Abstract Objective To study the regulatory mechanism of MS275, a histone deacetylase inhibitor, on the p38 MAPK signaling pathway in rats with convulsion in the developmental stage. Methods Thirty-two male rats were randomly divided into four groups: control, pentylenetetrazol (PTZ), PTZ+3 mg/kg MS275, and PTZ+6 mg/kg MS275 (n=8 each). A rat model of convulsion in the developmental stage was prepared by an intraperitoneal injection of PTZ. The rats in the control group were given an injection of normal saline alone. MS275 was given by an intraperitoneal injection at 2 hours before PTZ injection. At 24 hours after successful modeling, 6 rats were taken from each group. Western blot and qRT-PCR were used to measure the protein and mRNA expression of p38, MK2, cAMP response element-binding protein (CREB), and interleukin-6 (IL-6) in the hippocampus. Hematoxylin-eosin (HE) staining was used to observe brain pathological changes. Western blot was used to measure the expression of CD11b as a marker for the activation of microglial cells. Results Compared with the control group, the PTZ group had significant increases in the mRNA and protein expression of p38, MK2, CREB, and IL-6 (P < 0.05). MS275 significantly inhibited the mRNA and protein expression of the above markers in the rats with convulsion in the developmental stage (P < 0.05), and 6 mg/kg MS275 had a significantly better inhibitory effect on the mRNA and protein expression of IL-6 and CREB than 3 mg/kg MS275 (P < 0.05). HE staining showed that the PTZ group had marked neuron apoptosis, cellular edema, and inflammatory cell infiltration, while MS275 intervention alleviated neuron apoptosis and cellular edema and reduced inflammatory cell infiltration in the rats with convulsion. The PTZ group had a significant increase in the activation of microglial cells, while MS275 significantly inhibited the activation of microglial cells in the rats with convulsion (P < 0.05); 6 mg/kg MS275 had a significantly better inhibitory effect than 3 mg/kg MS275 (P < 0.05). Conclusions In rats with convulsion in the developmental stage, the histone deacetylase inhibitor MS275 can inhibit the p38 MAPK signaling pathway, the apoptosis of hippocampal neurons, and the activation of microglial cells and thus reduce inflammatory response and convulsion-induced brain injury in a dose-dependent manner.
PENG Fang,HU Qing-Peng,HUANG Xiang-Yi. Regulatory mechanism of MS275 on the p38 MAPK signaling pathway in rats with convulsion in the developmental stage[J]. CJCP, 2020, 22(8): 909-915.
PENG Fang,HU Qing-Peng,HUANG Xiang-Yi. Regulatory mechanism of MS275 on the p38 MAPK signaling pathway in rats with convulsion in the developmental stage[J]. CJCP, 2020, 22(8): 909-915.
Quinlan SMM, Rodriguez-Alvarez N, Molloy EJ, et al. Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia-induced seizures[J]. Sci Rep, 2018, 8(1):9986.
[2]
Zhang M, Lin JM, Li XS, et al. Quercetin ameliorates LPS-induced inflammation in human peripheral blood mononuclear cells by inhibition of the TLR2-NF-κB pathway[J]. Genet Mol Res, 2016, 15(2):gmr.15028297.
[3]
Okamoto OK, Janjoppi L, Bonone FM, et al. Whole transcriptome analysis of the hippocampus:toward a molecular portrait of epileptogenesis[J]. BMC Genomics, 2010, 11:230.
[4]
Sun H, Kennedy PJ, Nestler EJ. Epigenetics of the depressed brain:role of histone acetylation and methylation[J]. Neuropsychopharmacology, 2013, 38(1):124-137.
[5]
Kang HH, Kim IK, Lee HI, et al. Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-κB signaling pathways[J]. Biochem Biophys Res Commun, 2017, 490(2):349-355.
[6]
Dhir A. Pentylenetetrazol (PTZ) kindling model of epilepsy[J]. Curr Protoc Neurosci, 2012, 58:9.37.1-9.37.12.
[7]
Groot LJ, Gosens N, Vles JS, et al. Inter-and intraobserver agreement of seizure behavior scoring in the amygdala kindled rat[J]. Epilepsy Behav, 2015, 42:10-13.
[8]
Hao F, Jia LH, Li XW, et al. Garcinol upregulates GABAA and GAD65 expression, modulates BDNF-TrkB pathway to reduce seizures in pentylenetetrazole (PTZ)-induced epilepsy[J]. Med Sci Monit, 2016, 22:4415-4425.
[9]
Libbey JE, Hanak TJ, Doty DJ, et al. NBQX, a highly selective competitive antagonist of AMPA and KA ionotropic glutamate receptors, increases seizures and mortality following picornavirus infection[J]. Exp Neurol, 2016, 280:89-96.
[10]
Thomas T, Hitti E, Kotlyarov A, et al. MAP-kinase-activated protein kinase 2 expression and activity is induced after neuronal depolarization[J]. Eur J Neurosci, 2008, 28(4):642-654.
[11]
Zhu X, Dubey D, Bermudez C, et al. Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy[J]. Epilepsia, 2015, 56(12):1870-1878.
[12]
Mizushima H, Zhou CJ, Dohi K, et al. Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1[J]. J Comp Neurol, 2002, 448(2):203-216.
[13]
Friedman LK, Mancuso J, Patel A, et al. Transcriptome profiling of hippocampal CA1 after early-life seizure-induced preconditioning may elucidate new genetic therapies for epilepsy[J]. Eur J Neurosci, 2013, 38(1):2139-2152.
[14]
Jian M, Kwan JS, Bunting M, et al. Adiponectin suppresses amyloid-β oligomer (AβO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-κB signaling pathway[J]. J Neuroinflammation, 2019, 16(1):110.
[15]
Kim JE, Park H, Choi SH, et al. Roscovitine attenuates microglia activation and monocyte infiltration via p38 MAPK inhibition in the rat frontoparietal cortex following status epilepticus[J]. Cells, 2019, 8(7):746.
[16]
Szalay G, Martinecz B, Lénárt N, et al. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke[J]. Nat Commun, 2016, 7:11499.
