Abstract: Blood-brain barrier (BBB) disruption underlies the vasogenic edema and neuronal cell death induced by acute ischemic stroke. Reducing this disruption has therapeutic potential. Transcranial focused ultrasound stimulation has shown neuromodulatory and neuroprotective effects in various brain diseases including ischemic stroke. Ultrasound stimulation can reduce inflammation and promote angiogenesis and neural circuit remodeling. However, its effect on the BBB in the acute phase of ischemic stroke is unknown. In this study of mice subjected to middle cerebral artery occlusion for 90 minutes, low-intensity low-frequency (0.5 MHz) transcranial focused ultrasound stimulation was applied 2, 4, and 8 hours after occlusion. Ultrasound stimulation reduced edema volume, improved neurobehavioral outcomes, improved BBB integrity (enhanced tight junction protein ZO-1 expression and reduced IgG leakage), and reduced secretion of the inflammatory factors tumor necrosis factor-α and activation of matrix metalloproteinase-9 in the ischemic brain. Our results show that low-intensity ultrasound stimulation attenuated BBB disruption and edema formation, which suggests it may have therapeutic use in ischemic brain disease as a protector of BBB integrity. 

Key words: blood-brain barrier, brain edema, cerebral blood flow, ischemia, matrix metalloproteinase-9, neurobehavioral outcomes, tight junction, transcranial ultrasound