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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats

Authors: Min Jung Park, Farida Sohrabji

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Sodium butyrate (NaB) is a histone deacetylase (HDAC) inhibitor exhibiting anti-inflammatory and neuroprotective effects in a rat ischemic model of stroke as well as a myocardial ischemia model. Although clinical evidence shows that older women are at higher risk for stroke occurrence and greater stroke severity, no studies have evaluated the effectiveness of NaB either in females or in older animals.

Methods

To determine the effects of NaB on stroke in older females, acyclic middle-aged Sprague-Dawley female rats (9–11 months old, constant diestrus) were subject to middle cerebral artery occlusion (MCAo) by intracerebral injection of recombinant endothelin-1. Rats were treated with NaB (300 mg/kg, i.p.) at 6 and 30 h following ET-1 injection. Animals were sacrificed at the early (2 days) or late (5 days) acute phase after MCAo. Serum and tissue lysates were collected for biochemical analyses.

Results

NaB treatment reduced infarct volume and ameliorated sensory motor impairment in middle-aged female rats, when measured at 2 and 5 days post MCAo. At the early acute phase (2 days post stroke), NaB treatment decreased brain lipid peroxides, and reduced serum levels of GFAP, a surrogate marker of blood-brain barrier (BBB) permeability. NaB also reduced expression of the inflammatory cytokine IL-1beta in circulation and IL-18 in the ischemic hemisphere. At the late acute phase (5 days post stroke), NaB treatment further suppressed MCAo-induced increase of IL-1beta, IL-17A, and IL-18 in brain lysates (cortex and striatum) from the ischemic hemisphere, and decreased ischemia-induced upregulation of IL-1beta and IL-18 in circulation, indicating a potent anti-inflammatory effect of the HDAC inhibitor. Moreover, NaB treatment also increased expression of IGF-1, a known neuroprotectant, in peripheral tissue including serum, liver, and spleen at the late acute phase.

