Minocycline blocks acute bilirubin-induced neurological dysfunction in jaundiced Gunn rats.
BACKGROUND
Extreme hyperbilirubinemia is treated with double volume exchange transfusion, which may take hours to commence. A neuroprotective agent that could be administered immediately might be clinically useful. Minocycline, an anti-inflammatory and anti-apoptotic semisynthetic tetracycline, prevents hyperbilirubinemia-induced cerebellar hypoplasia in Gunn rats. Acute brainstem auditory evoked potential (BAEP) abnormalities occur after giving sulfadimethoxine to 16-day-old jaundiced Gunn rats to displace bilirubin into tissue including brain.


OBJECTIVE
To assess whether minocycline is neuroprotective in this model of acute bilirubin encephalopathy.


METHODS
We recorded BAEPs at baseline and 6 h after injecting sulfadimethoxine. Minocycline 0.5 mg/kg (n = 4), 5 mg/kg (n = 9), 50 mg/kg (n = 9) or 500 mg/kg (n = 3, all died) was administered 15 min before sulfadimethoxine (0 h). Controls received saline followed by either sulfadimethoxine (n = 13) or saline (n = 7).


RESULTS
At 6 h total plasma bilirubin decreased from 10.84 +/- 0.88 mg/dl (mean +/- SD) to 0.70 +/- 0.35 mg/dl (p <10(-9)) in all sulfadimethoxine-injected groups. At 6 h, there was complete protection against decreased amplitudes of BAEP waves II and III and increased I-II and I-III interwave intervals (brainstem conduction times corresponding to I-III and I-V in humans) with 50 mg/kg minocycline, and partial protection with lower doses.


CONCLUSIONS
Minocycline 50 mg/kg 15 min prior to an intervention that normally produces acute bilirubin neurotoxicity is neuroprotective in jaundiced Gunn rat pups. Further studies are needed to investigate the temporal course and mechanism of neuroprotection. Minocycline, administered immediately, may be clinically useful in treating extreme neonatal hyperbilirubinemia and preventing kernicterus. We believe our model provides an efficient in vivo model to screen and evaluate new agents that are neuroprotective against bilirubin toxicity and kernicterus.
Geiger
Angela S
AS
Department of Neurology and Physiology, Virginia Commonwealth University Medical Center, Virginia Commonwealth University, Richmond, VA, USA.
Rice
Ann C
AC
Shapiro
Steven M
SM
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D000890:Anti-Infective Agents; D001663:Bilirubin / Q000009:adverse effects* / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects / Q000502:physiology; D005260:Female; D007565:Jaundice / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D007647:Kernicterus / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008911:Minocycline / Q000627:therapeutic use*; D009431:Neural Conduction / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D011911:Rats, Gunn; D013412:Sulfadimethoxine
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D013412:Sulfadimethoxine; D008911:Minocycline; D001663:Bilirubin