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Melatonin promotes recovery from ischemic stroke by modulating microglia polarization and inhibiting oligodendrocyte
Yuanyuan Ran1, Haiyue Zhang2, Linhong Mo1
1Beijing Rehabilitation Hospital, Capital Medical University, Beijing, 100144, P. R. China.
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.
Insights
Melatonin treatment reduced white matter damage and oligodendrocyte pyroptosis after ischemic stroke by modulating microglia polarization via the RORα pathway, promoting stroke recovery.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Ischemic stroke causes white matter damage and oligodendrocyte pyroptosis.
- Microglia polarization plays a critical role in post-stroke inflammation and injury.
- The RORα/AMPKα/STAT1 pathway is implicated in neuroinflammation and cell death.
Purpose of the Study:
- To investigate the therapeutic effects of melatonin on white matter damage and oligodendrocyte pyroptosis after ischemic stroke.
- To elucidate the role of melatonin in modulating microglia polarization via the RORα/AMPKα/STAT1 pathway.
- To assess melatonin's potential as a neuroprotective agent for stroke recovery.
Main Methods:
- A middle cerebral artery occlusion (MCAO) mouse model was established.
- Melatonin was administered post-reperfusion, and neurological function and white matter damage were assessed.
- In vitro studies utilized oxygen-glucose deprivation (OGD) and Transwell co-cultures to examine oligodendrocyte pyroptosis and microglia polarization, with RORα modulation via siRNA and shRNA.
Main Results:
- Melatonin administration significantly reduced white matter injury and inhibited oligodendrocyte pyroptosis.
- Melatonin treatment improved sensorimotor function and shifted microglia towards an anti-inflammatory phenotype.
- These beneficial effects were dependent on RORα signaling and linked to the inhibition of pyroptosis markers (caspase-1, GSDMD).
Conclusions:
- Melatonin demonstrates neuroprotective effects in ischemic stroke by reducing neuroinflammation and preserving white matter integrity.
- The therapeutic action of melatonin is mediated through the RORα signaling pathway, influencing microglia polarization and inhibiting oligodendrocyte pyroptosis.
- Melatonin holds promise as a potential therapeutic agent for enhancing stroke recovery.
Related Concept Videos
01:15Ischemic Stroke ll: Pathophysiology
01:15Ischemic Stroke l: Introduction