Inhibition of caspase-1-mediated inflammasome activation reduced blood coagulation in cerebrospinal fluid after subarachnoid haemorrhage

Abstract

Background Neuroinflammation and blood coagulation responses in cerebrospinal fluid (CSF) contribute to the poor outcome associated with subarachnoid haemorrhage (SAH). We explored the role of caspase-1-mediated inflammasome activation on extrinsic blood coagulation in CSF after SAH.Methods Post-SAH proteomic changes and correlation between caspase-1 with extrinsic coagulation factors in human CSF after SAH were analysed. Time course and cell localisation of brain inflammasome and extrinsic coagulation proteins after SAH were explored in a rat SAH model. Pharmacological inhibition of caspase-1 via VX-765 was used to explore the role of caspase-1 in blood clearance and CSF circulation after SAH in rats. Primary astrocytes were used to evaluate the role of caspase-1 in haemoglobin-induced pyroptosis and tissue factor (TF) production/ release.Findings Neuroinflammation and blood coagulation activated after SAH in human CSF. The caspase-1 levels significantly correlated with the extrinsic coagulation factors. The activated caspase-1 and extrinsic coagulation initiator TF was increased on astrocytes after SAH in rats. VX-765 attenuated neurological deficits by accelerating CSF circulation and blood clearance through inhibiting pyroptotic neuroinflammation and TF-induced fibrin deposition in the short-term, and improved learning and memory capacity by preventing hippocampal neuronal loss and hydrocephalus in the long-term after SAH in rats. VX-765 reduced haemoglobin-induced pyroptosis and TF production/release in primary astrocytes.

Rethinking the initial changes in subarachnoid haemorrhage: Focusing on real-time metabolism during early brain injury

“…One is haemolytic product-induced secondary neuroinflammatory factors, such as inflammasome-derived caspase-1 activity, which is tightly associated with blood coagulation in CSF and poor prognosis of SAH patients. 6 Elevated CSF lipocalin-2 mediates neuroinflammation and iron homeostasis and is reported to be a biomarker for unfavourable outcomes of SAH patients 7 and a potential therapeutic target for long-term neurological rehabilitation. 8 …”

Biological Effects and Mechanisms of Caspases in Early Brain Injury after Subarachnoid Hemorrhage

“…In a recent study, VX-765 treatment alleviated the release of neuroinflammatory factors caused by pyroptosis after SAH. It eased the SAH-induced loss of neurons in the hippocampal CA1 region, improving the long-term outcome of SAH [ 132 ]. An in-depth study of VX-765 might be a potential and promising direction for EBI treatment after SAH.…”

NLRP3 Inflammasome Overactivation in Patients with Aneurysmal Subarachnoid Hemorrhage

“…For instance, MCC-950 attenuated early brain injury and cerebral vasospasm after experimental SAH in animal models [49,50]. Besides, a plethora of other molecules of uneven origin rather than NLRP3i, such as melatonin [10,11], resolvin D1 [12], the HSP90 inhibitor 17-AAG [13], the saponin dioscin [14], also plant-derived antioxidants such as resveratrol, pterostilbene, and luteolin [15][16][17], caspase inhibitors [30,51,52], and commercialized drugs from ansiolitics [18][19][20] to antibiotics [21], have demonstrated to alleviate neurological deficits and improve neurobehavioral outcomes in SAH animal models by targeting, from diverse pathways, NLRP3 inflammasome axis.…”

“…Moreover, tissue factor (TF), an essential initiator of coagulation cascades involved in the pathophysiology of several diseases [27], is released from pyroptotic macrophages [28]. Interestingly, patients with aSAH present increased levels of TF in cerebrospinal fluid which was related to CVS development [29][30][31][32], suggesting a possible role of TF in aSAH severity. However, the expression of serum TF has not yet been assessed in aSAH patients.…”