Scholarlink

<p>Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequently accompanied by cognitive deficits for which effective treatments are lacking. Neuroinflammation, particularly microglia-mediated immune responses, is pivotal in epileptogenesis. Although the stimulator of interferon genes (STING) pathway is a key cytosolic DNA-sensing mechanism driving innate immunity, its specific role in epilepsy-related cognitive dysfunction remains unclear. This study investigated the function of the STING pathway in epilepsy pathology and its therapeutic potential. Adult male Sprague-Dawley rats (250–300&#xa0;g) were subjected to lithium chloride-pilocarpine-induced status epilepticus (SE). The study consisted of two parts. In the first part, the temporal expression of hippocampal STING was examined at 1, 3, 7, 14, and 30 days after SE. In the second part, rats were randomly divided into control (Con+Vehicle), epilepsy (EP+Vehicle), and C-176-treated (EP + C-176) groups. Vehicle (1000 µL) or C-176 (2&#xa0;mg/rat in 1000 µL) was administered intraperitoneally once daily from 1&#xa0;day before SE to 6 days after SE. Seizure severity was assessed using the Racine scale. Hippocampal tissues were collected on day 7 after SE for analysis, and cognitive function was evaluated by the Morris water maze test on days 30–35 after SE. The results showed that hippocampal STING expression peaked on day 7 after SE compared with the control group, accompanied by cytosolic double-stranded DNA (dsDNA) accumulation and a shift of microglia toward a pro-inflammatory M1 phenotype. C-176 treatment significantly inhibited STING expression, reduced p-TBK1 and p-NF-κB p65 levels, reversed M1 microglial polarization with decreased iNOS and increased Arg-1 expression, decreased levels of pro-inflammatory cytokines (including IL-6, cleaved IL-1β, and TNF-α), attenuated neuronal damage, and improved learning and memory in SE rats. Our findings suggest that status epilepticus induces neuronal injury and dsDNA release, activating the STING pathway in microglia and driving neuroinflammation via the TBK1/NF-κB axis, leading to cognitive dysfunction. Inhibiting STING alleviates these effects by promoting microglial phenotypic switching from M1 to M2 via regulation of the TBK1/NF-κB pathway. This study identifies STING as a critical regulator of neuroinflammation and a novel therapeutic target for epilepsy-related cognitive dysfunction.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

STING Mediates Microglial Polarization to Promote Neuroinflammation in Epilepsy-Related Cognitive Dysfunction

  • 期刊论文

  • 发表日期：

    2026年3月25日

查看全文
  • Hongmei Yang,
  • Weina Wang,
  • Xiang Liu,
  • Mengting Shi,
  • Houfen Wang,
  • Xuling Wu,
  • Ying Liu,
  • Yunli Yu

摘要

Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequently accompanied by cognitive deficits for which effective treatments are lacking. Neuroinflammation, particularly microglia-mediated immune responses, is pivotal in epileptogenesis. Although the stimulator of interferon genes (STING) pathway is a key cytosolic DNA-sensing mechanism driving innate immunity, its specific role in epilepsy-related cognitive dysfunction remains unclear. This study investigated the function of the STING pathway in epilepsy pathology and its therapeutic potential. Adult male Sprague-Dawley rats (250–300 g) were subjected to lithium chloride-pilocarpine-induced status epilepticus (SE). The study consisted of two parts. In the first part, the temporal expression of hippocampal STING was examined at 1, 3, 7, 14, and 30 days after SE. In the second part, rats were randomly divided into control (Con+Vehicle), epilepsy (EP+Vehicle), and C-176-treated (EP + C-176) groups. Vehicle (1000 µL) or C-176 (2 mg/rat in 1000 µL) was administered intraperitoneally once daily from 1 day before SE to 6 days after SE. Seizure severity was assessed using the Racine scale. Hippocampal tissues were collected on day 7 after SE for analysis, and cognitive function was evaluated by the Morris water maze test on days 30–35 after SE. The results showed that hippocampal STING expression peaked on day 7 after SE compared with the control group, accompanied by cytosolic double-stranded DNA (dsDNA) accumulation and a shift of microglia toward a pro-inflammatory M1 phenotype. C-176 treatment significantly inhibited STING expression, reduced p-TBK1 and p-NF-κB p65 levels, reversed M1 microglial polarization with decreased iNOS and increased Arg-1 expression, decreased levels of pro-inflammatory cytokines (including IL-6, cleaved IL-1β, and TNF-α), attenuated neuronal damage, and improved learning and memory in SE rats. Our findings suggest that status epilepticus induces neuronal injury and dsDNA release, activating the STING pathway in microglia and driving neuroinflammation via the TBK1/NF-κB axis, leading to cognitive dysfunction. Inhibiting STING alleviates these effects by promoting microglial phenotypic switching from M1 to M2 via regulation of the TBK1/NF-κB pathway. This study identifies STING as a critical regulator of neuroinflammation and a novel therapeutic target for epilepsy-related cognitive dysfunction.

Graphical Abstract