Molecular pathophysiology of cerebral hemorrhage: secondary brain injury

Abstract

Intracerebral hemorrhage (ICH) is an often fatal type of stroke that kills approximately 30,000 people annually in the United States. If the patient survives the ictus, then the resulting hematoma within brain parenchyma triggers a series of adverse events causing secondary insults and severe neurological deficits. This article discusses selected aspects of secondary brain injury after ICH and outlines key mechanisms associated with hematoma toxicity, oxidative stress, and inflammation. Finally, this review discusses the relevance of hematoma resolution processes as a target for ICH therapy and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with ICH injury.

Fig 1

During ICH blood is released into the brain matter. Erythrocytes (RBC) are cleared from the parenchyma by microglia/macrophages through cell-surface scavenger receptor CD36-mediated phagocytosis. Timely clearance of the extravasated RBCs and irreversibly injured cells prevents them from undergoing lyses and subsequent spillage of toxic contents into the brain parenchyma. In the case of hemolysis, what unavoidably occurs after ICH, hemoglobin (Hb) needs to be removed quickly from the extracellular space to avoid its cytotoxic effects. Haptoglobin (Hp), a protein arrived to the brain from blood and synthesized locally by oligodendroglia, tightly binds Hb forming less toxic Hb-Hp complexes which are endocytosed by microglia/macrophages through scavenger receptor, CD163. The toxic extracellular free heme generated from Hb can be neutralized by binding to hemopexin (Hx). The heme-Hx complexes are subsequently removed by phagocytes via CD91 scavenger receptor-mediated endocytosis. In phagocyte heme is metabolized by heme oxygenase (HO) (primarily HO-1) to biliverdin, carbon monoxide (CO) and pro-oxidative iron. To prevent oxidative cell damage iron is sequestrated within phagocyte by iron binding proteins such as hemosiderin or ferritin. Excessive production of iron may saturate storing capacity of hemosiderin, leading to oxidative injury from the free irons. CD36 is expressed under control of PPARγ and Hp expression is increased with Nrf2. Both Nrf2 and PPARγ increase expression of antioxidant proteins (e.g. catalase or superoxide dismutase, SOD). Thus activation of these transcription factors may represent new targets for ICH treatment.

Fig 2

Intracerebral hemorrhage activates transcription factor NF-κB., which then perpetuates inflammation that along with oxidative stress leads to secondary brain damage. Transcription factors PPARγ via inhibition of NF-κB and induction of anti-oxidative defense components reduces inflammation and oxidative stress and protects ICH-affected brain. Transcription factor Nrf2 acts as an effective regulator of oxidative stress and blood detoxification components. In addition, PPARγ stimulates phagocytosis-mediated hematoma cleanup, thus facilitating removal of hematoma, the source of toxicity and inflammation.