Transcranial focused ultrasound stimulation reduces vasogenic edema after middle cerebral artery occlusion in mice

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-αand 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.

Neuroprotective effect of high-dose hyperbaric oxygenation on rats with acute cerebral infarction in super-early stage:Curative comparison between 9-hour and 18-hour therapeutic protocols

BACKGROUND： Previously, only single short-time low-dose hyperbaric oxygenation （HBO） protocol was administrated to treat acute ischemic stroke in early stage and the conflicting results were obtained. There are few studies to report the outcome of administering long-time （can cover all the natural pathologic progression period） high-dose HBO to treat the disease. OBJECTIVE： To evaluate the therapeutic effect between two kinds of high-dose hyperbaric oxygenation on super-early stage of acute permanent middle cerebral artery occlusion （MCAO） in rats. DESIGN： A randomized controlled experimental study. SETTING： Beijing Tiantan Hospital, Capital Medical University; Beijing Research Institute of Neurosurgery. MATERIALS： Seventy-four male SD rats, aged 2.5 months old, weighing （ 280 ＋ 20） g, were provided by the Animal Institute, Chinese Academy of Medical Sciences. Hyperbaric oxygenation device was hyperbaric air cabin in which there was a self-made pure oxygen animal experimental cabin （made in China）. METHODS： This experiment was carried out in the municipal laboratory of Beijing Tiantan Hospital affiliated to Capital Medical University and Beijing Research Institute of Neurosurgery. ① Experimental intervention： All the rats were developed into models of permanent MCAO by suture embolism. Then, they were randomly divided into two HBO groups （9 hours and 18 hours） and control group, with 24 rats in each as well as 3-hour ultrastructure control group, with 2 rats. After being modeled for 3 hours, rats in the two HBO groups stayed in the hyperbaric cabin for 9 hours and 18 hours, separately. Rats in the 9-hour HBO group inhaled pure oxygen at hours 1, 3, 5, 7 and 9, and hyperbaric air at hours 2, 4, 6 and 8. Rats in the 18-hour HBO group inhaled pure oxygen at hours l, 3, 5, 7, 9, 11, 13, 15 and 17, and hyperbaric air at hours 2, 4, 6, 8, l0 12, 14, 16 and 18. After being created into models, rats in the control group and 3-hour ultrastructure control group breathed room air. ② Experimental evaluation： Neurologic functions of rat models in the 9-hour and 18-hour HBO groups as well as control group were scored by Bederson and Garica two neurological grading systems at hours 14 and 28 and on day 5; Infarct volume of rat models in the two HBO groups and control group was measured at hour 24 and on day 5 with NIH image processing software Image J; The pathological changes of brain tissue in the brain infarct region and its opposite region of rat models in the two HBO groups and 3-hour ultrastructure control group were observed with a Philips EM 208S transmission electron microscope. MAIN OUTCOME MEASURES： ① Neurobehavioral outcome. ② Rat brain infarct volume. ③ Ultrastructure of brain tissue in the ischemic penumbra of infarct models at the different time points RESULTS： ① Neurobehavioral outcome： After treatment, Garica score in the 9-hour and 18-hour HBO groups was significantly higher than that in the control group （P 〈 0.01）. Bederson score on day 5 after modeling in the 9-hour and 18-hour HBO groups was significantly lower than that in the control group （P 〈 0.01）. ② Cerebral infarct volume： Cerebral infarct volume in the 9-hour and 18-hour HBO groups was significantly smaller than that in the control group at hour 24 and on day 5 after modeling （P 〈 0.01）. In the 18-hour HBO group, infarct volume on day 5 after modeling was significantly larger than that at hour 24 after modeling （P 〈 0.05）. ③In the 3-hour ultrastructure control group, astrocyte edema and neuron damage around the capillary in the infarct cerebral tissue significantly relieved in the rats which were subjected to HBO. CONCLUSION： High dose of HBO is highly efficient in reducing infarct volume and improving neurobehavioral outcome of rats with acute cerebral infarction, and also has an important role in inhibiting the pathological progression of ischemic brain tissue after cerebral infarction.