Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Pharmacokinetics and Acute Toxicity of a Histone Deacetylase Inhibitor, Scriptaid, and its Neuroprotective Effects in Mice After Intracranial Hemorrhage

Author(s): Heng Yang, Xinjie Gao, Jiabin Su, Hanqiang Jiang, Yu Lei, Wei Ni* and Yuxiang Gu*

Volume 19, Issue 1, 2020

Page: [55 - 65] Pages: 11

DOI: 10.2174/1871527319666191220111126

Price: $65

Abstract

Background & Objective: The pharmacokinetics and acute toxicity of a histone deacetylase inhibitor, Scriptaid, was unknown in the mouse. The aim of this study was to determine the pharmacokinetics, acute toxicity, and tissue distribution of Scriptaid, a new histone deacetylase inhibitor, in mice, and its neuroprotective efficacy in a mouse intracranial hemorrhage (ICH) model.

Methods: The pharmacokinetics, acute toxicity, and tissue distribution were determined in C57BL/6 male and female mice after the intraperitoneal administration of a single dose. Behavioral tests, as well as investigations of brain atrophy and white matter injury, were used to evaluate the neuroprotective effect of Scriptaid after ICH. Western blotting was used to investigate if Scriptaid could offer antiinflammatory benefits after ICH.

Results: No significant differences were observed in body weight or brain histopathology between the group that received Scriptaid at 50 mg/kg and the group that received dimethyl sulfoxide (control). The pharmacokinetics of Scriptaid in mice was nonlinear, and it was cleared rapidly at low doses and slowly at higher doses. Consistent with the pharmacokinetic data, Scriptaid was found to distribute in several tissues, including the spleen and kidneys. In the ICH model, we found that Scriptaid could reduce neurological deficits, brain atrophy, and white matter injury in a dose-dependent manner. Western blotting results demonstrated that Scriptaid could decrease the expression of pro-inflammatory cytokines IL1β and TNFα, as well as iNOS, after ICH.

Conclusion: These findings indicate that Scriptaid is safe and can alleviate brain injury after ICH, thereby providing a foundation for the pharmacological action of Scriptaid in the treatment of brain injury after ICH.

Keywords: Scriptaid, pharmacokinetics, toxicology, tissue distribution, ICH, neuroprotection.

