Atorvastatin ameliorates early brain injury after subarachnoid hemorrhage via inhibition of pyroptosis and neuroinflammation

Abstract

Subarachnoid hemorrhage (SAH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapy. Atorvastatin has been reported to alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH) via reducing reactive oxygen species, antiapoptosis, regulated autophagy, and neuroinflammation. Which was the related to the pyroptosis? Pyroptosis can be defined as a highly specific inflammatory programmed cell death, distinct from classical apoptosis and necrosis. However, the precise role of pyroptosis in atorvastatin‐mediated neuroprotection following SAH has not been confirmed. The present study aimed to investigate the neuroprotection and potential molecular mechanisms of atorvastatin in the SAH‐induced EBI via regulating neural pyroptosis using the filament perforation model of SAH in male C57BL/6 mice, and the hemin‐induced neuron damage model in HT‐22. Atorvastatin or vehicle was administrated 2 h after SAH and hemin‐induced neuron damage. The mortality, neurological score, brain water content, and neuronal death were evaluated. The results show that the atorvastatin treatment markedly increased survival rate, neurological score, greater survival of neurons, downregulated the protein expression of NLRP1, cleaved caspase‐1, interleukin‐1β (IL‐1β), and IL‐18, which indicated that atorvastatin‐inhibited pyroptosis and neuroinflammation, ameliorated neuron death in vivo/vitro subjected to SAH. Taken together, this study demonstrates that atorvastatin improved the neurological outcome in rats and reduced the neuron death by against neural pyroptosis and neuroinflammation.

Hydrogen gas post‑conditioning attenuates early neuronal pyroptosis in a rat model of subarachnoid hemorrhage through the mitoKATP signaling pathway

“…A number of previous studies have demonstrated that SAH-induced brain injury can be alleviated by modulating ROS and caspase-dependent neuronal death ( 31-33 ). In agreement with a previous study, brain edema and cortical neuronal pyroptosis was observed in a SAH model, where the pathologic changes may be attributed to deficits in neurologic function ( 34 ). In addition, it was also shown that brain edema occurred on bilateral hemisphere regardless of the perforation side ( 2 ).…”

Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

“…The severity of brain edema was evaluated by measuring the brain water content using the standard wet-dry method, as previously reported ( 15 , 33 , 34 ). The mice were sacrificed 72 h following ICH, and the entire brain was harvested and separated into the ipsilateral and contralateral cortex, ipsilateral and contralateral basal ganglia, and cerebellum (wet weight).…”

“…Cells were then washed in prewarmed PBS (37°C) and assessed by an MTT assay as per the manufacturer's instructions (Promega Corporation). As determined in a prior study ( 15 ), neurons were stimulated with 80 mM hemin for 72 h to mimic intracranial hemorrhage conditions.…”

“…Increasing evidence shows that red blood cell debris, hemoglobin, its degradation products, and blood components trigger secondary brain injury following ICH and contribute to a series of damaging events, including neuroinflammation, brain edema, oxidative stress, blood-brain barrier damage, and neuronal death ( 9 – 14 ). In recent years, an increasing number of studies have been conducted with a focus on the mechanisms underlying ICH-induced secondary injury to investigate better therapeutic targets for ICH ( 6 , 15 ).…”

APC Overexpression Suppresses the Pyroptosis of Subarachnoid Hemorrhage Model Cells through Regulating NLRP3 Inflammasome Pathway

“…Additionally, previous studies indicated that NLRP3 in ammasome could activate caspase-1 and promote the secretion of proin ammatory cytokines (IL-1β and IL-18) (Kelley, et al 2019). Pyroptosis, which was activated by IL-1β and IL-18, was implicated to induce neuroin ammation in SAH-induced EBI (Chen, et al 2021). Our study showed that the application of 3K3A-APC and the inhibition of NLRP3 could signi cantly reduce the level of IL-1β and IL-18 as well as the proportion of pyroptosis cells in SAH rat and cell models.…”