Minocycline blocks bilirubin neurotoxicity and prevents hyperbilirubinemia-induced cerebellar hypoplasia in the Gunn rat.
Encephalopathy induced by hyperbilirubinemia in infants has been described in the medical literature for over a century but neither the cellular nor molecular mechanisms underlying bilirubin neurotoxicity are well understood. In this study, we have demonstrated that minocycline potently protects primary cultured rat cerebellar granule neurons against bilirubin neurotoxicity (IC50 approximately 2 microm) and almost completely blocks cerebellar hypoplasia and the profound loss of Purkinje and granule neurons observed in homozygous Gunn rats, a genetic model of hyperbilirubinemia-induced neurotoxicity. Minocycline-treated newborn Gunn rats had nearly equivalent numbers of viable Purkinje and granule neurons in the cerebellum as did control animals. Moreover, minocycline inhibits the bilirubin-induced phosphorylation of p38 mitogen-activated protein kinase both in vivo as well as in vitro. Taken together our data demonstrate that minocycline is able to greatly reduce bilirubin-induced neurotoxicity and suggest that minocycline's neuroprotective effects may be due in part to an inhibition of p38 mitogen-activated protein kinase activity. Our findings may lead to novel approaches for treating bilirubin-induced encephalopathy.
Lin
Suizhen
S
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Wei
Xing
X
Bales
Kelly R
KR
Paul
Aaron B C
AB
Ma
Zhizhong
Z
Yan
Guangmei
G
Paul
Steven M
SM
Du
Yansheng
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000150:complications; D007647:Kernicterus / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011911:Rats, Gunn; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline