Histone Deacetylases Regulation by δ-Opioids in Human Optic Nerve Head Astrocytes

Invest Ophthalmol Vis Sci. 2020 Sep 1;61(11):17. doi: 10.1167/iovs.61.11.17.


Purpose: We determined whether δ-opioid receptor agonist (SNC-121) regulates acetylation homeostasis via controlling histone deacetylases (HDACs) activity and expression in optic nerve head (ONH) astrocytes.

Methods: ONH astrocytes were treated with SNC-121 (1 µM) for 24 hours. The HDAC activity was measured using HDAC-specific fluorophore-conjugated synthetic substrates, Boc-Lys(Ac)-AMC and (Boc-Lys(Tfa)-AMC). Protein and mRNA expression of each HDAC was determined by Western blotting and quantitative real-time PCR. IOP in rats was elevated by injecting 2.0 M hypertonic saline into the limbal veins.

Results: Delta opioid receptor agonist, SNC-121 (1 µM), treatment increased acetylation of histone H3, H2B, and H4 by 128 ± 3%, 45 ± 1%, and 68 ± 2%, respectively. The addition of Garcinol, a histone-acetyltransferase inhibitor, fully blocked SNC-121-induced histone H3 acetylation. SNC-121 reduced the activities of class I and IIb HDACs activities significantly (17 ± 3%) and this decrease in HDACs activities was fully blocked by a selective δ-opioid receptors antagonist, naltrindole. SNC-121 also decrease the mRNA expression of HDAC-3 and HDAC-6 by 19% and 18%, respectively. Furthermore, protein expression of HDAC 1, 2, 3, and 6 was significantly (P < 0.05) decreased by SNC-121 treatment. SNC-121 treatment also reduced lipopolysaccharide-induced TNF-α production from ONH astrocytes and glial fibrillary acidic protein immunostaining in the optic nerve of ocular hypertensive animals.

Conclusions: We provided evidence that δ-opioid receptor agonist activation increased histone acetylation, decrease HDACs class I and class IIb activities, mRNA, and protein expression, lipopolysaccharide-induced TNF-α production in ONH astrocytes. Our data also demonstrate that SNC-121 treatment decrease glial fibrillary acidic protein immunostaining in the optic nerves of animals with ocular hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Aged
  • Aged, 80 and over
  • Animals
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Benzamides / pharmacology*
  • Blotting, Western
  • Cadaver
  • Cells, Cultured
  • Electroretinography
  • Female
  • Histone Deacetylases / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Optic Disk / drug effects*
  • Optic Disk / metabolism
  • Optic Disk / pathology
  • Piperazines / pharmacology*
  • Rats
  • Rats, Inbred BN
  • Receptors, Opioid, delta / agonists
  • Retinal Ganglion Cells / drug effects*
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology


  • Benzamides
  • Piperazines
  • Receptors, Opioid, delta
  • SNC 121
  • Histone Deacetylases