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 disrup-tion 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, apoptosis-unrelated forms kinds of pro-grammed 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 sig-nificantly contribute to our understanding of post-ICH pathology and can contribute to development of new therapeutic ap-proaches, decreasing mortality and improving ICH patients’ quality of life.

Activation of PPAR-β/δ Attenuates Brain Injury by Suppressing Inflammation and Apoptosis in a Collagenase-Induced Intracerebral Hemorrhage Mouse Model

“…Previous studies have shown that activation of apoptosis plays an important role in the pathology of brain injury triggered by ICH [39,40]. The results of TUNEL staining (Fig.…”

“…Neuronal death is a crucial pathological characteristic of ICH. Loss of neurons is strongly linked to the poor outcome of patients with ICH [40]. Many factors that activate post-ICH pathophysiological pathways cause cell death in perihematomal tissue.…”

“…The extrinsic apoptotic pathway requires cell surface receptors, whereas the intrinsic pathway is initiated by mitochondrial outer membrane permeabilization and the Bcl-2 family. Bax is a member of the Bcl-2 family that promotes neuronal apoptosis; the other member is the anti-apoptotic protein Bcl-2 [40]. The Bax-Bax heterodimer forms with increased Bax expression, resulting in apoptosis.…”

Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro

“…Pyroptosis, as a pro‐inflammatory form of lytic cell death, is associated with pathogenesis in many chronic inflammatory diseases. Pyroptosis can be triggered by various pathological stimuli, such as microbial infection, heart attack, obesity, brain injury, and cancer (Bergsbaken, Fink, & Cookson, ; Bobinger, Burkardt, Huttner, & Manaenko, ; Liu et al, ). One hallmark characteristic of pyroptosis is membrane rupture, distinct from apoptosis, resulting in the release of intracellular pathogens, and pro‐inflammatory mediators (e.g., IL‐1β and IL‐18), which is induced by canonical inflammasomes activation, and can promote brain tissue injury.…”

A Role for Endoplasmic Reticulum Stress in Intracerebral Hemorrhage

“…The most common inflammasome sensors are absent in melanoma 2 (AIM2), and pyrin and nucleotide-binding oligomerization domain-like receptors (NLRs). The most prevalently studied inflammasome is NLR pyrin domain containing 3 (NLRP3) and it is thought to mediate various neurodegenerative and neurological disorders [22,27]. Pyroptosis involves the release of proinflammatory cytokines, especially IL-1β/IL-18; this, when combined with caspase-1 and inflammasome activity, causes the cells to swell and burst, thus leading to cell death.…”