Programmed Cell Death after Intracerebral Hemorrhage

Abstract

Background: Intracerebral hemorrhage (ICH) accounts for up to 15% of all strokes and is characterized by high rates of mortality and morbidity. The post-ICH brain injury can be distinguished in 1) primary, which are caused by disruption and mechanical deformation of brain tissue due to hematoma growth and 2) secondary, which are induced by microglia activation, mitochondrial dysfunction, neurotransmitter and inflammatory mediator release. Although these events typically lead to necrosis, the occurrence of programmed cell death has also been reported after ICH.

Methods: We reviewed recent publications describing advance in pre- and clinic ICH research.

Results: At present, treatment of ICH patients is based on oral anticoagulant reversal, management of blood pressure and other medical complications. Several pre-clinical studies showed promising results and demonstrated that anti-oxidative and anti-inflammatory treatments reduced neuronal cell death, however, to date, all of these attempts have failed in randomized controlled clinical trials. Yet, the time frame of administration may be crucial in translation from animal to clinical studies. Furthermore, the latest pre-clinical research points toward the existence of other, apoptosisunrelated forms kinds of programmed cell death.

Conclusion: Our review summarizes current knowledge of pathways leading to programmed cell death after ICH in addition to data from clinical trials. Some of the pre-clinical results have not yet demonstrated clinical confirmation, however they significantly contribute to our understanding of post-ICH pathology and can contribute to development of new therapeutic approaches, decreasing mortality and improving ICH patients' quality of life.

Keywords: Cell death; ICH; apoptosis; intracerebral hemorrhage; necrosis; pyroptosis..

Fig. (1)

Schematic presentation of major pathways leading to the programed cell death and clinical relevant interventions improving cell survival after ICH. Attenuation of programed cell death via: 1 Acceleration of hematoma clearance and CD36 mediated phagocytosis (PPARγ-agonists). 2 Surgical evacuation of hematoma. 3 Decrease of hematoma size via aggressive blood pressure reductions (INTERACT-2 and ATACH trials). 4 Free iron scavenging (deferoxamine Hi-Def (NCT NCT01662895) trial). 5 ROS scavenging (Minocycline, MACH trial; Edaravone, disufenton sodium (NXY-059), CHANT-trial). 6 Anti-inflammatory approaches (e.g. COX-2 inhibitors [celecoxib]). 7 Direct targeting of apoptosis (G-CSF). 8 Attenuation of post-ICH release of SICs and consequently brain infiltration by SIC (FTY-720).

Fig. (2)

Schematic presentation of Pyroptosis. Pyroptosis is induced by nucleotide-binding oligomerization domain-like receptors (NLR) located in the cytosol. After binding, NLR initiates assembling a multiprotein-complex, the inflammasome, leading to cell damage.