Abstract
Subarachnoid hemorrhage (SAH) is a cerebrovascular disease associated with high morbidity and mortality. CXCR4 provides neuroprotective effects, which can alleviate brain injury and inflammation induced by stroke. Previous studies have suggested that CXCR4 reduces the pyroptosis of LPS-stimulated BV2 cells. The purpose of this study was to evaluate the antipyroptosis effects and mechanisms of CXCR4 after SAH. SAH animal model was induced via endovascular perforation. A total of 136 male Sprague-Dawley rats were used. Recombinant human cysteine-X-cysteine chemokine ligand 12 (rh-CXCL-12) was administered intranasally at 1 h after SAH induction. To investigate the underlying mechanism, the inhibitor of CXCR4, AMD3100, was administered intraperitoneally at 1 h before SAH. The neurobehavior tests were assessed, followed by performing Western blot and immunofluorescence staining. The Western blot results suggested that the expressions of endogenous CXCL-12, CXCR4, and NLRP1 were increased and peaked at 24 h following SAH. Immunofluorescence staining showed that CXCR4 was expressed on neurons, microglia, and astrocytes. Rh-CXCL-12 treatment improved the neurological deficits and reduced the number of FJC-positive cells, IL-18-positive neurons, and cleaved caspase-1(CC-1)-positive neurons after SAH. Meanwhile, rh-CXCL-12 treatment increased the levels of CXCL-12 and CXCR4, and reduced the levels of NLRP1, IL-18, IL-1β, and CC-1. Moreover, the administration of AMD3100 abolished antipyroptosis effects of CXCL-12 and its regulation of CXCR4 post-SAH. The CXCR4/NLRP1 signaling pathway may be involved in CXCL-12-mediated neuronal pyroptosis after SAH. Early administration of CXCL-12 may be a preventive and therapeutic strategy against brain injury after SAH.
Highlights
The novel coronavirus disease 2019 (COVID-19) is a global pandemic with international concern
Our results showed that the activation of CXC chemokine receptor type 4 (CXCR4) with rh-CXCL-12 may exert a neuroprotective effect and improve neurological function by reducing neuronal pyroptosis after subarachnoid hemorrhage (SAH), and these effects were at least in part via activation of the CXCR4/NACHT Leucine-rich-repeat protein 1 (NLRP1) signaling pathway
We found that CXCR4 colocalized with neurons, microglia, and astrocytes using the double immunofluorescence method, and the number of CXCR4-positive neurons, microglia, and astrocytes was significantly increased at 24 after SAH, which indicated that CXCR4 was involved in neuronal pyroptosis in Early brain injury (EBI) after SAH
Summary
The novel coronavirus disease 2019 (COVID-19) is a global pandemic with international concern. Aneurysmal subarachnoid hemorrhage (SAH) is a devastating and life-threatening disease associated with high mortality and disability [1, 2]. The annual worldwide incidence of SAH is approximately 9.1 per 100,000 people [3], and SAH resulting from intracranial aneurysm rupture accounts for 5-10% of strokes [4]. Brain injury (EBI) appears in the first 3 days following SAH, which is the major cause of poor prognosis regarding high mortality and delayed neurological deficits. EBI begins immediately after a ruptured intracranial aneurysm, which has been proven to be the primary cause of poor outcome after SAH. During the EBI period, ruptured intracranial aneurysms result in many physiological derangements, including elevated intracranial pressure, decreased cerebral blood flow, and global cerebral ischemia
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