Inhibition of HDAC Increases BDNF Expression and Promotes Neuronal Rewiring and Functional Recovery After Brain Injury

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2020 Aug 20

PMID 32811822

Citations 27

Authors

Naoki Sada

Yuki Fujita

Nanano Mizuta

Masaki Ueno

Takahisa Furukawa

Toshihide Yamashita

Affiliations

Soon will be listed here.

Abstract

Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.

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References

Murphy T, Corbett D . Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009; 10(12):861-72. DOI: 10.1038/nrn2735. View

Nudo R . Mechanisms for recovery of motor function following cortical damage. Curr Opin Neurobiol. 2006; 16(6):638-44. DOI: 10.1016/j.conb.2006.10.004. View

Benowitz L, Carmichael S . Promoting axonal rewiring to improve outcome after stroke. Neurobiol Dis. 2009; 37(2):259-66. PMC: 2818530. DOI: 10.1016/j.nbd.2009.11.009. View

Stoeckel M, Binkofski F . The role of ipsilateral primary motor cortex in movement control and recovery from brain damage. Exp Neurol. 2009; 221(1):13-7. DOI: 10.1016/j.expneurol.2009.10.021. View

Jones T . Motor compensation and its effects on neural reorganization after stroke. Nat Rev Neurosci. 2017; 18(5):267-280. PMC: 6289262. DOI: 10.1038/nrn.2017.26. View

Ward N . Restoring brain function after stroke - bridging the gap between animals and humans. Nat Rev Neurol. 2017; 13(4):244-255. DOI: 10.1038/nrneurol.2017.34. View

Carmichael S, Chesselet M . Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult. J Neurosci. 2002; 22(14):6062-70. PMC: 6757933. DOI: 20026605. View

Cramer S, Shah R, Juranek J, Crafton K, Le V . Activity in the peri-infarct rim in relation to recovery from stroke. Stroke. 2005; 37(1):111-5. DOI: 10.1161/01.STR.0000195135.70379.1f. View

Lenzlinger P, Shimizu S, Marklund N, Thompson H, Schwab M, Saatman K . Delayed inhibition of Nogo-A does not alter injury-induced axonal sprouting but enhances recovery of cognitive function following experimental traumatic brain injury in rats. Neuroscience. 2005; 134(3):1047-56. DOI: 10.1016/j.neuroscience.2005.04.048. View

10.

Liu Z, Li Y, Qu R, Shen L, Gao Q, Zhang X . Axonal sprouting into the denervated spinal cord and synaptic and postsynaptic protein expression in the spinal cord after transplantation of bone marrow stromal cell in stroke rats. Brain Res. 2007; 1149:172-80. PMC: 1950288. DOI: 10.1016/j.brainres.2007.02.047. View

11.

Ueno M, Hayano Y, Nakagawa H, Yamashita T . Intraspinal rewiring of the corticospinal tract requires target-derived brain-derived neurotrophic factor and compensates lost function after brain injury. Brain. 2012; 135(Pt 4):1253-67. DOI: 10.1093/brain/aws053. View

12.

Zai L, Ferrari C, Subbaiah S, Havton L, Coppola G, Strittmatter S . Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb. J Neurosci. 2009; 29(25):8187-97. PMC: 2856695. DOI: 10.1523/JNEUROSCI.0414-09.2009. View

13.

Omoto S, Ueno M, Mochio S, Takai T, Yamashita T . Genetic deletion of paired immunoglobulin-like receptor B does not promote axonal plasticity or functional recovery after traumatic brain injury. J Neurosci. 2010; 30(39):13045-52. PMC: 6633514. DOI: 10.1523/JNEUROSCI.3228-10.2010. View

14.

Lee S, Ueno M, Yamashita T . Axonal remodeling for motor recovery after traumatic brain injury requires downregulation of γ-aminobutyric acid signaling. Cell Death Dis. 2011; 2:e133. PMC: 3101813. DOI: 10.1038/cddis.2011.16. View

15.

Tanaka T, Fujita Y, Ueno M, Shultz L, Yamashita T . Suppression of SHP-1 promotes corticospinal tract sprouting and functional recovery after brain injury. Cell Death Dis. 2013; 4:e567. PMC: 3641325. DOI: 10.1038/cddis.2013.102. View

16.

Liu Z, Zhang R, Li Y, Cui Y, Chopp M . Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice. Stroke. 2009; 40(7):2546-51. PMC: 2704262. DOI: 10.1161/STROKEAHA.109.547265. View

17.

Wu J, Grunstein M . 25 years after the nucleosome model: chromatin modifications. Trends Biochem Sci. 2000; 25(12):619-23. DOI: 10.1016/s0968-0004(00)01718-7. View

18.

Kazantsev A, Thompson L . Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov. 2008; 7(10):854-68. DOI: 10.1038/nrd2681. View

19.

de Ruijter A, van Gennip A, Caron H, Kemp S, van Kuilenburg A . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2002; 370(Pt 3):737-49. PMC: 1223209. DOI: 10.1042/BJ20021321. View

20.

Falkenberg K, Johnstone R . Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014; 13(9):673-91. DOI: 10.1038/nrd4360. View