AMPA antagonist LY293558 does not affect the severity of hypoxic-ischemic injury in newborn pigs.
OBJECTIVE
LY293558 is a systemically active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) excitatory amino acid antagonist. AMPA antagonists have shown promise in several adult hypoxic-ischemic brain injury models, and we wanted to see if this work could be extended to a newborn animal.


METHODS
Seventy-six (beta error < .10) 0- to 3-day-old piglets under 1.5% isoflurane anesthesia underwent placement of carotid snares and arterial and venous catheters. While paralyzed with succinylcholine under 0.5% isoflurane, 50% nitrous oxide, piglets were randomly assigned to receive either 5 mg/kg or 15 mg/kg of LY293558 or saline at time--10 minutes and again 10 hours later. At time 0, both carotid arteries were clamped, and blood was withdrawn to reduce the blood pressure to two thirds of normal. At time 15 minutes, inspired oxygen was reduced to 6%. At time 30 minutes, the carotid snares were released, the withdrawn blood was reinfused, and the oxygen was switched to 100%. On the third day after the hypoxic-ischemic injury, the animals were killed by perfusion of the brain with 10% formalin. Brain pathology was scored by a blinded observer.


RESULTS
There were no significant differences between the drug-treated and control groups.


CONCLUSIONS
The systemically active AMPA antagonist LY293558, when given at a dose of 5 mg/kg or 15 mg/kg before injury and 10 hours later, does not affect the severity of hypoxic-ischemic brain injury in newborn piglets. Neither AMPA receptor activity nor NMDA receptor activity are important in brain injury in this model.
LeBlanc
M H
MH
Department of Pediatrics, University of Mississippi School of Medicine, Jackson 39216-4505, USA.
Li
X Q
XQ
Huang
M
M
Patel
D M
DM
Smith
E E
EE
D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D002245:Carbon Dioxide / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000473:pathology / Q000517:prevention & control*; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013552:Swine; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
D018690:Excitatory Amino Acid Agonists; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; D002245:Carbon Dioxide; C082309:tezampanel; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D010100:Oxygen