Abstract：Objective To investigate the protective effect of histone acetylation against hypoxic-ischemic cortical injury in neonatal rats. Methods A total of 90 neonatal rats aged 3 days were divided into three groups: sham-operation, cortical injury model, and sodium butyrate (a histone deacetylase inhibitor) treatment. The rats in the model and the sodium butyrate treatment groups were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg), and then right common carotid artery ligation was performed 2 hours later and the rats were put in a hypoxic chamber (oxygen concentration 6.5%) for 90 minutes. The rats in the sham-operation group were intraperitoneally injected with normal saline and the right common carotid artery was only separated and exposed without ligation or hypoxic treatment. The rats in the sodium butyrate treatment group were intraperitoneally injected with sodium butyrate (300 mg/kg) immediately after establishment of the cortical injury model once a day for 7 days. Those in the sham-operation and the model groups were injected with the same volume of normal saline. At 7 days after establishment of the model, Western blot was used to measure the protein expression of histone H3 (HH3), acetylated histone H3 (AH3), B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (BAX), cleaved caspase-3 (CC3), and brain-derived neurotrophic factor (BDNF). Immunofluorescence assay was used to measure the expression of 5-bromo-2'-deoxyuridine (BrdU) as the cortex cell proliferation index. Results The sodium butyrate treatment group had a significantly lower HH3/AH3 ratio than the model group (P < 0.05), which suggested that the sodium butyrate treatment group had increased acetylation of HH3. Compared with the model group, the sodium butyrate treatment group had a significant increase in Bcl-2/Bax ratio, a significant reduction in CC3 expression, and a significant increase in BDNF expression (P < 0.05). The sodium butyrate treatment group had a significant increase in the number of BrdU-positive cells in the cortex compared with the model group (P < 0.05), and BrdU was mainly expressed in the neurons. Conclusions Increased histone acetylation may protect neonatal rats against cortical injury by reducing apoptosis and promoting regeneration of neurons. The mechanism may be associated with increased expression of BDNF.
Volpe JJ. Brain injury in the premature infant:overview of clinical aspects, neuropathology, and pathogenesis[J]. Semin Pediatr Neurol, 1998, 5(3):135-151.
[2]
Eaton-Rosen Z, Melbourne A, Orasanu E, et al. Longitudinal measurement of the developing grey matter in preterm subjects using multi-modal MRI[J]. Neuroimage, 2015, 111:580-589.
[3]
Zhang H, Shang YP, Chen HY, et al. Histone deacetylases function as novel potential therapeutic target for cancer[J]. Hepatol Res, 2016.[Epub ahead of print].
[4]
Wang ZF, Fessler EB, Chuang DM. Beneficial effects of mood stabilizers lithium, valproate and lamotrigine in experimental stroke models[J]. Acta Pharmacol Sin, 2011, 32(12):1433-1445.
[5]
Shein NA, Shohami E. Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries[J]. Mol Med, 2011, 17(5-6):448-456.
[6]
Chuang DM, Leng Y, Marinova Z, et al. Multiple roles of HDAC inhibition in neurodegenerative conditions[J]. Trends Neurosci, 2009, 32(11):591-601.
[7]
Langley B, Brochier C, Rivieccio MA. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke[J]. Stroke, 2009, 40(8):2899-2905.
[8]
Ziemka-Nalecz M, Zalewska T. Neuroprotective effects of histone deacetylase inhibitors in brain ischemia[J]. Acta Neurobiol Exp (Wars), 2014, 74(4):383-395.
[9]
Volpe JJ, Kinney HC, Jensen FE, et al. The developing oligodendrocyte:key cellular target in brain injury in the premature infant[J]. Int J Dev Neurosci, 2011, 29(4):423-440.
[10]
Vincer MJ, Allen AC, Allen VM, et al. Trends in the prevalence of cerebral palsy among very preterm infants (< 31 weeks' gestational age)[J]. Paediatr Child Health, 2014, 19(4):185-189.
[11]
Chenouard A, Gascoin G, Gras-Le Guen C, et al. Neurodevelop-mental impairment in preterm infants with late-onset infection:not only in extremely preterm infants[J]. Eur J Pediatr, 2014, 173(8):1017-1023.
[12]
Yang D, Sun YY, Lin X, et al. Taming neonatal hypoxic-ischemic brain injury by intranasal delivery of plasminogen activator inhibitor-1[J]. Stroke, 2013, 44(9):2623-2627.
[13]
Wang X, Svedin P, Nie C, et al. N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury[J]. Ann Neurol, 2007, 61(3):263-271.
[14]
Dean JM, Moravec MD, Grafe M, et al. Strain-specific differences in perinatal rodent oligodendrocyte lineage progression and its correlation with human[J]. Dev Neurosci, 2011, 33(3-4):251-260.
[15]
Wang LW, Chang YC, Lin CY, et al. Low-dose lipopolysac-charide selectively sensitizes hypoxic ischemia-induced white matter injury in the immature brain[J]. Pediatr Res, 2010, 68(1):41-47.
[16]
Fessler EB, Chibane FL, Wang Z, et al. Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery[J]. Curr Pharm Des, 2013, 19(28):5105-5120.
[17]
Yang PM, Tseng HH, Peng CW, et al. Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy[J]. Int J Oncol, 2012, 40(2):469-478.
Siddiqui WA, Ahad A, Ahsan H. The mystery of BCL2 family:Bcl-2 proteins and apoptosis:an update[J]. Arch Toxicol, 2015, 89(3):289-317.
[20]
Kim G, Kim E. The effects of antecedent exercise on motor function recovery and brain-derived neurotrophic factor expression after focal cerebral ischemia in rats[J]. J Phys Ther Sci, 2013, 25(5):553-556.
[21]
Wang NQ, Wang LY, Zhao HP, et al. Luoyutong treatment promotes functional recovery and neuronal plasticity after cerebral ischemia-reperfusion injury in rats[J]. Evid Based Complement Alternat Med, 2015, 2015:369021.
[22]
Kim HJ, Leeds P, Chuang DM. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain[J]. J Neurochem, 2009, 110(4):1226-1240.
[23]
Heiser JH, Schuwald AM, Sillani G, et al. TRPC6 channel-mediated neurite outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI3K, and CAMKIV signaling[J]. J Neurochem, 2013, 127(3):303-313.
