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Published on: November 2, 2017
Transcranial direct current stimulation improves cerebral ischemiareperfusion injury by regulating microglial
Yongjun Gao1, Xiuli Han2, Yong Yuan1
1Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, China.
Background:
Neuroinflammation triggered by microglia plays a critical role in cerebral ischemia-reperfusion injury (CIRI). Previous studies have reported that transcranial direct current stimulation (tDCS) has ameliorative effects on CIRI, but its regulatory effect on microglia in CIRI remains poorly understood.
Methods:
A middle cerebral artery occlusion/reperfusion (MCAO/R)-induced CIRI rat model and an oxygenglucose deprivation/reperfusion (OGD/R)-induced BV2 cell injury model were established for experimental investigation. The severity of CIRI in rats and cell damage were assessed using the mNSS, TTC staining, HE staining, Nissl staining, CCK-8, and immunofluorescence. The expression levels of related proteins and cytokines were determined via Western blotting, immunohistochemistry, and ELISA.
Results:
First, tDCS treatment effectively improved CIRI in rats and inhibited M1 polarization of microglia in the ischemic penumbra. Second, ferroptosis plays an important role in OGD/R-induced BV2 cell death, and direct current stimulation (DCS) significantly suppressed OGD/R-induced ferroptosis in BV2 cells. Additionally, DCS inhibited the expression of M1 polarization markers and proinflammatory factors in BV2 cells while promoting the expression of M2 polarization markers and anti-inflammatory factors. Mechanistically, we found that KLF4 expression was downregulated in CIRI and that tDCS treatment upregulated KLF4 expression. Knockdown of KLF4 partially attenuated the therapeutic effects of tDCS on CIRI in rats. Furthermore, overexpression of KLF4 inhibited ferroptosis and M1 polarization in BV2 cells by promoting xCT expression.
Conclusion:
tDCS ameliorates CIRI in rats by suppressing microglial ferroptosis and M1 polarization through the activation of KLF4/xCT expression.
Insights
Transcranial direct current stimulation (tDCS) reduces brain injury after stroke by inhibiting microglial ferroptosis and M1 polarization. This neuroprotective effect is mediated by the KLF4/xCT pathway, offering a potential therapeutic strategy for cerebral ischemia-reperfusion injury.
Area of Science:
- Neuroscience
- Cell Biology
- Biomedical Engineering
Background:
- Microglia-driven neuroinflammation is central to cerebral ischemia-reperfusion injury (CIRI).
- Transcranial direct current stimulation (tDCS) shows promise for CIRI, but its microglial regulatory mechanisms are unclear.
Purpose of the Study:
- To investigate the effects of tDCS on microglia and its underlying mechanisms in CIRI.
- To elucidate the role of ferroptosis and KLF4 in tDCS-mediated neuroprotection.
Main Methods:
- Established rat models of middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reperfusion (OGD/R) in BV2 cells.
- Assessed CIRI severity and cell damage using neurological scores, staining, and cell viability assays.
- Analyzed protein and cytokine expression via Western blotting, immunohistochemistry, and ELISA.
Main Results:
- tDCS improved CIRI outcomes and suppressed M1 microglial polarization in rats.
- Direct current stimulation (DCS) inhibited ferroptosis and M1 polarization in BV2 cells, while promoting M2 polarization.
- tDCS upregulated KLF4, which was crucial for its therapeutic effects, and KLF4 promoted xCT expression to inhibit ferroptosis and M1 polarization.
Conclusions:
- tDCS ameliorates CIRI by suppressing microglial ferroptosis and M1 polarization.
- The KLF4/xCT pathway is a key mediator of tDCS's neuroprotective effects in CIRI.
