The Chemical Basis of Intracerebral Hemorrhage and Cell Toxicity With Contributions From Eryptosis and Ferroptosis.

Paul J Derry,Joy Mitra,James M Tour,Anh Tran Tram Vo,Ah-Lim Tsai,Muralidhar L Hegde,Thomas A Kent,Anton V Liopo,Aswini Gnanansekaran

doi:10.3389/fncel.2020.603043

Abstract

Intracerebral hemorrhage (ICH) is a particularly devastating event both because of the direct injury from space-occupying blood to the sequelae of the brain exposed to free blood components from which it is normally protected. Not surprisingly, the usual metabolic and energy pathways are overwhelmed in this situation. In this review article, we detail the complexity of red blood cell degradation, the contribution of eryptosis leading to hemoglobin breakdown into its constituents, the participants in that process, and the points at which injury can be propagated such as elaboration of toxic radicals through the metabolism of the breakdown products. Two prominent products of this breakdown sequence, hemin, and iron, induce a variety of pathologies including free radical damage and DNA breakage, which appear to include events independent from typical oxidative DNA injury. As a result of this confluence of damaging elements, multiple pathways of injury, cell death, and survival are likely engaged including ferroptosis (which may be the same as oxytosis but viewed from a different perspective) and senescence, suggesting that targeting any single cause will likely not be a sufficient strategy to maximally improve outcome. Combination therapies in addition to safe methods to reduce blood burden should be pursued.

Highlights

Intracerebral hemorrhage (ICH), contributing to 50% of all stroke morbidity and mortality, is an often devastating neurovascular disease without an effective therapy, affects more than 15 million people worldwide annually
In addition to the initial injury, processes associated with brain injury during ICH include red blood cell (RBC) lysis, which results in the release of free hemoglobin (Hb; Augustynek et al, 2014; Dang et al, 2017)
Ferroptosis appears to be a form of cell death that can be triggered by glutathione (GSH) depletion and iron excess which leads to the accumulation of lipid reactive oxygen species (L-ROS; Cao and Dixon, 2016; Figure 4)

Summary

Introduction

Intracerebral hemorrhage (ICH), contributing to 50% of all stroke morbidity and mortality, is an often devastating neurovascular disease without an effective therapy, affects more than 15 million people worldwide annually. In addition to the initial injury, processes associated with brain injury during ICH include red blood cell (RBC) lysis, which results in the release of free hemoglobin (Hb; Augustynek et al, 2014; Dang et al, 2017).

Results

Conclusion