Neuroprotective effects and mechanisms of selective histone deacetylases inhibitor MS-275 on lithium-pilocarpine induced seizures in rats_Journal of Epilepsy

Authors：

 QIAOShan , HANTao , LIWenna , WANGShengjun , ZHAOXiuhe , SuLei , XUGuangrun , YANGXue , 遲兆富 ,  LIUXuewu

Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China;

Corresponding?author：

LIUXuewu, Email: snlxw1966@163.com

Keywords：

Seizures; MS-275; Histone acetylation; Hippocampus; Neuroprotection; Rats

DOI：

10.7507/2096-0247.20150008

Video：

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Objective To investigate the neuroprotective effects and mechanisms of selective histone deacetylases inhibitor MS-275 on rats after seizures. Methods A total of 75 rats were randomly divided into 5 groups for treatment:control group,pilocarpine group, treatment group Ⅰ(administered with MS-275, 20mg/kg, once a day,intraperitoneally in 7 consecutive days), treatment group Ⅱ(administered with MS-275, 40mg/kg, once a day, intraperitoneally in 7 consecutive days), MS-275 pretreatment group. We used lithium and pilocarpin to induce seizures. Behaviors of rats in each group were observed. At 72 hours after seizures, Nissl staining and immunohistochemical were respectively used to evaluate the loss of neurons and histone acetylation levels of hippocampal CA1 and CA3 regions in each group. Escape latency in the control group, treatment group Ⅰ, treatment group Ⅱ and MS-275 pretreatment group were longer than pilocarpine group(P<0.05). Results Compared with the pilocarpine group, rats in MS-275 pretreatment group could delay pilocarpine-induced seizures and reduce mortality (P<0.05). Degree of neuronal loss and degeneration in both treatment group Ⅰ and treatment group Ⅱ were reduced compared with the pilocarpine group (P<0.05) and the level of histone acetylation in hippocampal CA1 and CA3 regions of the rats were increased compared with the pilocarpine group (P<0.05). Conclusion HDACs inhibitors MS-275 can improve the neuronal damage, histone deacetylation of rats' brain and rats cognitive decline, which can exert an neuroprotective effect on rats after seizures, whose mechanism may be related to its antiinflammatory effect.

Citation： QIAOShan, HANTao, LIWenna, WANGShengjun, ZHAOXiuhe, SuLei, XUGuangrun, YANGXue, LIUXuewu. Neuroprotective effects and mechanisms of selective histone deacetylases inhibitor MS-275 on lithium-pilocarpine induced seizures in rats. Journal of Epilepsy, 2015, 1(1): 48-53. doi: 10.7507/2096-0247.20150008 Copy

1.	?Solomon L Moshé, Emilio Perucca, Philippe Ryvlin,et al. Epilepsy:new advances. Lancet, 2015, 385(9971):884-898.
2.	Lasoń W, Chlebicka M, Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharmacol Rep, 2013, 65(4):787-801.
3.	Butler KV, Kozikowski AP. Chemical origins of isoform selectivity in histone deacetylase inhibitors. Curr Pharm Des, 2008,14(6):505-528.
4.	Baltan S, Murphy SP, Danilov CA, et al. Histone deacetylase (HDAC) Inhibitors preserve white matter Structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci, 2011, 31(11):3990-3999.
5.	Rossetti F, de Araujo Furtado M, Pak T,et al. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology, 2012, 33(3):500-511.
6.	Gardian G, Browne SE, Choi DK, et al. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. Biol Chem, 2005, 280(1):556-563.
7.	Simonini MV,Camargo LM,Dong E,et al.The benzamide MS-275 is a potent,long-lasting brain region-selective inhibitor of histone deaeetylases.Proc Natl Acad Sci USA, 2006, 103(5):1587-1592.
8.	Racine RJ. Modification of seizure activity by electrical stimulation. Ⅱ. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3):281-294.
9.	Xu-WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors:molecular mechanisms of action. Oncogene, 2007, 26(37):5541-5552.
10.	Thomas EA. Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders:therapeutic implications for selective HDAC1/HDAC3 inhibitors.Pharmaceuticals (Basel), 2014, 7(6):634-661.
11.	陳剛,鄧艷春.組蛋白乙酰化與癲癇相關基因轉錄調控研究進展. 中華神經外科疾病研究雜志, 2008, 7(2):188-190.
12.	Endres M, Meisel A, Biniszkiewicz D, et al. DNA methyltransferase contributes to delayed ischemic brain injury. Neurosci, 2000, 120(9):3175-3181.
13.	Rossetti F, de Araujo Furtado M, Pak T,et al. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology, 2012, 33(3):500-511.
14.	Kosonowska E, Janeczko K, Setkowicz Z. Inflammation induced at different developmental stages affects differently the range of microglial reactivity and the course of seizures evoked in the adult rat.Epilepsy Behav, 2015,16. pii:S1525-5050(15)00242-5.
15.	Cantley MD, Fairlie DP, Bartold PM, et al. Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis. Rheumatology (Oxford), 2015, 31. pii:kev022.
16.	Zhang B, West EJ, Van KC, et al. HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats.Brain Res, 2008, 1226:181-191.

