Uridine protects against hypoxic-ischemic brain injury by reducing histone deacetylase activity in neonatal rats

Restor Neurol Neurosci. 2015;33(5):777-84. doi: 10.3233/RNN-150549.


Purpose: A significant cause of neurological disability in newborns is hypoxic-ischemic encephalopathy (HIE), a disorder which involves an enhancement in histone deacetylase (HDAC) activity among underlying pathological mechanisms. We showed recently that exogenous administration of uridine to newborn rats with HIE reduced brain injury in a dose-dependent manner. The present study was performed to investigate whether uridine modulates histone acetylation/deacetylation balance in a neonatal rat model of HIE.

Methods: Newborn rats that were subjected to hypoxic-ischemic (HI) insult on postnatal day 7 (P7) were injected intraperitoneally with either saline or uridine (500 mg/kg) for three consecutive days. One day after completion of treatment, brains of pups were collected for evaluation of brain infarct volume, apoptosis, HDAC activity and acetylated-Histone H3 (Ac-H3) and H4 (Ac-H4) protein levels.

Results: Results revealed that uridine administration reduced infarct volume, active Caspase-3 levels and HDAC activity while increasing the expressions of Ac-H3 and Ac-H4 proteins.

Conclusions: We conclude that one mechanism by which uridine provides neuroprotection in neonatal rat HIE model involves reduction in HDAC activity.

Keywords: Hypoxic-ischemic encephalopathy; histone deacetylase; neonatal; neuroprotection; rat; uridine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Brain / drug effects*
  • Brain / enzymology
  • Brain / pathology
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / enzymology
  • Hypoxia-Ischemia, Brain / pathology
  • Injections, Intraperitoneal
  • Male
  • Neuroprotective Agents / pharmacology*
  • Random Allocation
  • Rats, Sprague-Dawley
  • Treatment Outcome
  • Uridine / pharmacology*


  • Histone Deacetylase Inhibitors
  • Neuroprotective Agents
  • Casp3 protein, rat
  • Caspase 3
  • Histone Deacetylases
  • Uridine