Tin-mesoporphyrin, a potent heme oxygenase inhibitor, for treatment of intracerebral hemorrhage: in vivo and in vitro studies.
Spontaneous intracerebral hemorrhage (ICH) is the stroke subtype with highest mortality and morbidity. ICH can also occur following traumatic brain injury and thrombolysis for ischemic stroke and myocardial infarction. Development of ICH-induced hemispheric edema can elevate intracranial pressure and cause death. In survivors, edema-related white matter injury can lead to life-long neurological deficits. At present, there are no scientifically proven treatments for ICH. Heme oxygenase products, particularly iron and bilirubin, can be toxic to cells. In cerebral ischemia models, metalloporphyrins that are potent heme oxygenase inhibitors, reduce edema and infarct size. Tin-mesoporphyrin (SnMP) is a neuroprotectant that has also been used clinically to treat hyperbilirubinemia. Presently, we tested the hypothesis that SnMP treatment would reduce edema development following experimental ICH. We produced hematomas in pentobarbital-anesthetized pigs (9-11 kg) by infusing autologous blood into the frontal white matter. To maximize tissue concentrations, SnMP (87.5 microM in DMSO) or DMSO (vehicle controls) was included in the infused blood. Pig brains were frozen in situ at 24 hrs. following ICH and hematoma and edema volumes were determined on coronal sections by computer-assisted image analysis. We also examined the effects of SnMP in vitro on ferritin iron release, the formation of iron-induced thiobarbituric acid reactive substances (TBARS) and initial clot formation and hemolysis. SnMP treatment significantly reduced intracerebral mass following ICH. This was due to significant decreases in hematoma (0.68+/-0.08 vs. 1.39+/-0.30 cc, vehicle controls p<0.025) and edema volumes (edema = 1. 16+/-0.33 vs. 1.77+/-0.31 cc, p<0.05). In vitro, SnMP did not stabilize ferritin iron against reductive release nor did it decrease iron-induced TBARS formation in brain homogenates. SnMP or DMSO added to pig blood did not alter clot weights. In conclusion, SnMP reduced intracerebral mass in an ICH model by decreasing both hematoma and edema volumes SnMP's mechanism of action is presently unknown but may involve its potent inhibition of heme oxygenase activity. SnMP's effect appears unrelated to ferritin iron release, antioxidant activity or initial clot formation. Since SnMP treatment could be brain protective following ICH, further investigations into neurological and neuropathological outcomes and as well as into its mechanism of action are warranted.
Wagner
K R
KR
Department of Neurology, University of Cincinnati College of Medicine, Ohio 45267, USA. wagnerkr@email.uc.edu
Hua
Y
Y
de Courten-Myers
G M
GM
Broderick
J P
JP
Nishimura
R N
RN
Lu
S Y
SY
Dwyer
B E
BE
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D001929:Brain Edema / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D005293:Ferritins / Q000378:metabolism; D006406:Hematoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism; D008665:Metalloporphyrins / Q000378:metabolism / Q000627:therapeutic use*; D013552:Swine
D000975:Antioxidants; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; C055421:tin mesoporphyrin; D005293:Ferritins; D007501:Iron; D006419:Heme Oxygenase (Decyclizing)