Necroptosis is one of the modalities of cell death accompanying ischemic brain stroke: from pathogenesis to therapeutic possibilities

Abstract

Due to very limited therapeutic options, ischemic brain injury is one of the leading causes of death and lifelong disability worldwide, which imposes enormous public health burden. One of the main events occurring with ischemic brain stroke is cell death. Necroptosis is a type of cell death described as a regulated necrosis characterized by cell membrane disruption mediated by phosphorylated mixed lineage kinase like protein (MLKL). It can be triggered by activation of death receptors (eg, FAS, TNFR1), which lead to receptor-interacting serine/threonine-protein kinase 3 (RIPK3) activation by RIPK1 in the absence of active caspase-8. Here, we review articles that have reported that necroptosis significantly contributes to negative events occurring with the ischemic brain stroke, and that its inhibition is protective both in vitro and in vivo . We also review articles describing positive effects obtained by reducing necroptosis, including the reduction of infarct volume and improved functional recovery in animal models. Since necroptosis is characterized by cell content leakage and subsequent inflammation, in addition to reducing cell death, inhibition of necroptosis in ischemic brain stroke also reduces some inflammatory cytokines. By comparing various approaches in inhibition of necroptosis, we analyze the achieved effects from the perspective of controlling necroptosis as a part of future therapeutic interventions in brain ischemia.

Regenerative Neurology and Regenerative Cardiology: Shared Hurdles and Achievements

“…At this stage, clinically confirmed beneficial effects were shown by CTX0E03 cells (hNSCs), administered one month after cerebral ischemia (a single intracerebral dose of up to 20 million cells), and SB623 (allogeneic MSCs), administered several times with 2.5, 5, and 10 million cells for a period of 6–60 months after stroke [ 129 , 131 ]. As the systemic inflammatory response is a major pathological component in secondary post-ischemic cell death [ 156 ], including some specific types of death, like necroptosis [ 157 ], stem cell transplantation should to be the therapy of choice to reduce neuroinflammatory effects and help stroke outcomes. Considerable numbers of clinical trials with stem cell therapy for stroke are currently underway.…”

Calcium/Calmodulin–Dependent Protein Kinase II in Cerebrovascular Diseases

“…Necrosis is generally identified as the cells present swollen organelle phenotypes, which subsequently burst to release their contents into the extracellular space, whereas apoptotic cells undergo nuclear and cytoplasmic condensation, followed by cell fragmentation and phagocytosis by phagocytes [ 91 ]. Necrosis occurs during first post-stroke minutes, primarily in the ischemic core [ 92 , 93 ], whereas apoptosis develops later, for hours or days, mainly in the surrounding penumbra. Overloaded cytosolic Ca 2+ can induce necrosis via activation of proteases, phospholipases, and mitochondrial permeability transition [ 94 ].…”

Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications

“…Of note, it is also involved in the regulation of the immune system and inflammatory response and participates in the elimination of infected cells in host defense [31,53]. Thus, great caution should be exercised when using necroptosis inhibitors for the management of age-associated ND, since their chronic administration could evoke undesired effects in immune system functioning [20,54]. Nevertheless, some experimental data from studies with transgenic models and enzymatic inhibitors suggest that RIP1, RIP3 or MLKL could be targeted for the treatment of various inflammatory, degenerative and infectious disorders including also acute and chronic neurodegenerative diseases [20,30,40,54].…”

“…In the case of ischemic stroke, the obstruction of blood supply to the brain evokes metabolic disturbances resulting in increased oxidative stress and inflammation. These events lead to non-selective death of neuronal and other types of cells, which could be further exacerbated during reperfusion [20,21]. In hemorrhagic stroke, a less common but also life-threatening form of stroke, the iron derived from blood, which enters the brain tissue, initiates a cascade of pathophysiological changes, such as depolarization, excitotoxicity, oxidative stress, disrupted ionic homeostasis, cell edema, inflammatory response and secondary BBB (blood-brain barrier) disruption [22].…”