Phenobarbital augments hypothermic neuroprotection.
Seizures are associated with adverse outcome in infants with hypoxic-ischemic encephalopathy. We hypothesized that early administration of the anticonvulsant phenobarbital after cerebral hypoxia ischemia could enhance the neuroprotective efficacy of delayed-onset hypothermia. We tested this hypothesis in a neonatal rodent model. Seven-d-old rats (n = 104) underwent right carotid ligation, followed by 90 min 8% O2 exposure; 15 min later, they received injections of phenobarbital (40 mg/kg) or saline. One or 3 h later, all were treated with hypothermia (30 degrees C, 3 h). Function and neuropathology were evaluated after 7 d (early outcomes) or 1 mo (late outcomes). Early outcome assessment demonstrated better sensorimotor performance and less cortical damage in phenobarbital-treated groups; there were no differences between groups in which the hypothermia delay was shortened from 3 to 1 h. Late outcome assessment confirmed sustained benefits of phenobarbital + hypothermia treatment; sensorimotor performance was better (persistent attenuation of contralateral forepaw placing deficits and absence of contralateral forepaw neglect); neuropathology scores were lower (median, phenobarbital 2 and saline 8.5, p < 0.05); and less ipsilateral cerebral hemisphere %Damage (mean +/- SD, 11 +/- 17 versus 28 +/- 22, p < 0.05). These results suggest that early posthypoxia-ischemia administration of phenobarbital may augment the neuroprotective efficacy of therapeutic hypothermia.
Barks
John D
JD
Departments of Pediatrics and Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA. jbarks@med.umich.edu
Liu
Yi-Qing
YQ
Shangguan
Yu
Y
Silverstein
Faye S
FS
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D010634:Phenobarbital / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055139:Sensory Gating / Q000187:drug effects; D013997:Time Factors
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D010634:Phenobarbital