Heme oxygenase-1 (HSP-32) and heme oxygenase-2 induction in neurons and glial cells of cerebral regions and its relation to iron accumulation after focal cortical photothrombosis.
Cerebral ischemic injury results in the liberation of heme from degenerating heme-containing proteins. The neurotoxic heme is usually detoxified by the constitutive heme oxygenase-2 (HO-2) and its inducible isoform HO-1(heat shock protein 32) resulting in the formation of biliverdin which becomes reduced to bilirubin, carbon monoxide (CO), and iron. Biliverdin and bilirubin have antioxidative properties whereas CO is discussed as a signaling molecule. Iron if it remains free could catalyze Haber--Weiss and Fenton reactions causing the formation of highly toxic radicals. We have studied the alterations of cerebral HO-2 and HO-1 in relation to iron accumulations after defined cortical photothrombosis within the hindlimb area of the rat. HO-2 immunohistochemistry showed that the number of HO-2-positive neurons in most perilesional regions remained constant. However, much stronger systemic immunoreactivity for HO-2 was observed between days 1 and 7 postlesion. For HO-1 a systemic increase of immunoreactivity occurred also between days 1 and 7. In addition HO-1-positive astrocytes and microglia appeared as early as 4 h postlesion and increased up to day 3 followed by a sharp decline toward day 14 within the injured hemisphere. HO-1-positive astrocytes and microglia occurred in ipsilateral cortex, corpus callosum, hippocampus, striatum, and thalamic nuclei. Additionally an increase of HO-1 in myelin-associated globulin-positive oligodendrocytes was found in ipsilateral and contralateral cortex. Next to the lesion iron accumulation occurred after day 3 and increased strongly toward day 14 at times when HO-1 and -2 had decreased, suggesting that HO activity does not directly contribute to postlesional iron deposition.
Bidmon
H J
HJ
Institute of Neuroanatomy, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Emde
B
B
Oermann
E
E
Kubitz
R
R
Witte
O W
OW
Zilles
K
K
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000096:biosynthesis*; D051547:Heme Oxygenase-1; D006614:Hindlimb / Q000294:innervation; D007150:Immunohistochemistry; D020767:Intracranial Thrombosis / Q000201:enzymology* / Q000473:pathology; D007501:Iron / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D009457:Neuroglia / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012395:Rose Bengal; D013997:Time Factors
D012395:Rose Bengal; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2