Recently, new details of the pathophysiological mechanisms involved in edema formation after ICH have been reported. These include clot retraction in the first several hours, the coagulation cascade and thrombin formation in the 1st day, and RBC lysis and hemoglobin neurotoxicity a few days later.4,22–25,48,51,54 Because hemoglobin-induced edema formation is triggered a few days after ICH, therapy targeted at hemoglobin and its degradation products may offer a new approach to therapy for ICH.
Hemoglobin breakdown products may have a key role in the formation of brain edema. Metabolism of hemoglobin by HO after RBC lysis results in the release of iron, carbon monoxide, and biliverdin.27 Subsequently, biliverdin reductase catalyzes the conversion of biliverdin to bilirubin.20 Both enzymes are found in the brain,8 and inhibition of HO is associated with attenuation of brain edema after ICH.47
Intracortical injection of iron, a potent catalyst for lipid peroxidation, causes focal epileptiform discharges and brain edema.49,50 Hemoglobin induces neuronal death in vitro, a process that is blocked by deferoxamine, an iron chelator.36 In addition, bilirubin is toxic to brain tissue, although it is considered to be an antioxidant at low concentrations.29,42
In this study, we examined the effects of hemoglobin degradation products on the formation of brain edema. We also studied the effects of an HO inhibitor, SnPP, and the iron chelator deferoxamine, on hemoglobin-induced brain edema. Upregulation of HO-1 protein was examined using Western blot analysis and immunohistochemistry.
Gutteridge JM: The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917:219–2231987Gutteridge JM: The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917:
Jackson IJ: Aseptic hemogenic meningitis. An experimental study of aseptic meningeal reactions due to blood and its breakdown products. Arch Neurol Psychiatry 62:572–5891949Jackson IJ: Aseptic hemogenic meningitis. An experimental study of aseptic meningeal reactions due to blood and its breakdown products. Arch Neurol Psychiatry 62:
This study was supported by Grant Nos. NS-17760 and NS-39866 from the NIH to Drs. Hoff and Xi, respectively.