Conclusions

These data provide the first evidence that delayed (>6 h) NaB treatment post-stroke is neuroprotective in older female rats. Additionally, these data also show that in addition to its well-known anti-inflammatory actions, NaB may exert a biphasic effect after stroke, operating initially to reduce BBB permeability and oxidative stress in the brain, and later, elevating IGF-1 expression in peripheral tissues.
Literature
1.
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres J-P, Fullerton HJ, Howard VJ. Heart disease and stroke statistics-2015 update: a report from the American heart association. Circulation. 2015;131:e29.CrossRefPubMed
2.
Andersen KK, Andersen ZJ, Olsen TS. Age- and gender-specific prevalence of cardiovascular risk factors in 40,102 patients with first-ever ischemic stroke: a nationwide Danish Study. Stroke. 2010;41:2768–74.CrossRefPubMed
3.
Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7:915–26.CrossRefPubMedPubMedCentral
4.
5.
Selvamani A, Sohrabji F. Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiol Aging. 2010;31:1618–28.CrossRefPubMed
6.
7.
8.
Butler R, Bates GP. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci. 2006;7:784–96.CrossRefPubMed
9.
Kim HJ, Chuang D-M. HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am J Transl Res. 2014;6:206.PubMedPubMedCentral
10.
Wang Z, Leng Y, Tsai LK, Leeds P, Chuang DM. Valproic acid attenuates blood-brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition. J Cereb Blood Flow Metab. 2011;31:52–7.CrossRefPubMed
11.
12.
Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW, Chuang DM, Hong JS. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience. 2007;149:203–12.CrossRefPubMedPubMedCentral
13.
Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther. 2007;321:892–901.CrossRefPubMed
14.
Bourassa MW, Alim I, Bultman SJ, Ratan RR. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health? Neurosci Lett. 2016;625:56–63.CrossRefPubMed
15.
Lakhan SE, Kirchgessner A, Tepper D, Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol. 2013;4:32.PubMedPubMedCentral
16.
Jickling GC, Liu D, Stamova B, Ander BP, Zhan X, Lu A, Sharp FR. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab. 2014;34:185–99.CrossRefPubMed
17.
Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26:248–54.CrossRefPubMed
18.
Candelario-Jalil E. Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics. Curr Opin Investig Drugs. 2009;10:644–54.PubMed
19.
Chisholm NC, Henderson ML, Selvamani A, Park MJ, Dindot S, Miranda RC, Sohrabji F. Histone methylation patterns in astrocytes are influenced by age following ischemia. Epigenetics. 2015;10:142–52.CrossRefPubMedPubMedCentral
20.
Selvamani A, Sohrabji F. The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1. J Neurosci. 2010;30:6852–61.CrossRefPubMedPubMedCentral
21.
Balden R, Selvamani A, Sohrabji F. Vitamin D deficiency exacerbates experimental stroke injury and dysregulates ischemia-induced inflammation in adult rats. Endocrinology. 2012;153:2420–35.CrossRefPubMedPubMedCentral
22.
Bake S, Selvamani A, Cherry J, Sohrabji F. Blood brain barrier and neuroinflammation are critical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats. PLoS One. 2014;9:e91427.CrossRefPubMedPubMedCentral
23.
Chollet F, DiPiero V, Wise R, Brooks D, Dolan R, Frackowiak R. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol. 1991;29:63–71.CrossRefPubMed
24.
Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology. 2000;39:777–87.CrossRefPubMed
25.
Nylén K, Csajbok LZ, Öst M, Rashid A, Blennow K, Nellgård B, Rosengren L. Serum glial fibrillary acidic protein is related to focal brain injury and outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:1489–94.CrossRefPubMed
26.
Ren C, Kobeissy F, Alawieh A, Li N, Li N, Zibara K, Zoltewicz S, Guingab-Cagmat J, Larner SF, Ding Y: Assessment of serum UCH-L1 and GFAP in acute stroke patients. Scientific Reports. 2016;6:24588.
27.
Lumpkins KM, Bochicchio GV, Keledjian K, Simard JM, McCunn M, Scalea T. Glial fibrillary acidic protein is highly correlated with brain injury. J Trauma Acute Care Surg. 2008;65:778–84.CrossRef
28.
Sharma B, Singh N. Attenuation of vascular dementia by sodium butyrate in streptozotocin diabetic rats. Psychopharmacology (Berl). 2011;215:677–87.CrossRef
29.
Steckert AV, Valvassori SS, Varela RB, Mina F, Resende WR, Bavaresco DV, Ornell F, Dal-Pizzol F, Quevedo J. Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of D-AMPH. Neurochem Int. 2013;62:425–32.CrossRefPubMed
30.
Berni Canani R, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clin Epigenetics. 2012;4:4.CrossRefPubMedPubMedCentral
31.
Canani RB, Costanzo MD, Leone L, Pedata M, Meli R, Calignano A. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17:1519–28.CrossRefPubMedPubMedCentral
32.
Yagi K: Simple assay for the level of total lipid peroxides in serum or plasma. Free radical and antioxidant protocols 1998;108:101-6.
33.
