Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Abstract

Intracranial bleeding is one of the most prominent aspects in the clinical diagnosis and prognosis of traumatic brain injury (TBI). Substantial amounts of blood products, such as heme, are released because of traumatic subarachnoid hemorrhages, intraparenchymal contusions, and hematomas. Despite this, surprisingly few studies have directly addressed the role of blood products, in particular heme, in the setting of TBI. Heme is degraded by heme oxygenase (HO) into three highly bioactive products: iron, bilirubin, and carbon monoxide. The HO isozymes, in particular HO-1 and HO-2, exhibit significantly different expression patterns and appear to have specific roles after injury. Developmentally, differences between the adult and immature brain have implications for endogenous protection from oxidative stress. The aim of this paper is to review recent advances in the understanding of heme regulation and metabolism after brain injury and its specific relevance to the developing brain. These findings suggest novel clinical therapeutic options for further translational study.

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

“…119 Iron reacts with hydrogen peroxide to form hydroxyl radicals ( Figure 1) and with lipids to generate alkoxy and peroxy radicals. As discussed in the previous section, the immature brain may be especially vulnerable to the adverse effects of oxidative stress, making iron a potential target for therapy after trauma to the immature brain.…”

“…124 Iron accumulation after injury to the developing brain. Iron accumulates in the developing brain after TBI 119 (Figure 2). However, it is unclear how such accumulation may modulate pathogenesis.…”

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

“…Iron accumulates in the developing brain after TBI 119 ( Figure 2). However, it is unclear how such accumulation may modulate pathogenesis.…”

Screening for the Formation of Reactive Oxygen Species and of NO in Muscle Tissue and Remote Organs upon Mechanical Trauma to the Mouse Hind Limb

“…Potential pathways for an ROS-induced alteration of the glutathione homeostasis include direct oxidation of GSH by different (possibly secondarily formed) ROS and an increased formation of hydrogen peroxide that is degraded via the GSH-consuming enzyme glutathione peroxidase [27] . Pathophysiological mechanisms that may be responsible for increased cellular ROS formation include augmented leakage of superoxide from the mitochondrial electron transport chain, enhanced activity of xanthine or NADPH oxidase, release of redox-active iron via breakdown of hemoglobin, and activation of the arachidonic acid cascade [28][29][30] . ROS sources, however, may vary over the posttraumatic period.…”