Hyperbilirubinemia protects against focal ischemia in rats.
Heme oxygenase-1 (HO1) catalyzes oxidation of the heme molecule in concert with NADPH-cytochrome P450 reductase following the specific cleavage of heme into carbon monoxide, iron, and biliverdin, which is rapidly metabolized to bilirubin. HO1 is a stress-inducible protein that protects cells against oxidative injury, but its protective mechanism is not fully understood. The Eizai hyperbilirubinemic rat (EHBR), a mutant strain derived from the Sprague-Dawley rat (SDR), has a mutation in the gene for the canalicular multispecific organic anion transporter, which results in a phenotype of hyperbilirubinemia, and thus is a model of Dubin-Johnson syndrome in humans. In this study, we compared EHBR and SDR with regard to neuronal death induced by 2 hr of occlusion of the middle cerebral artery and reperfusion. In EHBR, the area that was immunoreactive for microtubule-associated protein-2 was significantly reduced, and the HO1-immunoreactive area was smaller than that in SDR. These results suggest that bilirubin has essentially a neuroprotective effect against focal ischemia and may participate in HO1-induced neuroprotection.
Kitamura
Yoshihisa
Y
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto, Japan. yo-kita@mb.kyoto-phu.ac.jp
Ishida
Yuji
Y
Takata
Kazuyuki
K
Mizutani
Hiroto
H
Kakimura
Jun-ichi
J
Inden
Masatoshi
M
Nakata
Junko
J
Taniguchi
Takashi
T
Tsukahara
Tetsuya
T
Akaike
Akinori
A
Shimohama
Shun
S
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1; D006932:Hyperbilirubinemia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity
D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1