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.
Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Asphyxia Neonatorum / drug therapy*
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Asphyxia Neonatorum / metabolism
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Asphyxia Neonatorum / physiopathology
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Brain / drug effects
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Brain / metabolism
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Brain / physiopathology
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Calpain / antagonists & inhibitors
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Calpain / metabolism
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Cell Death / drug effects
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Cell Death / physiology
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Cytoprotection / drug effects
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Cytoprotection / physiology
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Disease Models, Animal
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Encephalitis / drug therapy*
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Encephalitis / physiopathology
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Encephalitis / prevention & control
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Humans
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Hypoxia-Ischemia, Brain / drug therapy*
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Hypoxia-Ischemia, Brain / metabolism
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Hypoxia-Ischemia, Brain / physiopathology
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Infant, Newborn
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Inflammation Mediators / antagonists & inhibitors
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Microglia / drug effects
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Microglia / physiology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Nerve Degeneration / drug therapy*
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Nerve Degeneration / physiopathology
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Nerve Degeneration / prevention & control
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Pyruvates / pharmacology*
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Pyruvates / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Treatment Outcome
Substances
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Inflammation Mediators
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NF-kappa B
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Neuroprotective Agents
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Pyruvates
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ethyl pyruvate
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Calpain