Heme oxygenase-1 contributes to pathology associated with thrombin-induced striatal and cortical injury in organotypic slice culture.
The blood coagulation factor thrombin that leaks from ruptured vessels initiates brain tissue damage after intracerebral hemorrhage. We have recently shown that mitogen-activated protein kinases (MAPKs) activated by thrombin exacerbate hemorrhagic brain injury via supporting survival of neuropathic microglia. Here, we investigated whether induction of heme oxygenase (HO)-1 is involved in these events. Zinc protoporphyrin IX (ZnPP IX), a HO-1 inhibitor, attenuated thrombin-induced injury of cortical cells in a concentration-dependent manner (0.3-3 microM) and tended to inhibit shrinkage of the striatal tissue at 0.3 microM. HO-1 expression was induced by thrombin in microglia and astrocytes in both the cortex and the striatum. The increase of HO-1 protein was suppressed by a p38 MAPK inhibitor SB203580, and early activation of p38 MAPK after thrombin treatment was observed in neurons and microglia in the striatum. Notably, concomitant application of a low concentration (0.3 microM) of ZnPP IX with thrombin induced apoptotic cell death in striatal microglia and significantly decreased the number of activated microglia in the striatal region. On the other hand, a carbon monoxide releaser reversed the protective effect of ZnPP IX on thrombin-induced injury of cortical cells. Overall, these results suggest that p38 MAPK-dependent induction of HO-1 supports survival of striatal microglia during thrombin insults. Thrombin-induced cortical injury may be also regulated by the expression of HO-1 and the resultant production of heme degradation products such as carbon monoxide.
Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Gakuencho-1, Fukuyama, Hiroshima 729-0292, Japan.
Masatoshi
M
Ohnishi
Hiroshi
H
Katsuki
Kazuhiro
K
Unemura
Yasuhiko
Y
Izumi
Toshiaki
T
Kume
Yuki
Y
Takada-Takatori
Akinori
A
Akaike
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D001930:Brain Injuries / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017628:Microglia / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D011524:Protoporphyrins / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017262:Siderophores / Q000494:pharmacology; D013917:Thrombin / Q000633:toxicity*; D013997:Time Factors
D004791:Enzyme Inhibitors; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D011524:Protoporphyrins; D011725:Pyridines; D017262:Siderophores; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D013917:Thrombin; D003676:Deferoxamine; C093642:SB 203580