A systematic review on the dual roles of microRNAs in ischemic stroke: mechanisms and effects.

BACKGROUND

MicroRNAs (miRNAs) regulate key pathways in ischemic stroke with both protective and detrimental effects. Understanding these dual roles is important to developing novel therapeutic strategies for cerebral ischemia. This systematic review highlights key miRNAs under investigation, the dysregulation of miRNA expression, and the overall mechanism of miRNA function after ischemic stroke.

METHODS

A total of 20 preclinical in vivo studies from multiple databases (PubMed, Scopus, and Web of Science (WoS)) that modulate miRNA expression post-stroke, published within the last 5 years, were analyzed. To confirm its effectiveness, studies must include miRNA expression level, neurological function test, and infarction volume. Due to the heterogeneity of these studies, as evaluated by the SYRCLE risk of bias tool, a descriptive synthesis was employed to summarize the findings. This review was registered with PROSPERO (CRD42024552558).

RESULTS

During the onset of ischemia, there is a sudden upregulation of detrimental miRNAs, accompanied by downregulation of beneficial neuroprotective miRNAs. Beneficial miRNAs inhibited apoptosis, suppressed inflammation, reduced oxidative damage, protected the blood-brain barrier (BBB), promoted angiogenesis, and stimulated neurogenesis. Detrimental miRNAs inhibited critical neuroprotective signaling pathways, suppressed cellular defense mechanisms, promoted Reactive oxygen species (ROS) production, and accelerated ischemic injury. Some miRNAs play dual roles, promoting both apoptosis and neurogenesis.

DISCUSSION: MiRNA modulation demonstrated greater therapeutic potential when used in rationally designed combination therapies, such as two beneficial miRNAs (e.g., miR-210 + miR-126) or a combination of miRNA with other agents (e.g., miR-199a-5p inhibitor + AKT activator IGF-1). Despite the enormous potential of miRNA modulation therapy and numerous preclinical data, translating it from bench to bedside remains a challenge.

CONCLUSION

MiRNAs play dual roles in ischemic stroke, mediating both injury and repair. Their pleiotropic actions position them as promising multi-targeted candidates for stroke therapy, provided translational barriers can be overcome.