Mechanism by which low-intensity focused ultrasound promotes angiogenesis and neurogenesis after traumatic brain injury in a rat model via the OXA/MAPK signaling pathway

Low-intensity focused ultrasound is a type of ultrasound that primarily relies on cavitation and mechanical effects. It is non-invasive, transient, and well tolerated. Previous studies have confirmed that low-intensity focused ultrasound can reduce neuroinflammation after traumatic brain injury and exert neuroprotective effects. However, whether it can also induce angiogenesis and neurogenesis in the brain, as well as the underlying mechanisms, remains unclear. In this preclinical study, a rat model of traumatic brain injury was established using a controlled cortical impact device. The rats were then received 14 days of low-intensity focused ultrasound treatment targeting the thalamus. The results showed that low-intensity focused ultrasound effectively reduced cerebral edema and mitigated blood-brain barrier damage in rats with traumatic brain injury, leading to improved neurological function. Further investigation showed that low-intensity focused ultrasound significantly un-regulated Orexin-A/Orexin-A receptor 1 expression, and intraperitoneal administration of the Orexin-A receptor 1 inhibitor SB334867 prevented the neuroprotective effects of low-intensity focused ultrasound. Subsequent transcriptome sequencing revealed that low-intensity focused ultrasound activated the MAPK signaling pathway. Finally, in an in vitro cell injury model created using tumor necrosis factor-alpha, low-intensity focused ultrasound enhanced endothelial cell migration, stimulated angiogenesis, and supported hippocampal neuron migration and growth. Moreover, the MAPK signaling pathway inhibitor LY3214996 suppressed these effects. Taken together, our findings suggest that low-intensity focused ultrasound enhances angiogenesis and neurogenesis and improves neurological function following traumatic brain injury by regulating the expression of Orexin-A/Orexin-A receptor 1, which activates the MAPK signaling pathway.