Semaglutide alleviates early brain injury following subarachnoid hemorrhage by suppressing ferroptosis and neuroinflammation via SIRT1 pathway.

Abstract

Subarachnoid hemorrhage (SAH) is a major cause of incapacity and death, imposing a significant economic burden globally. Additionally, SAH is the third most prevalent form of stroke. Semaglutide affects oxidative stress, inflammation, and mitochondrial biogenesis. Specifically, the potential neuroprotective effect of semaglutide in SAH and its underlying mechanism is unclear. Accordingly, the present research intended to explore the neuroprotective effect of semaglutide in SAH and its potential molecular mechanisms. We constructed a C57BL/6 mouse model of SAH. The parameters assessed were neuronal ferroptosis, neuroinflammatory cytokine levels, reactive oxygen species (ROS) levels, glutathione (GSH) and malondialdehyde (MDA) levels, brain water content, and neurological score. The results showed that the activation of semaglutide significantly increased neurological scores, relieved cerebral edema, decreased the levels of inflammatory cytokine nuclear factor kappa B, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha, MDA, and ROS, and increased the levels of GSH. Suppression of SIRT1 reversed these effects, indicating that semaglutide activated SIRT1 to reduce neuroinflammation, ferroptosis, and neuronal cell death after SAH. Thus, the activation of the Nrf2/HO-1 signaling pathway contributes to the neuroprotective properties of semaglutide. Semaglutide can improve murine neurological outcomes and reduce neuronal damage against neuroinflammation and ferroptosis.