Novel targets, treatments, and advanced models for intracerebral haemorrhage

Abstract

Intracerebral haemorrhage (ICH) is the second most common type of stroke and a major cause of mortality and disability worldwide. Despite advances in surgical interventions and acute ICH management, there is currently no effective therapy to improve functional outcomes in patients. Recently, there has been tremendous progress uncovering new pathophysiological mechanisms underlying ICH that may pave the way for the development of therapeutic interventions. Here, we highlight emerging targets, but also existing gaps in preclinical animal modelling that prevent their exploitation. We particularly focus on (1) ICH aetiology, (2) the haematoma, (3) inflammation, and (4) post-ICH pathology. It is important to recognize that beyond neurons and the brain, other cell types and organs are crucially involved in ICH pathophysiology and successful interventions likely will need to address the entire organism. This review will spur the development of successful therapeutic interventions for ICH and advanced animal models that better reflect its aetiology and pathophysiology.

Keywords: Aetiology; Animal models; Brain haemorrhage; Haematoma; Inflammation; Recovery.

Figure 1

The haematoma as a therapeutic target in ICH. The haematoma can cause brain injury via mass effect and the release of potentially toxic, plasma- or erythrocyte-derived factors. Surgical haematoma evacuation and accelerating endogenous haematoma clearance via phagocytosis are potential approaches, as is delaying erythrocyte lysis and inhibiting deleterious effects of clot-derived factors. RBC, red blood cell; MAC, membrane attack complex; Hb, haemoglobin; CA1, carbonic anhydrase 1; Prx2, peroxiredoxin-2; SIRPα, signal regulatory protein alpha.

Figure 2

Inflammation as a therapeutic target in ICH. The haematoma induces local inflammatory events, mediated by microglia and astrocytes, as well as acute systemic inflammation, resulting in the recruitment of immune cells to the brain. The injured CNS then triggers systemic immunosuppression and changes in the gut-brain axis.

Figure 3

Therapeutic targets and approaches in ICH.