3):175909141559306. https://doi.org/10.1177/1759091415593066

    Article  CAS  Google Scholar 

  9. Biermann J, Grieshaber P, Goebel U, Martin G, Thanos S, Di Giovanni S, Lagrèze WA (2010) Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells. Invest Ophthalmol Vis Sci 51:526–534. https://doi.org/10.1167/iovs.09-3903

    Article  PubMed  Google Scholar 

  10. Zhang ZZ, Gong YY, Shi YH, Zhang W, Qin XH, Wu XW (2012) Valproate promotes survival of retinal ganglion cells in a rat model of optic nerve crush. Neuroscience 224:282–293. https://doi.org/10.1016/j.neuroscience.2012.07.056

    Article  CAS  PubMed  Google Scholar 

  11. Berezhnaya EV, Bibov MY, Komandirov MA, Neginskaya MA, Rudkovskii MV, Uzdensky AB (2017) Involvement of MAPK, Akt/GSK-3β and AMPK/mTOR signaling pathways in protection of remote glial cells from axotomy-induced necrosis and apoptosis in the isolated crayfish stretch receptor. Mol Cell Neurosci 83:1–5. https://doi.org/10.1016/j.mcn.2017.06.003

    Article  CAS  PubMed  Google Scholar 

  12. Khaitin A, Rudkovskii M, Uzdensky A (2018) Ca2+ mediates axotomy-induced necrosis and apoptosis of satellite glial cells remote from the transection site in the isolated crayfish mechanoreceptor. Mol Cell Neurosci 88:7–15. https://doi.org/10.1016/j.mcn.2017.12.004

    Article  CAS  PubMed  Google Scholar 

  13. Uzdensky AB (2018) Axotomy induces damage to glial cells remote from the transection site in the peripheral nervous system. Neural Regen Res 13:639–640. https://doi.org/10.4103/1673-5374.230285

    Article  PubMed  PubMed Central  Google Scholar 

  14. Savastano LE, Laurito SR, Fitt MR, Rasmussen JA, Gonzalez Polo V, Patterson S (2014) Sciatic nerve injury: a simple and subtle model for investigating many aspects of nervous system damage and recovery. J Neurosci Methods 227:166–180. https://doi.org/10.1016/j.jneumeth.2014.01.020

    Article  PubMed  Google Scholar 

  15. Bolte S, Cordelières FP (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224(Pt 3):213–232. https://doi.org/10.1111/j.1365-2818.2006.01706.x

    Article  CAS  PubMed  Google Scholar 

  16. Manders EM, Verbeek FJ, Aten JA (1993) Measurement of colocalization of objects in dual-colour confocal images. J Microsc 169:375–382

    Article  Google Scholar 

  17. Chen JY, Chu LW, Cheng KI, Hsieh SL, Juan YS, Wu BN (2018) Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model. Sci Rep 8:16457. https://doi.org/10.1038/s41598-018-34915-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, Kim JM, Park DK et al (2007) Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 26:464–472. https://doi.org/10.1016/j.nbd.2007.02.006

    Article  CAS  PubMed  Google Scholar 

  19. Cui SS, Yang CP, Bowen RC, Bai O, Li XM, Jiang W, Zhang X (2003) Valproic acid enhances axonal regeneration and recovery of motor function after sciatic nerve axotomy in adult rats. Brain Res 975:229–236. https://doi.org/10.1016/s0006-8993(03)02699-4

    Article  CAS  PubMed  Google Scholar 

  20. Demyanenko SV, Dzreyan VA, Neginskaya MA, Uzdensky AB (2020) Expression of histone deacetylases HDAC1 and HDAC2 and their role in apoptosis in the penumbra induced by photothrombotic stroke. Mol Neurobiol 57:226–238. https://doi.org/10.1007/s12035-019-01772-w

    Article  CAS  PubMed  Google Scholar 

  21. 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 19:5105–5120. https://doi.org/10.2174/1381612811319280009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sun J, Piao J, Li N, Yang Y, Kim KY, Lin Z (2019) Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer. FEBS J 287:2118–2133. https://doi.org/10.1111/febs.15122

    Article  CAS  PubMed  Google Scholar 

  23. Dubový P, Klusáková I, Hradilová-Svíženská I, Joukal M (2018) Expression of regeneration-associated proteins in primary sensory neurons and regenerating axons after nerve injury — an overview. Anat Rec (Hoboken) 301:1618–1627. https://doi.org/10.1002/ar.23843

    Article  CAS  Google Scholar 

  24. Muresan V, Ladescu Muresan Z (2015) Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms. Exp Cell Res 334:45–53. https://doi.org/10.1016/j.yexcr.2014.12.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bornstein N, Poon WS (2012) Accelerated recovery from acute brain injuries: clinical efficacy of neurotrophic treatment in stroke and traumatic brain injuries. Drugs Today (Barc) 48 Suppl A:43–61. https://doi.org/10.1358/dot.2012.48(Suppl.A).1739723

