Neurosurgeon Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medicine School,
Introduction: Subarachnoid hemorrhage (SAH) is a common acute disease in neurosurgery that is known for its high death and disability rates. After SAH, the inflammatory response, with microglia at its core, plays a significant role in nerve damage. It was discovered that decreasing microglia's inflammatory response and encouraging its phagocytosis could significantly boost SAH patients' prognoses. How to effectively regulate the functional transformation of microglia has become a new direction of research. As a caspase-1 inhibitor, VX765 can successfully reduce M1 microglia activation and increase M2 activation in traumatic brain injury, although it is yet unknown if VX765 can control the functional transition of SAH microglia. The purpose of this study is to determine whether VX765 can prevent microglia from causing inflammation after SAH and establish phagocytosis and its mechanism.
Methods: To create the mouse model of SAH, the internal carotid artery was punctured. By activating BV2 and primary microglia with hemoglobin (HB), an in vitro SAH model was created. Microglial function was examined using Western blotting (WB), real-time fluorescent PCR (PCR), immunofluorescence (IF), and flow cytometry (FCM). Network pharmacology predicted the likely targets of VX765 and SAH microglia functional transition, and functional recovery studies and immunoprecipitation confirmed these predictions.
Results: PCR results showed that, compared with the SAH group, VX765 significantly decreased IL-6, IL-1β, and TNF-α. IF results showed that VX765 reduced the proportion of M1-type microglia (CD86) and increased the number of M2-type microglia (CD206) after SAH. FCM also found that VX765 can increase the post-SAH CD206/CD86 ratio.
Conclusion : Inhibiting neuroinflammation, enhancing the phagocytic activity of microglia, regulating the functional shift in microglia following SAH, and protecting nerve function are all possible effects of VX765.
