Protective Effect of Low-Intensity Pulsed Ultrasound on Memory Impairment and Brain Damage in a Rat Model of Vascular Dementia.

Purpose To investigate the neuroprotective effects of low-intensity pulsed (LIP) ultrasound on memory impairment and central nervous system injury in a rat model of vascular dementia. Materials and Methods All animal experiments were approved by the animal care and use committee and adhered to experimental animal care guidelines. A 1.0-MHz focused ultrasound transducer was used to stimulate the brain noninvasively with 50-msec bursts at a 5% duty cycle, repetition frequency of 1 Hz, and spatial peak temporal average intensity of 528 mW/cm2. LIP ultrasound treatment was performed daily with triple sonications in each hemisphere. The duration of each sonicaton was 5 minutes, with a 5-minute interval between each sonication. Permanent bilateral common carotid artery occlusion (BCCAO) was used as a model of vascular dementia. After 2 weeks of LIP ultrasound, neuroprotective effects of LIP ultrasound were evaluated with behavioral analysis, including the passive avoidance task and elevated plus maze. Myelin content was detected with carbon 11 (11C) Pittsburgh compound B (PIB). Brain sections were stained with hematoxylin-eosin and Luxol fast blue. Two-way analysis of variance and Student t test were used for statistical analyses, with a significance level of .05. Results Protein expressions of brain-derived neurotrophic factor (BDNF) in the BCCAO rats treated with LIP ultrasound were significantly higher than those in BCCAO rats (1.1 ± 0.0 vs 0.8 ± 0.1, P < .05). BCCAO rats exhibited neuronal damage and demyelination. Compared with the BCCAO group, 11C PIB accumulation in the BCCAO rats treated with LIP ultrasound was significantly (P < .05) increased by 67.4% and 203.0% in the hippocampus and corpus callosum, respectively. Hematoxylin-eosin staining showed that neuronal injury in the hippocampal cornu ammonis 1 region was alleviated with LIP ultrasound. Luxol fast blue staining of the corpus callosum was significantly greater in the BCCAO rats treated with LIP ultrasound than in the untreated BCCAO rats (mean, 94.5% ± 2.3 [standard error] vs 86.6% ± 1.0; P < .05). Moreover, LIP ultrasound stimulation significantly improved learning and memory abilities and morphology in rats with vascular dementia compared with rats with untreated vascular dementia (P < .05). Conclusion These results suggest LIP ultrasound stimulation protects against brain injury in the hippocampus and corpus callosum in rats with vascular dementia. The beneficial effect of LIP ultrasound may be partly induced by upregulation of protein expression of BDNF. © RSNA, 2016.

Controllable permeability of blood-brain barrier and reduced brain injury through low-intensity pulsed ultrasound stimulation.

It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue. Thus, the safety issue associated with FUS-induced BBB disruption (BBBD) needs to be investigated for future clinical applications. This study demonstrated the neuroprotective effects induced by low-intensity pulsed ultrasound (LIPUS) against brain injury in the sonicated brain. Rats subjected to a BBB disruption injury received LIPUS exposure for 5 min after FUS/MB application. Measurements of BBB permeability, brain water content, and histological analysis were then carried out to evaluate the effects of LIPUS. The permeability and time window of FUS-induced BBBD can be effectively modulated with LIPUS. LIPUS also significantly reduced brain edema, neuronal death, and apoptosis in the sonicated brain. Our results show that brain injury in the FUS-induced BBBD model could be ameliorated by LIPUS and that LIPUS may be proposed as a novel treatment modality for controllable release of drugs into the brain.

Enhancement of Neurotrophic Factors in Astrocyte for Neuroprotective Effects in Brain Disorders Using Low-intensity Pulsed Ultrasound Stimulation.

BACKGROUND: Astrocytes play an important role in the growth and survival of developing neurons by secreting neurotrophic factors. OBJECTIVE: The goal of this study was to investigate how low-intensity pulsed ultrasound (LIPUS) stimulation directly affects brain astrocyte function. METHODS: Here, we report that LIPUS stimulation increased protein levels of BDNF, GDNF, VEGF, and GLUT1 in rat brain astrocytes as measured by western blot analysis. Histological outcomes including demyelination and apoptosis were examined in rats after administration of aluminum chloride (AlCl3). RESULTS: At the mechanistic level, integrin inhibitor (RGD peptide) attenuated the LIPUS-induced neurotrophic factor expression. The data suggest that neurotrophic factor protein levels may be promoted by LIPUS through activation of integrin receptor signaling. In addition, LIPUS stimulation protected cells against aluminum toxicity as demonstrated by an increase in the median lethal dose for AlCl3 from 3.77 to 6.25 mM. In in vivo histological evaluations, LIPUS significantly reduced cerebral damages in terms of myelin loss and apoptosis induced by AlCl3. CONCLUSIONS: The results of this study demonstrate that transcranial LIPUS is capable of enhancing the protein levels of neurotrophic factors, which could have neuroprotective effects against neurodegenerative diseases.