    Article  CAS  Google Scholar 

  26. Gerin CG, Madueke IC, Perkins T, Hill S, Smith K, Haley B, Allen SA, Garcia RP et al (2011) Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury. Synapse 65:1255–1281. https://doi.org/10.1002/syn.20903

    Article  CAS  PubMed  Google Scholar 

  27. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210. https://doi.org/10.1038/35093019

    Article  CAS  PubMed  Google Scholar 

  28. Lawson SN (1979) The postnatal development of large light and small dark neurons in mouse dorsal root ganglia: a statistical analysis of cell numbers and size. J Neurocytol 8:275–294

    Article  CAS  Google Scholar 

  29. Simon RP (2016) Epigenetic modulation of gene expression governs the brain’s response to injury. Neurosci Lett 625:16–19. https://doi.org/10.1016/j.neulet.2015.12.024

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Demyanenko S, Uzdensky A (2019) Epigenetic alterations induced by photothrombotic stroke in the rat cerebral cortex: deacetylation of histone H3, upregulation of histone deacetylases and histone acetyltransferases. Int J Mol Sci 20:E2882. https://doi.org/10.3390/ijms20122882

    Article  CAS  PubMed  Google Scholar 

  32. Bardai FH, Price V, Zaayman M, Wang L, D'Mello SR (2012) Histone deacetylase-1 (HDAC1) is a molecular switch between neuronal survival and death. J Biol Chem 287:35444–35453. https://doi.org/10.1074/jbc.M112.394544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  Google Scholar 

  35. Dzreyan VA, Rodkin SV, Nikul VV, Pitinova MA, Uzdensky AB (2020) Apoptosis of satellite glial cells and protein expression in the rat dorsal root ganglia after sciatic nerve transection. (In press)

  36. McKay Hart A, Brannstrom T, Wiberg M, Terenghi G (2002) Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat. Time course of cell death and elimination. Exp Brain Res 142:308–318. https://doi.org/10.1007/s00221-001-0929-0

    Article  PubMed  Google Scholar 

  37. Barron KD (2004) The axotomy response. J Neurol Sci 220:119–121. https://doi.org/10.1016/j.jns.2004.03.009

    Article  PubMed  Google Scholar 

  38. Khaitin AM, Rudkovskii MV, Uzdensky AB (2015) The method of isolation of the crayfish abdominal stretch receptor maintaining a connection of the sensory neuron to the ventral nerve cord ganglion. Invertebr Neurosci 15:176. https://doi.org/10.1007/s10158-014-0176-2

    Article  CAS  Google Scholar 

  39. Anderson KD, Merhege MA, Morin M, Bolognani F, Perrone-Bizzozero NI (2003) Increased expression and localization of the RNA-binding protein HuD and GAP-43 mRNA to cytoplasmic granules in DRG neurons during nerve regeneration. Exp Neurol 183:100–108. https://doi.org/10.1016/s0014-4886(03)00103-1

    Article  CAS  PubMed  Google Scholar 

  40. Chuang D-M, Leng Y, Marinova Z, Kim HJ, Chiu CT (2009) Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 32:591–601. https://doi.org/10.1016/j.tins.2009.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takase K, Oda S, Kuroda M, Funato H (2013) Monoaminergic and neuropeptidergic neurons have distinct expression profiles of histone deacetylases. PLoS One 8(3):e58473. https://doi.org/10.1371/journal.pone.0058473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tanabe K, Bonilla I, Winkles JA, Strittmatter SM (2003) Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. J Neurosci 23:9675–9686

    Article  CAS  Google Scholar 

  43. Lewis SE, Mannion RJ, White FA, Coggeshall RE, Beggs S, Costigan M, Martin JL, Dillmann WH et al (1999) A role for HSP27 in sensory neuron survival. J Neurosci 19:8945–8953

    Article  CAS  Google Scholar 

  44. Wu D, Huang W, Richardson PM, Priestley JV, Liu M (2008) TRPC4 in rat dorsal root ganglion neurons is increased after nerve injury and is necessary for neurite outgrowth. J Biol Chem 283:416–426. https://doi.org/10.1074/jbc.M703177200

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by the grant of the Ministry of Science and Higher Education of the Russian Federation #0852-2020-0028.

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Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Southern Federal University, 194/1 Stachky Ave, Rostov-on-Don, 344090, Russia

    V. A. Dzreyan, S. V. Rodkin, M. A. Pitinova & Anatoly B. Uzdensky

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  1. V. A. Dzreyan
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  3. M. A. Pitinova
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VD: data generation and analysis (western blotting); SR: data generation (DRG visualization, determination of apoptosis); MP: data generation; AU: conception, experimental design, data analysis and interpretation, and manuscript writing.

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Correspondence to Anatoly B. Uzdensky.

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Dzreyan, V.A., Rodkin, S.V., Pitinova, M.A. et al. HDAC1 Expression, Histone Deacetylation, and Protective Role of Sodium Valproate in the Rat Dorsal Root Ganglia After Sciatic Nerve Transection. Mol Neurobiol 58, 217–228 (2021). https://doi.org/10.1007/s12035-020-02126-7

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