« Previous Next »
Graphical Abstract

[1]
Pietrocola, F.; Galluzzi, L.; Bravo-San Pedro, J.M.; Madeo, F.; Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab., 2015, 21(6), 805-821.
[http://dx.doi.org/10.1016/j.cmet.2015.05.014] [PMID: 26039447]
[2]
Hahnen, E.; Hauke, J.; Tränkle, C.; Eyüpoglu, I.Y.; Wirth, B.; Blümcke, I. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin. Investig. Drugs, 2008, 17(2), 169-184.
[http://dx.doi.org/10.1517/13543784.17.2.169] [PMID: 18230051]
[3]
Marks, P.; Rifkind, R.A.; Richon, V.M.; Breslow, R.; Miller, T.; Kelly, W.K. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer, 2001, 1(3), 194-202.
[http://dx.doi.org/10.1038/35106079] [PMID: 11902574]
[4]
Dokmanovic, M.; Clarke, C.; Marks, P.A. Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res., 2007, 5(10), 981-989.
[http://dx.doi.org/10.1158/1541-7786.MCR-07-0324] [PMID: 17951399]
[5]
Blanchard, F.; Chipoy, C. Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov. Today, 2005, 10(3), 197-204.
[http://dx.doi.org/10.1016/S1359-6446(04)03309-4] [PMID: 15708534]
[6]
Gupta, KD.; Shakespear, M.R.; Iyer, A.; Fairlie, D.P.; Sweet, M.J. Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases. Clin. Transl. Immunology, 2016, 5(1)e62
[http://dx.doi.org/10.1038/cti.2015.46] [PMID: 26900475]
[7]
Adcock, I.M. HDAC inhibitors as anti-inflammatory agents. Br. J. Pharmacol., 2007, 150(7), 829-831.
[http://dx.doi.org/10.1038/sj.bjp.0707166] [PMID: 17325655]
[8]
Sukumari-Ramesh, S.; Alleyne, C.H., Jr; Dhandapani, K.M. The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) confers acute neuroprotection after intracerebral hemorrhage in mice. Transl. Stroke Res., 2016, 7(2), 141-8.
[http://dx.doi.org/10.1007/s12975-015-0421-y] [PMID: 26338677]
[9]
Wang, G.; Shi, Y.; Jiang, X. HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. Proc. Natl. Acad. Sci. USA, 2015, 112(9), 2853-8.
[http://dx.doi.org/10.1073/pnas.1501441112] [PMID: 25691750]
[10]
Takai, N.; Ueda, T.; Nishida, M.; Nasu, K.; Narahara, H. A novel histone deacetylase inhibitor, Scriptaid, induces growth inhibition, cell cycle arrest and apoptosis in human endometrial cancer and ovarian cancer cells. Int. J. Mol. Med., 2006, 17(2), 323-329.
[http://dx.doi.org/10.3892/ijmm.17.2.323] [PMID: 16391833]
[11]
Keen, J.C.; Yan, L.; Mack, K.M. A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine. Breast Cancer Res. Treat., 2003, 81(3), 177-86.
[http://dx.doi.org/10.1023/A:1026146524737] [PMID: 14620913]
[12]
Giacinti, L.; Giacinti, C.; Gabellini, C.; Rizzuto, E.; Lopez, M.; Giordano, A. Scriptaid effects on breast cancer cell lines. J. Cell. Physiol., 2012, 227(10), 3426-33.
[http://dx.doi.org/10.1002/jcp.24043] [PMID: 22213035]
[13]
Sharma, V.; Koul, N.; Joseph, C.; Dixit, D.; Ghosh, S.; Sen, E. HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J. Cell. Mol. Med., 2010, 14(8), 2151-61.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00844.x] [PMID: 19583803]
[14]
Wang, G.; Jiang, X.; Pu, H. Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic brain injury via modulation of PTEN and AKT pathway : scriptaid protects against TBI via AKT. Neurotherapeutics, 2013, 10(1), 124-42.
[http://dx.doi.org/10.1007/s13311-012-0157-2] [PMID: 23132328]
[15]
Ghio, L.; Gotelli, S.; Cervetti, A. Duration of untreated depression influences clinical outcomes and disability. J. Affect. Disord., 2015, 175, 224-228.
[http://dx.doi.org/10.1016/j.jad.2015.01.014] [PMID: 25658495]
[16]
Bliss, C.I. The determination of dosage mortality curve from small numbers. J. Pharm. Pharmacol., 1938, 11(2), 192-216.
[17]
Ma, B.; Zhang, Q.; Wang, G. Synthesis and pharmacokinetics of strontium fructose 1,6-diphosphate (Sr-FDP) as a potential anti-osteoporosis agent in intact and ovariectomized rats. J. Inorg. Biochem., 2011, 105(4), 563-8.