Armstrong D, Browne R: The analysis of free radicals, lipid peroxides, antioxidant enzymes and compounds related to oxidative stress as applied to the clinical chemistry laboratory. In Free radicals in diagnostic medicine. Springer; 1994;366:43-58.
34.
Tsubaki J, Choi WK, Ingermann AR, Twigg SM, Kim HS, Rosenfeld RG, Oh Y. Effects of sodium butyrate on expression of members of the IGF-binding protein superfamily in human mammary epithelial cells. J Endocrinol. 2001;169:97–110.CrossRefPubMed
35.
Walker GE, Wilson EM, Powell D, Oh Y. Butyrate, a histone deacetylase inhibitor, activates the human IGF binding protein-3 promoter in breast cancer cells: molecular mechanism involves an Sp1/Sp3 multiprotein complex. Endocrinology. 2001;142:3817–27.CrossRefPubMed
36.
Li S, Overman JJ, Katsman D, Kozlov SV, Donnelly CJ, Twiss JL, Giger RJ, Coppola G, Geschwind DH, Carmichael ST. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat Neurosci. 2010;13:1496–504.CrossRefPubMedPubMedCentral
37.
Sohrabji F: Estrogen-IGF-1 interactions in neuroprotection: ischemic stroke as a case study. Front Neuroendocrinol. 2014;36:1-14.
38.
Sohrabji F, Williams M. Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia. J Neuroendocrinol. 2013;25:1173–81.CrossRefPubMed
39.
40.
Fessler EB, Chibane FL, Wang Z, Chuang DM. Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. Curr Pharm Des. 2013;19:5105–20.CrossRefPubMed
41.
Sun J, Wang F, Li H, Zhang H, Jin J, Chen W, Pang M, Yu J, He Y, Liu J, Liu C. Neuroprotective effect of sodium butyrate against cerebral ischemia/reperfusion injury in mice. Biomed Res Int. 2015;2015:395895.PubMedPubMedCentral
42.
Gibson CL, Murphy SP. Benefits of histone deacetylase inhibitors for acute brain injury: a systematic review of animal studies. J Neurochem. 2010;115:806–13.CrossRefPubMedPubMedCentral
43.
44.
Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946–50.CrossRefPubMed
45.
Bake S, Okoreeh AK, Alaniz RC, Sohrabji F. Insulin-like growth factor (IGF)-I modulates endothelial blood-brain barrier function in ischemic middle-aged female rats. Endocrinology. 2016;157:61–9.CrossRefPubMed
46.
Lewis DK, Bake S, Thomas K, Jezierski MK, Sohrabji F. A high cholesterol diet elevates hippocampal cytokine expression in an age and estrogen-dependent manner in female rats. J Neuroimmunol. 2010;223:31–8.CrossRefPubMedPubMedCentral
47.
Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26:654–65.CrossRefPubMed
48.
Offner H, Vandenbark AA, Hurn PD. Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience. 2009;158:1098–111.CrossRefPubMed
49.
Yuen CM, Chiu CA, Chang LT, Liou CW, Lu CH, Youssef AA, Yip HK. Level and value of interleukin-18 after acute ischemic stroke. Circ J. 2007;71:1691–6.CrossRefPubMed
50.
Zaremba J, Losy J. Interleukin-18 in acute ischaemic stroke patients. Neurol Sci. 2003;24:117–24.CrossRefPubMed
51.
Oh SH, Kim OJ, Shin DA, Song J, Yoo H, Kim YK, Kim JK. Alteration of immunologic responses on peripheral blood in the acute phase of ischemic stroke: blood genomic profiling study. J Neuroimmunol. 2012;249:60–5.CrossRefPubMed
52.
Dinarello CA. IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol. 1999;103:11–24.CrossRefPubMed
53.
Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. 2001;12:53–72.CrossRefPubMed
54.
55.
Conti B, Park LC, Calingasan NY, Kim Y, Kim H, Bae Y, Gibson GE, Joh TH. Cultures of astrocytes and microglia express interleukin 18. Brain Res Mol Brain Res. 1999;67:46–52.CrossRefPubMed
56.
Sugama S, Cho BP, Baker H, Joh TH, Lucero J, Conti B. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS. Brain Res. 2002;958:1–9.CrossRefPubMed
57.
Koyama N, Koschmieder S, Tyagi S, Nurnberger H, Wagner S, Bocker U, Hoelzer D, Gerhard Ottmann O, Kalina U. Differential effects of histone deacetylase inhibitors on interleukin-18 gene expression in myeloid cells. Biochem Biophys Res Commun. 2002;292:937–43.CrossRefPubMed
58.
Glauben R, Sonnenberg E, Wetzel M, Mascagni P, Siegmund B. Histone deacetylase inhibitors modulate interleukin 6-dependent CD4+ T cell polarization in vitro and in vivo. J Biol Chem. 2014;289:6142–51.CrossRefPubMedPubMedCentral
59.
Kim SW, Hooker JM, Otto N, Win K, Muench L, Shea C, Carter P, King P, Reid AE, Volkow ND, Fowler JS. Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET. Nucl Med Biol. 2013;40:912–8.CrossRefPubMedPubMedCentral
60.
Manwani B, Liu F, Scranton V, Hammond MD, Sansing LH, McCullough LD. Differential effects of aging and sex on stroke induced inflammation across the lifespan. Exp Neurol. 2013;249:120–31.CrossRefPubMed
61.
Zhang B, Subramanian S, Dziennis S, Jia J, Uchida M, Akiyoshi K, Migliati E, Lewis AD, Vandenbark AA, Offner H, Hurn PD. Estradiol and G1 reduce infarct size and improve immunosuppression after experimental stroke. J Immunol. 2010;184:4087–94.CrossRefPubMedPubMedCentral
Metadata
Title
The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats
Authors
Min Jung Park
Farida Sohrabji
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0765-6

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