Ursolic acid ameliorates traumatic brain injury in mice by regulating microRNA-141-mediated PDCD4/PI3K/AKT signaling pathway

Abstract

Background: Neuronal apoptosis and inflammation are the key pathogenic features of secondary brain injury, which results in the neurological impairment that traumatic brain injury (TBI) patients experience. Ursolic Acid (UA) has been shown to have neuroprotective properties against brain damage, however, detailed mechanisms have not been fully disclosed. Research on brain-related microRNAs (miRNAs) has opened up new possibilities for the neuroprotective treatment of UA by manipulating miRNAs. The present study was designed to investigate the impact of UA on neuronal apoptosis and the inflammatory response in TBI mice.

Methods: The mice's neurologic condition was assessed using the modified neurological severity score (mNSS) and the learning and memory abilities were assessed using the Morris water maze (MWM). Cell apoptosis, oxidative stress, and inflammation were utilized to examine the impact of UA on neuronal pathological damage. miR-141-3p was selected to evaluate whether UA influences miRNAs in a way that has neuroprotective benefits.

Results: The results showed that UA markedly decreased brain edema and neuronal mortality through oxidative stress and neuroinflammation in TBI mice. Using data from the GEO database, we found that miR-141-3p was considerably downregulated in TBI mice and that this downregulation was reversed by UA treatment. Further studies have shown that UA regulates miR-141-3p expression to exhibit its neuroprotective effect in mouse models and cell injury models. Then, miR-141-3p was discovered to directly target PDCD4 in TBI mice and neurons, a well-known PI3K/AKT pathway regulator in the neurons. Most importantly, the upregulation of phosphorylated (p)-AKT and p-PI3K provided the most compelling evidence that UA reactivated the PI3K/AKT pathway in the TBI mouse model, which was through regulating miR-141-3p.

Conclusion: Our findings support the notion that UA can improve TBI by modulating miR-141 mediated PDCD4/PI3K/AKT signaling pathway.

Keywords: PDCD4; PI3K/AKT pathway; Traumatic brain injury; Ursolic Acid; miR-141-3p.