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 highe st mortality and morbidity. ICH can also occur following traumatic brain in jury and thrombolysis for ischemic stroke and myocardial infarction. Develo pment of ICH-induced hemispheric edema can elevate intracranial pressure an d cause death. In survivors, edema-related white matter injury can lead to life-long neurological deficits. At present, there are no scientifically pr oven treatments for ICH. Heme oxygenase products, particularly iron and bil irubin, can be toxic to cells. In cerebral ischemia models, metalloporphyri ns that are potent heme oxygenase inhibitors, reduce edema and infarct size . Tin-mesoporphyrin (SnMP) is a neuroprotectant that has also been used cli nically to treat hyperbilirubinemia. Presently, we tested the hypothesis th at SnMP treatment would reduce edema development following experimental ICH . We produced hematomas in pentobarbital-anesthetized pigs (9-11 kg) by inf using autologous blood into the frontal white matter. To maximize tissue co ncentrations, SnMP (87.5 mu M in DMSO) or DMSO (vehicle controls) was inclu ded in the infused blood. Pig brains were frozen in situ at 24 hrs. followi ng ICH and hematoma acid edema volumes were determined on coronal sections by computer-assisted image analysis. We also examined the effects of SnMP i n vitro on ferritin iron release, the formation of iron-induced thiobarbitu ric acid reactive substances (TBARS) and initial clot formation and hemolys is. 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 ferriti n iron against reductive release nor did it decrease iron-induced TBARS for mation in brain homogenates. SnMP or DMSO added to pig blood did not alter clot weights. In conclusion, SnMP reduced intracerebral mass in an ICH mode l by decreasing both hematoma and edema volumes SnMP's mechanism of action is presently unknown but may involve its potent inhibition of heme oxygenas e activity. SnMP's effect appears unrelated to ferritin iron release, antio xidant activity or initial clot formation. Since SnMP treatment could be br ain protective following ICH, further investigations into neurological and neuropathological outcomes and as well as into its mechanism of action are warranted.