Changes in Class I and IIb HDACs by δ-Opioid in Chronic Rat Glaucoma Model

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2020 Dec 2

PMID 33263714

Citations 7

Authors

Syed A H Zaidi

Wendy Guzman

Sudha Singh

Shikhar Mehrotra

Shahid Husain

Affiliations

Soon will be listed here.

Abstract

Purpose: This study determines if δ-opioid receptor agonist (i.e. SNC-121)-induced epigenetic changes via regulation of histone deacetylases (HDACs) for retinal ganglion cell (RGC) neuroprotection in glaucoma model.

Methods: Intraocular pressure was raised in rat eyes by injecting 2M hypertonic saline into the limbal veins. SNC-121 (1 mg/kg; i.p.) was administered to the animals for 7 days. Retinas were collected at days 7 and 42, post-injury followed by measurement of HDAC activities, mRNA, and protein expression by enzyme assay, quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry.

Results: The visual acuity, contrast sensitivity, and pattern electroretinograms (ERGs) were declined in ocular hypertensive animals, which were significantly improved by SNC-121 treatment. Class I and IIb HDACs activities were significantly increased at days 7 and 42 in ocular hypertensive animals. The mRNA and protein expression of HDAC 1 was increased by 1.33 ± 0.07-fold and 20.2 ± 2.7%, HDAC 2 by 1.4 ± 0.05-fold and 17.0 ± 2.4%, HDAC 3 by 1.4 ± 0.06-fold and 17.4 ± 3.4%, and HDAC 6 by 1.5 ± 0.09-fold and 15.1 ± 3.3% at day 7, post-injury. Both the mRNA and protein expression of HDACs were potentiated further at day 42 in ocular hypertensive animals. HDAC activities, mRNA, and protein expression were blocked by SNC-121 treatment at days 7 and 42 in ocular hypertensive animals.

Conclusions: Data suggests that class I and IIb HDACs are activated and upregulated during early stages of glaucoma. Early intervention with δ-opioid receptor activation resulted in the prolonged suppression of class I and IIb HDACs activities and expression, which may, in part, play a crucial role in RGC neuroprotection.

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References

Akhter N, Nix M, Abdul Y, Singh S, Husain S . Delta-opioid receptors attenuate TNF-α-induced MMP-2 secretion from human ONH astrocytes. Invest Ophthalmol Vis Sci. 2013; 54(10):6605-11. PMC: 3803137. DOI: 10.1167/iovs.13-12196. View

Wang Z, Zang C, Cui K, Schones D, Barski A, Peng W . Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell. 2009; 138(5):1019-31. PMC: 2750862. DOI: 10.1016/j.cell.2009.06.049. View

Vajaranant T, Nayak S, Wilensky J, Joslin C . Gender and glaucoma: what we know and what we need to know. Curr Opin Ophthalmol. 2010; 21(2):91-9. PMC: 4326058. DOI: 10.1097/ICU.0b013e3283360b7e. View

Kim H, Rowe M, Ren M, Hong J, Chen P, Chuang D . 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(3):892-901. DOI: 10.1124/jpet.107.120188. View

Boland M, Quigley H . Risk factors and open-angle glaucoma: classification and application. J Glaucoma. 2007; 16(4):406-18. DOI: 10.1097/IJG.0b013e31806540a1. View

Rawal S, Munasinghe P, Thevkar Nagesh P, Lew J, Jones G, Williams M . Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart. Clin Sci (Lond). 2017; 131(9):847-863. DOI: 10.1042/CS20160916. View

Sung M, Heo H, Eom G, Kim S, Piao H, Guo Y . HDAC2 Regulates Glial Cell Activation in Ischemic Mouse Retina. Int J Mol Sci. 2019; 20(20). PMC: 6829428. DOI: 10.3390/ijms20205159. View

Rivieccio M, Brochier C, Willis D, Walker B, DAnnibale M, McLaughlin K . HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci U S A. 2009; 106(46):19599-604. PMC: 2780768. DOI: 10.1073/pnas.0907935106. View

Biermann J, Grieshaber P, Goebel U, Martin G, Thanos S, Di Giovanni S . Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells. Invest Ophthalmol Vis Sci. 2009; 51(1):526-34. DOI: 10.1167/iovs.09-3903. View

10.

Alkozi H, Franco R, Pintor J . Epigenetics in the Eye: An Overview of the Most Relevant Ocular Diseases. Front Genet. 2017; 8:144. PMC: 5643502. DOI: 10.3389/fgene.2017.00144. View

11.

Husain S, Liou G, Crosson C . Opioid receptor activation: suppression of ischemia/reperfusion-induced production of TNF-α in the retina. Invest Ophthalmol Vis Sci. 2011; 52(5):2577-83. PMC: 3088550. DOI: 10.1167/iovs.10-5629. View

12.

Pelzel H, Schlamp C, Waclawski M, Shaw M, Nickells R . Silencing of Fem1cR3 gene expression in the DBA/2J mouse precedes retinal ganglion cell death and is associated with histone deacetylase activity. Invest Ophthalmol Vis Sci. 2012; 53(3):1428-35. PMC: 3339913. DOI: 10.1167/iovs.11-8872. View

13.

Schmitt H, Pelzel H, Schlamp C, Nickells R . Histone deacetylase 3 (HDAC3) plays an important role in retinal ganglion cell death after acute optic nerve injury. Mol Neurodegener. 2014; 9:39. PMC: 4190472. DOI: 10.1186/1750-1326-9-39. View

14.

Zaidi S, Thakore N, Singh S, Guzman W, Mehrotra S, Gangaraju V . Histone Deacetylases Regulation by δ-Opioids in Human Optic Nerve Head Astrocytes. Invest Ophthalmol Vis Sci. 2020; 61(11):17. PMC: 7488628. DOI: 10.1167/iovs.61.11.17. View

15.

Husain S . Delta Opioids: Neuroprotective Roles in Preclinical Studies. J Ocul Pharmacol Ther. 2018; 34(1-2):119-128. PMC: 5963634. DOI: 10.1089/jop.2017.0039. View

16.

Seidel C, Schnekenburger M, Dicato M, Diederich M . Histone deacetylase 6 in health and disease. Epigenomics. 2015; 7(1):103-18. DOI: 10.2217/epi.14.69. View

17.

Husain S, Abdul Y, Potter D . Non-analgesic effects of opioids: neuroprotection in the retina. Curr Pharm Des. 2012; 18(37):6101-8. DOI: 10.2174/138161212803582441. View

18.

Saha R, Pahan K . HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ. 2005; 13(4):539-50. PMC: 1963416. DOI: 10.1038/sj.cdd.4401769. View

19.

Lebrun-Julien F, Suter U . Combined HDAC1 and HDAC2 Depletion Promotes Retinal Ganglion Cell Survival After Injury Through Reduction of p53 Target Gene Expression. ASN Neuro. 2015; 7(3). PMC: 4720215. DOI: 10.1177/1759091415593066. View

20.

Pili R, Quinn D, Hammers H, Monk P, George S, Dorff T . Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870). Clin Cancer Res. 2017; 23(23):7199-7208. PMC: 5712266. DOI: 10.1158/1078-0432.CCR-17-1178. View