Targeting pyroptosis as a preventive and therapeutic approach for stroke

Abstract

Stroke has caused tremendous social stress worldwide, yet despite decades of research and development of new stroke drugs, most have failed and rt-PA (Recombinant tissue plasminogen activator) is still the accepted treatment for ischemic stroke. the complexity of the stroke mechanism has led to unsatisfactory efficacy of most drugs in clinical trials, indicating that there are still many gaps in our understanding of stroke. Pyroptosis is a programmed cell death (PCD) with inflammatory properties and are thought to be closely associated with stroke. Pyroptosis is regulated by the GSDMD of the gasdermin family, which when cleaved by Caspase-1/Caspase-11 into N-GSDMD with pore-forming activity can bind to the plasma membrane to form small 10–20 nm pores, which would allow the release of inflammatory factors IL-18 and IL-1β before cell rupture, greatly exacerbating the inflammatory response. The pyroptosis occurs mainly in the border zone of cerebral infarction, and glial cells, neuronal cells and brain microvascular endothelial cells (BMECs) all undergo pyroptosis after stroke, which largely exacerbates the breakdown of the blood-brain barrier (BBB) and thus aggravates brain injury. Therefore, pyroptosis may be a good direction for the treatment of stroke. In this review, we focus on the latest mechanisms of action of pyroptosis and the process by which pyroptosis regulates stroke development. We also suggest potential therapeutic stroke drugs that target the pyroptosis pathway, providing additional therapeutic strategies for the clinical management of stroke.

Caspase-1 deletion reveals pyroptosis participates in neural damage induced by cerebral ischemia/reperfusion in tMCAO model mice

“…The blockade of NLRP3/caspase-1/GSDMD pathway should be considered as the reasonable approach to against the pyroptosis process, as evidenced by a recent study [19]. Furthermore, literature suggests that the pyroptosis might participate in ischemic stroke at multiple sites [25]. Some evidence indicates that pyroptosis mostly happens in glia, while other work and our study show the process also happens in neuron [26].…”

“…Ischemic stroke could cause devastating brain damage and functional deficits, but the detail molecular mechanism is still unclear. Ample evidence suggests that programmed cell death pathways and inflammatory response might be critical [2,20], such as apoptosis [21], necrosis [22], autophagy [23], ferroptosis [24], and pyroptosis [25]. Previous studies show that these pathways have respective manners in the distinct regions after ischemia/reperfusion attack.…”

“…Meanwhile, the expression of pyroptosis-related proteins significantly increased at 24 h, but not 6 h post ischemia/reperfusion attack. As the salvable site, penumbra is the most important for prevention of the developing damage after ischemia/reperfusion, so the downregulation of pyroptosis is considered as a potential strategy in clinics [25], compared with the ischemic core that causes deeply neuronal death [22]. Thus, the molecular mechanism of ischemia/reperfusion-related pyroptosis should be increasingly raising concerns [25].…”

Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

“…During cerebral ischemia, the activation of inflammasomes leads to the activation of caspase-1, which cleaves pro-IL-1β and IL-17 to produce IL-1β and IL-17, respectively, both of which are key inflammatory cytokines, inducing neuronal death along with other pro-inflammatory factors during pyroptosis [ 44 ]. Therefore, the mechanisms by which pyroptosis contributes to neuronal death in IS is believed to be the release of pro-inflammatory factors and the activation of inflammatory pathways, leading to neuroinflammation and exacerbating the damage caused by ischemia [ 45 ].…”

Mechanisms of immune response and cell death in ischemic stroke and their regulation by natural compounds

“…Pyroptosis is a form of regulatory necrosis mediated by caspase-1 and is mainly seen in the ischemic penumbra. Pyroptosis can be divided into inflammatory and non-inflammatory pathways ( 146 ). Inflammatory pathway is the main pathway, one is the classical inflammatory pathway mediated by caspase-1, the other is the non-classical inflammatory pathway mediated by caspase-11.…”