1. ?Solomon L Moshé, Emilio Perucca, Philippe Ryvlin,et al. Epilepsy:new advances. Lancet, 2015, 385(9971):884-898.
2. Lasoń W, Chlebicka M, Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharmacol Rep, 2013, 65(4):787-801.
3. Butler KV, Kozikowski AP. Chemical origins of isoform selectivity in histone deacetylase inhibitors. Curr Pharm Des, 2008,14(6):505-528.
4. Baltan S, Murphy SP, Danilov CA, et al. Histone deacetylase (HDAC) Inhibitors preserve white matter Structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci, 2011, 31(11):3990-3999.
5. Rossetti F, de Araujo Furtado M, Pak T,et al. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology, 2012, 33(3):500-511.
6. Gardian G, Browne SE, Choi DK, et al. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. Biol Chem, 2005, 280(1):556-563.
7. Simonini MV,Camargo LM,Dong E,et al.The benzamide MS-275 is a potent,long-lasting brain region-selective inhibitor of histone deaeetylases.Proc Natl Acad Sci USA, 2006, 103(5):1587-1592.
8. Racine RJ. Modification of seizure activity by electrical stimulation. Ⅱ. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3):281-294.
9. Xu-WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors:molecular mechanisms of action. Oncogene, 2007, 26(37):5541-5552.
10. Thomas EA. Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders:therapeutic implications for selective HDAC1/HDAC3 inhibitors.Pharmaceuticals (Basel), 2014, 7(6):634-661.
11. 陳剛,鄧艷春.組蛋白乙酰化與癲癇相關基因轉錄調控研究進展. 中華神經外科疾病研究雜志, 2008, 7(2):188-190.
12. Endres M, Meisel A, Biniszkiewicz D, et al. DNA methyltransferase contributes to delayed ischemic brain injury. Neurosci, 2000, 120(9):3175-3181.
13. Rossetti F, de Araujo Furtado M, Pak T,et al. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology, 2012, 33(3):500-511.
14. Kosonowska E, Janeczko K, Setkowicz Z. Inflammation induced at different developmental stages affects differently the range of microglial reactivity and the course of seizures evoked in the adult rat.Epilepsy Behav, 2015,16. pii:S1525-5050(15)00242-5.
15. Cantley MD, Fairlie DP, Bartold PM, et al. Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis. Rheumatology (Oxford), 2015, 31. pii:kev022.
16. Zhang B, West EJ, Van KC, et al. HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats.Brain Res, 2008, 1226:181-191.

Journal of Epilepsy

Neuroprotective effects and mechanisms of selective histone deacetylases inhibitor MS-275 on lithium-pilocarpine induced seizures in rats

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