Molecular, Cellular and Clinical Aspects of Intracerebral Hemorrhage: Are the Enemies Within?

Abstract

Hemorrhagic stroke is a disease with high incidence and mortality rates. In addition to the mass lesions that result from hemorrhagic stroke, substances such as the blood-derived products (BDP) (hemoglobin (Hb), heme and iron) induce a potent inflammatory response and exert direct toxic effects on neurons, astrocytes, and microglia. In the present review, we discuss the mechanisms of brain injury secondary to hemorrhagic stroke, focusing on the involvement of BDP as major players of cellular redox imbalance, inflammation, and glutamate excitotoxicity. Potential natural mechanisms of protection against free Hb and heme such as haptoglobin and hemopexin, respectively, are highlighted. We finally discuss the experimental and clinical trials targeting free iron and heme scavenging as well as inflammation, as potential new therapies to minimize the devastating effects of hemorrhagic stroke on brain structure and function.

Fig. (1)

Schematic summary of the main mechanisms of brain injury after hemorrhagic stroke. Hemoglobin and its metabolites can exert deleterious effects on brain tissue through NO depletion and vasospasm, ROS production, stimulation of inflammatory response, inhibition of DNA repair, and glutamate release. (Adapted from Larsen R et al.) [12].

Fig. (2)

Schematic summary of TLR4 activation by heme and its effects. Heme induces neutrophil migration across the blood-brain barrier and secretion of IL-8 and TNF- α by stimulating TLR4. The stimulation of inflammatory response and augmentation of vascular permeability contribute to brain edema. Besides promoting inflammatory reaction within the CNS, heme also induces programmed cell necrosis in monocytes/macrophages. Furthermore, the uptake of heme by neurons induces cell death, which further propagates the inflammatory response.

Fig. (3)

Schematic mechanism of brain protection and pharmacological compounds tested in experimental and clinical trials. Many drugs tested to this date act either by iron scavenging or by enhancing antioxidant response after hemorrhagic stroke (adapted from Larsen R, et al.) [12].