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Background <p>This study investigates how melatonin affects white matter damage and oligodendrocyte pyroptosis after ischemic stroke by modulating microglia polarization through the RORα/AMPKα/STAT1 pathway.</p> Methods <p>A mouse model of middle cerebral artery occlusion (MCAO) was used, with melatonin (20&#xa0;mg/kg) administered post-reperfusion and daily for 14 days. Neurological function and white matter damage were assessed, along with gasdermin D (GSDMD) and caspase-1 expression to evaluate pyroptosis. In vitro, a Transwell co-culture system of microglia and oligodendrocytes exposed to oxygen-glucose deprivation (OGD) was employed. The role of RORα in modulating microglia polarization and oligodendrocyte pyroptosis was explored using siRNA-mediated knockdown and AAV-based RORα shRNA microinjection.</p> Results <p>Melatonin reduced white matter injury, inhibited oligodendrocyte pyroptosis, and improved sensorimotor function. These effects were linked to reduced APC/caspase-1 and APC/GSDMD double-positive cells and were dependent on RORα signaling. Melatonin also shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype, an effect reversed by RORα knockdown. In vitro, melatonin inhibited OGD-induced pyroptosis via the RORα/AMPKα/STAT1 pathway.</p> Conclusions <p>These findings suggest that melatonin promotes long-term recovery by reducing neuroinflammation and protecting white matter integrity through RORα signaling, highlighting its potential as a therapeutic agent for stroke recovery.</p>

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Melatonin promotes recovery from ischemic stroke by modulating microglia polarization and inhibiting oligodendrocyte pyroptosis via the RORα/AMPKα/STAT1 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Yuanyuan Ran,
  • Haiyue Zhang,
  • Linhong Mo,
  • Chenye Qiao,
  • Zitong Ding,
  • Haiqing Song,
  • Jianing Xi,
  • Fangming Liu,
  • Lisha Ye,
  • Shuyan Qie,
  • Guohua Wang,
  • Zongjian Liu

摘要

Background

This study investigates how melatonin affects white matter damage and oligodendrocyte pyroptosis after ischemic stroke by modulating microglia polarization through the RORα/AMPKα/STAT1 pathway.

Methods

A mouse model of middle cerebral artery occlusion (MCAO) was used, with melatonin (20 mg/kg) administered post-reperfusion and daily for 14 days. Neurological function and white matter damage were assessed, along with gasdermin D (GSDMD) and caspase-1 expression to evaluate pyroptosis. In vitro, a Transwell co-culture system of microglia and oligodendrocytes exposed to oxygen-glucose deprivation (OGD) was employed. The role of RORα in modulating microglia polarization and oligodendrocyte pyroptosis was explored using siRNA-mediated knockdown and AAV-based RORα shRNA microinjection.

Results

Melatonin reduced white matter injury, inhibited oligodendrocyte pyroptosis, and improved sensorimotor function. These effects were linked to reduced APC/caspase-1 and APC/GSDMD double-positive cells and were dependent on RORα signaling. Melatonin also shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype, an effect reversed by RORα knockdown. In vitro, melatonin inhibited OGD-induced pyroptosis via the RORα/AMPKα/STAT1 pathway.

Conclusions

These findings suggest that melatonin promotes long-term recovery by reducing neuroinflammation and protecting white matter integrity through RORα signaling, highlighting its potential as a therapeutic agent for stroke recovery.