Heme oxygenase in experimental intracerebral hemorrhage: the benefit of tin-mesoporphyrin.
The prognosis of intracerebral hemorrhage (ICH) is unfavorable. Beyond immediate mass effect and tissue destruction, ICHs cause additional neuronal loss in a "perifocal reactive zone." Heme in ICH induces heme oxygenase-1 (HO-1), and the action of this enzyme on heme yields ferrous iron, biliverdin, and carbon monoxide. Iron is ultimately converted to ferritin and hemosiderin. Free iron is tissue-toxic, and inhibition of HO-1 should provide protection against additional damage. Experimental ICHs were made in adult rabbits by the stereotaxic injection of autologous blood, and the induction of HO-1 and increase in ferritin were followed by confocal immunofluorescence microscopy. Heme diffused rapidly through perivascular spaces, and HO-1 reaction product first occurred in perivascular cells and microglia. At this stage, HO-1 and ferritin showed extensive colocalization. As ICH resolution progressed, HO-1 immunoreactivity faded while ferritin and hemosiderin continued to accumulate. This process was accompanied by a gradient of destruction of neuronal cell bodies and dendrites in the perifocal reactive zone. In an effort to inhibit HO-1, repeated intravenous injections of tin-mesoporphyrin IX (SnMP) were given to ICH-bearing rabbits. The ICH disrupted the blood-brain barrier sufficiently to allow SnMP to enter the brain in pharmacological amounts, and the metalloporphyrin provided significant protection against neuronal loss.
Koeppen
Arnulf H
AH
Neurology Service, VA Medical Center, Albany, New York 12208, USA. arnulf.koeppen@med.va.gov
Dickson
Andrew C
AC
Smith
Joanne
J
D000818:Animals; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000627:therapeutic use*; D011817:Rabbits
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; C055421:tin mesoporphyrin; D006419:Heme Oxygenase (Decyclizing)