MALAT1 Up-Regulator Polydatin Protects Brain Microvascular Integrity and Ameliorates Stroke Through C/EBP/MALAT1/CREB/PGC-1/PPAR Pathway

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA contributing to protect the blood-brain barrier (BBB) after stroke. We searched for small molecules that may up-regulate MALAT1 and focused on polydatin (PD), a natural product, as a possible candidate. PD enhanced MALAT1 gene expression in rat brain microvascular endothelial cells, reducing cell toxicity and apoptosis after oxygen and glucose deprivation (OGD). These effects correlated with reduction of inflammatory factors and enhancement of expression of BBB markers. We found opposite changes after MALAT1 silencing. We determined that C/EBP is a key transcription factor for PD-mediated MALAT1 expression. PPAR activity is involved in MALAT1 protective effects through its coactivator PGC-1 and the transcription factor CREB. This suggests that PD activates the MALAT1/CREB/PGC-1/PPAR signaling pathway to protect endothelial cells against ischemia. PD administration to rats subjected to brain ischemia by transient middle cerebral artery occlusion (tMCAO) reduced cerebral infarct volume and brain inflammation, protected cerebrovascular endothelial cells and BBB integrity. These effects correlated with increased expression of MALAT1, C/EBP, and PGC-1. Our results strongly suggest that the beneficial effects of PD involve the C/EBP/MALAT1/CREB/PGC-1/PPAR pathway, which may provide a novel therapeutic strategy for brain ischemic stroke.