Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke

Abstract

Hemorrhagic stroke is a common cause of permanent brain damage, with a significant amount of the damage occurring in the weeks following a stroke. This secondary damage is partly due to the toxic effects of hemin, a breakdown product of hemoglobin. The serum proteins hemopexin and albumin can bind hemin, but these natural defenses are insufficient to cope with the extremely high amounts of hemin (10 mM) that can potentially be liberated from hemoglobin in a hematoma. The present review discusses how hemin gets into brain cells, and examines the multiple routes through which hemin can be toxic. These include the release of redox-active iron, the depletion of cellular stores of NADPH and glutathione, the production of superoxide and hydroxyl radicals, and the peroxidation of membrane lipids. Important gaps are revealed in contemporary knowledge about the metabolism of hemin by brain cells, particularly regarding how hemin interacts with hydrogen peroxide. Strategies currently being developed for the reduction of hemin toxicity after hemorrhagic stroke include chelation therapy, antioxidant therapy and the modulation of heme oxygenase activity. Future strategies may be directed at preventing the uptake of hemin into brain cells to limit the opportunity for toxic interactions.

Redox Reactions of Myoglobin

“…A multitude of interactions involving ferriprotoporphyrin IX, ferroprotoporphyrin IX, and H 2 O 2 that can facilitate lipid oxidation have been postulated, including the ability of dissociated ferryl protoporphyrin IX to be an initiator of lipid oxidation (64).…”

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

“…103 Its mechanism of action occurs through oxidative stress and the activation of caspases, resulting in the injury of astrocytes, neurons, and microglia. 102,135 However, microglia that clear hemin have protective mechanisms that prevent cell death.…”

“…103,156 This primarily occurs via the heme carrier protein 1. 103 Once within the cell, hemin is degraded by heme oxygenases, producing biliverdin, carbon monoxide, and iron.…”

“…103,156 This primarily occurs via the heme carrier protein 1. 103 Once within the cell, hemin is degraded by heme oxygenases, producing biliverdin, carbon monoxide, and iron. 70,103 Iron released due to hemin degradation can reach high levels within the brain following ICH, resulting in the formation of hydroxyl radicals and subsequent cellular stress and DNA damage via interaction with hydrogen peroxide.…”

A Label-free, Highly Sensitive and Selective Detection of Hemin Based on the Competition between Hemin and Protoporphyrin IX Binding to G-Quadruplexes

“…4 But the high concentration of hemin has toxic effects on neurons, causing permanent brain secondary damage after a hemorrhagic stroke. 5 Moreover, hemin has been widely applied to pharmaceutical, the food industry, environmental science, bioscience and technology. [6][7][8] However, many studies have mainly focused on the catalytic activity of hemin in analytical applications.…”