Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms

Neurobiol Dis. 2010 Mar;37(3):711-22. doi: 10.1016/j.nbd.2009.12.010. Epub 2009 Dec 21.

Abstract

Ethyl pyruvate (EP) is protective in experimental models of many illnesses. This study investigates whether EP can protect against neonatal hypoxic-ischemic (H-I) brain injury. Pre-treatment with EP significantly reduced brain damage at 7 days post-H-I, with 50 mg/kg EP achieving over 50% recovery in tissue loss compared to vehicle-treated animals. Delayed treatment with EP until 30 min after H-I was still neuroprotective. EP-afforded brain protection, together with neurological function improvement, was observed up to 2 months after H-I. We further demonstrated an inhibitory effect of EP on cell death, both in an in vivo model of H-I and in in vitro neuronal cultures subjected to OGD, by reducing calpain activation and calcium dysregulation. Moreover, EP exerted an anti-inflammatory effect in microglia by inhibiting NF-kappaB activation and subsequent release of inflammatory mediators. Taken together, our results suggest that EP confers potent neuroprotection against neonatal H-I brain injury via its anti-cell death and anti-inflammatory actions. EP is a potential novel therapeutic agent for neonatal H-I brain injury.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Asphyxia Neonatorum / drug therapy*
  • Asphyxia Neonatorum / metabolism
  • Asphyxia Neonatorum / physiopathology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Calpain / antagonists & inhibitors
  • Calpain / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Disease Models, Animal
  • Encephalitis / drug therapy*
  • Encephalitis / physiopathology
  • Encephalitis / prevention & control
  • Humans
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / metabolism
  • Hypoxia-Ischemia, Brain / physiopathology
  • Infant, Newborn
  • Inflammation Mediators / antagonists & inhibitors
  • Microglia / drug effects
  • Microglia / physiology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Pyruvates / pharmacology*
  • Pyruvates / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Treatment Outcome

Substances

  • Inflammation Mediators
  • NF-kappa B
  • Neuroprotective Agents
  • Pyruvates
  • ethyl pyruvate
  • Calpain