Kortikal Yayılan Depolarizasyonun cGAS-STING Yolağı Üzerindeki Etkisinin Araştırılması

Abstract

Cortical spreading depolarization (CSD) is a slowly spreading neuronal and glial depolarization wave through the cortex. CSD plays roles in ischemic and traumatic brain injury and it is thought to be responsible for aura and headache in migraine. CSD starts a sterile neuroinflammatory response in brain parenchyma and meninges. cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is an innate immune system pathway that induces type 1 interferon and inflammatory cytokine synthesis in the cell. It has been shown to have important roles in neuroinflammation and nociception. In this study, we aimed to elucidate the roles of cGAS-STING pathway in CSD-associated neuroinflammation and nociception. CSD was induced with non-invasive optogenetic method in Thy1-ChR2-YFP transgenic mice and cGAS-STING pathway activation in the cerebral cortex was investigated with immunofluorescent staining and capillary based Western blotting (WES). Expression of pathway proteins were assessed in neuron, astrocyte and microglia cell types. Additionally, cGAS-STING pathway activity was pharmacologically manipulated with specific STING antagonist C-176 (20 mg/kg) and STING agonist 2’3’ cGAMP (1 mg/kg) and its effects on CSD-associated microglial activation, CSD susceptibility and CSD-associated nociceptive behaviours were assessed. After CSD induction, cGAS-STING pathway activation and interferon-β synthesis was observed predominantly in neurons in the cerebral cortex with downstream effects on microglial activation. Pathway activation with 2’3’cGAMP decreased CSD susceptibility and significantly alleviated the development of periorbital allodynia following CSD. Our findings suggested that cGAS-STING pathway plays a role in CSD-associated neuroinflammation and nociception and that STING modulation has a therapeutic potential in CSD-associated neurological disorders.

This study is supported by Hacettepe University Scientific Research Projects Coordination Unit (Project no: TSA-2022-19749), Council of Higher Education (100/2000 PhD scholarship) and The Scientific and Technological Research Institution of Turkey (TÜBİTAK, 2211-A PhD scholarship).