[http://dx.doi.org/10.1016/j.jinorgbio.2011.01.001] [PMID: 21345324]
[18]
Ni, W.; Mao, S.; Xi, G.; Keep, R.F.; Hua, Y. Role of erythrocyte CD47 in intracerebral hematoma clearance. Stroke, 2016, 47(2), 505-511.
[http://dx.doi.org/10.1161/STROKEAHA.115.010920] [PMID: 26732568]
[19]
Hua, Y.; Schallert, T.; Keep, R.F.; Wu, J.; Hoff, J.T.; Xi, G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke, 2002, 33(10), 2478-2484.
[http://dx.doi.org/10.1161/01.STR.0000032302.91894.0F] [PMID: 12364741]
[20]
Wang, G.; Zhang, J.; Hu, X. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J. Cereb. Blood Flow Metab., 2013, 33(12), 1864-74.
[http://dx.doi.org/10.1038/jcbfm.2013.146] [PMID: 23942366]
[21]
Hou, X.; He, C.; Jin, Q.; Niu, Q.; Ren, G.; Cheng, H. Novel mutation of the NOTCH3 gene in a Chinese Pedigree with CADASIL. CNS Neurol. Disord. Drug Targets, 2017, 16(1), 30-35.
[http://dx.doi.org/10.2174/1871527315666161024125952] [PMID: 27781952]
[22]
Babu, R.; Bagley, J.H.; Di, C.; Friedman, A.H.; Adamson, C. Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg. Focus, 2012, 32(4)E8
[http://dx.doi.org/10.3171/2012.1.FOCUS11366] [PMID: 22463118]
[23]
Rajdev, K.; Mehan, S. Neuroprotective methodologies of Co-enzyme Q10 associated mitochondrial dysfunction in post brain hemorrhagic treatment: clinical and pre-clinical findings. CNS Neurol. Disord. Drug Targets, 2019, 18(6), 446-465.
[http://dx.doi.org/10.2174/1871527318666190610101144]
[24]
Li, L.; Wang, P.; Zhao, H.; Luo, Y. Noncoding RNAs and intracerebral hemorrhage. CNS Neurol. Disord. Drug Targets, 2019, 18(3), 205-11.
[http://dx.doi.org/10.2174/1871527318666190204102604] [PMID: 30714535]
[25]
Qu, S.; Liu, W.; Yang, H. Analysis of adverse events related to 720 cases of neural progenitor cell transplantation. CNS Neurol. Disord. Drug Targets, 2017, 16(2), 210-6.
[http://dx.doi.org/10.2174/1871527315666161207160258] [PMID: 27928951]
[26]
Yang, H.; Ni, W.; Jiang, H. Histone deacetylase inhibitor scriptaid alleviated neurological dysfunction after experimental intracerebral hemorrhage in mice. Behav. Neurol., 2018, 20186583267
[http://dx.doi.org/10.1155/2018/6583267] [PMID: 30159100]
[27]
Sinn, D.I.; Kim, S.J.; Chu, K. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol. Dis., 2007, 26(2), 464-72.
[http://dx.doi.org/10.1016/j.nbd.2007.02.006] [PMID: 17398106]
[28]
Baltan, S.; Morrison, R.S.; Murphy, S.P. Novel protective effects of histone deacetylase inhibition on stroke and white matter ischemic injury. Neurotherapeutics, 2013, 10(4), 798-807.
[http://dx.doi.org/10.1007/s13311-013-0201-x] [PMID: 23881453]
[29]
Liu, X.S.; Chopp, M.; Kassis, H. Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience, 2012, 220, 313-21.
[http://dx.doi.org/10.1016/j.neuroscience.2012.06.012] [PMID: 22704966]
[30]
Keep, R.F.; Hua, Y.; Xi, G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol., 2012, 11(8), 720-731.
[http://dx.doi.org/10.1016/S1474-4422(12)70104-7] [PMID: 22698888]
[31]
Wang, J.; Doré, S. Inflammation after intracerebral hemorrhage. J. Cereb. Blood Flow Metab., 2007, 27(5), 894-908.
[http://dx.doi.org/10.1038/sj.jcbfm.9600403] [PMID: 17033693]
[32]
Wang, J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog. Neurobiol., 2010, 92(4), 463-477.
[http://dx.doi.org/10.1016/j.pneurobio.2010.08.001] [PMID: 20713126]
[33]
Shakespear, M.R.; Hohenhaus, D.M.; Kelly, G.M. Histone deacetylase 7 promotes Toll-like receptor 4-dependent proinflammatory gene expression in macrophages. J. Biol. Chem., 2013, 288(35), 25362-74.
[http://dx.doi.org/10.1074/jbc.M113.496281] [PMID: 23853092]

Rights & Permissions Print Cite
Article Metrics
31
2
© 2024 Bentham Science Publishers | Privacy Policy