Perspectives on the mechanism of pyroptosis after intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a highly harmful neurological disorder with high rates of mortality, disability, and recurrence. However, effective therapies are not currently available. Secondary immune injury and cell death are the leading causes of brain injury and a poor prognosis. Pyroptosis is a recently discovered form of programmed cell death that differs from apoptosis and necrosis and is mediated by gasdermin proteins. Pyroptosis is caused by multiple pathways that eventually form pores in the cell membrane, facilitating the release of inflammatory substances and causing the cell to rupture and die. Pyroptosis occurs in neurons, glial cells, and endothelial cells after ICH. Furthermore, pyroptosis causes cell death and releases inflammatory factors such as interleukin (IL)-1β and IL-18, leading to a secondary immune-inflammatory response and further brain damage. The NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway plays the most critical role in pyroptosis after ICH. Pyroptosis can be inhibited by directly targeting NLRP3 or its upstream molecules, or directly interfering with caspase-1 expression and GSDMD formation, thus significantly improving the prognosis of ICH. The present review discusses key pathological pathways and regulatory mechanisms of pyroptosis after ICH and suggests possible intervention strategies to mitigate pyroptosis and brain dysfunction after ICH.

Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission

“…37 The canonical pyroptosis pathway is induced by an NLRP3 inflammasome sensor that can detect the DAMPs released after ICH. 7,15 NLRP3 binds adaptor protein ASC and subsequently activates caspase-1. Cl-caspase-1 enables the maturation of the pro–IL-1β and pro–IL-18 and the activation of GSDMD.…”

“…As ASC/NLRP3 inflammasome can activate caspase-1 and GSDMD to facilitate neuronal pyroptosis, 7 co-staining of NeuN with caspase-1 and GSDMD was applied to assess the neuronal pyroptosis 3 days after ICH. Compared with the sham group, more caspase-1-positive and GSDMD-positive neurons in the perihematomal region were observed, which were significantly reduced by OXT (Figure 2D through 2F).…”

“…6 DAMPs (damage-associated molecular patterns) released after ICH triggers the activation of NLRP3 (NOD-like receptor protein 3). 7,8 NLRP3 binds ASC (apoptosis-associated speck-like protein containing a CARD) and recruits caspase-1 to oligomerize inflammasomes. 9 The inflammasome cleaves caspase-1 into a mature form, cl-caspase-1 (cleaved caspase-1), that can process pro–IL (interleukin)-1β, pro–IL-18, and GSDMD (gasdermin D) to active IL-1β, IL-18, and N-GSDMD (N-terminal pore-forming domain of GSDMD).…”

“…10 These inflammatory cytokines aggravate the local neuroinflammation and further amplify the neuronal pyroptosis. 7 Thus, suppressing neuronal pyroptosis and inflammation could be a potential therapeutic approach to improve the poor prognosis of patients with ICH.…”

LDC7559 inhibits microglial activation and GSDMD-dependent pyroptosis after subarachnoid hemorrhage

“…Evidence indicates that different forms of cell death can occur in pathological processes of inflammatory response. In addition to common cell death, pyroptosis can be driven by inflammatory processes ( 9 , 10 ). Gasdermin D (GSDMD) is the inducer of pyroptosis.…”