Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms.
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.
Shen
Hongxia
H
State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences Fudan University, Shanghai 200032, China.
Hu
Xiaoming
X
Liu
Can
C
Wang
Suping
S
Zhang
Wenting
W
Gao
Hui
H
Stetler
R Anne
RA
Gao
Yanqin
Y
Chen
Jun
J
D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011773:Pyruvates / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
D018836:Inflammation Mediators; D016328:NF-kappa B; D018696:Neuroprotective Agents; D011773:Pyruvates; C046522:ethyl pyruvate; D002154:Calpain