Necroptosis Signaling Pathways in Stroke: From Mechanisms to Therapies

Abstract

It has been confirmed that apoptosis, autophagy and necrosis are the three major modes of cell death. For a long time, necrosis is regarded as a deranged or accidental cell demise. In recent years, there is evidence showing that necrotic cell death can be a well regulated and orchestrated event, which is also known as programmed cell death or "necroptosis". Necroptosis can be triggered by a variety of external stimuli and regulated by a caspase-independent pathway. It plays a key role in the pathogenesis of some diseases including neurological diseases. In the past two decades, a variety of studies have revealed that the necroptosis related pathway is activated in stroke, and plays a crucial role in the pathogenesis of stroke. Moreover, necroptosis may serve as a potential target in the therapy of stroke because genetic or pharmacological inhibition of necroptosis has been shown to be neuroprotective in stroke in vitro and in vivo. In this review, we briefly summarize recent advances in necroptosis, introduce the mechanism and strategies targeting necroptosis in stroke, and finally propose some issues in the treatment of stroke by targeting necroptosis.

Necroptosis: a crucial pathogenic mediator of human disease

“…Necroptosis-associated proteins have been implicated as therapeutic targets in various cardiovascular diseases, including heart failure, myocardial injury, aortic aneurysm, ischemic neural injury, and stroke (7,(111)(112)(113). In a mouse model of atherosclerosis (LDL receptor deficiency), Ripk3 and Ldlr double-knockout mice displayed reduced atherosclerotic lesions during the late state of disease progression and evidence of reduced macrophage necrosis but not apoptosis (114).…”

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

“…These plant derivatives might represent a promising approach in targeting neuroinflammation, and different studies are aiming to define their optimal bioavailability, even if their use in clinic has yet to be defined [112,113]. Another therapeutic approach to reduce neuroinflammation is blocking necroptotic pathways with synthetic inhibitors (RIP1 inhibitors, RIP3 inhibitors, MLKL inhibitors) to mitigate NDD progression [114]. Drug treatments aimed at manipulating inflammasome assembly therapeutically are currently used in clinic [115], but, despite their promising efficacy, they still do not resolve the disease.…”

Caspofungin suppresses brain cell necroptosis in the ischemic stroke rat via up-regulation of Pellino3

“…Assembly of RIPK1 and RIPK3 through a series of RIPK1 and RIPK3 auto-and trans-phosphorylation events leads to the formation of necrosome complex followed by the recruitment of MLKL and creation of a supramolecular protein complex at the plasma membrane, which is responsible for executing the necroptosis [13]. The studies from other labs and ours have repeatedly demonstrated that brain cell necroptosis occurred in ischemic stroke animal models and targeting necroptosis signi cantly reduced the cerebral ischemic injury in vivo and hypoxic injury in the cultured nerve cells [14][15][16][17].Since necroptosis is mediated by RIPK1/RIPK3/MLKL signaling pathway, most of the current interventions thus focus on RIPK1, RIPK3 or MLKL. For example, necrostatin-1 can reduce infarct volume and improve neurological scores in the ischemic stroke animals via inhibition of RIPK1 while GSK'872 can prevent brain cell necroptosis in stroke rats via targeting RIPK3 [18,19].…”