Magnetization transfer ratio for assessing remyelination after transcranial ultrasound stimulation in the lysolecithin rat model of multiple sclerosis.

It has been shown that transcranial ultrasound stimulation (TUS) is capable of attenuating myelin loss and providing neuroprotection in animal models of brain disorders. In this study, we investigated the ability of TUS to promote remyelination in the lysolecithin (LPC)-induced local demyelination in the hippocampus. Demyelination was induced by the micro-injection of 1.5 µL LPC (1%) into the rat hippocampus and the treated group received daily TUS for 5 or 12 days. Magnetic resonance imaging techniques, including magnetization transfer ratio (MTR) and T2-weighted imaging, were used to longitudinally characterize the demyelination model. Furthermore, the therapeutic effects of TUS on LPC-induced demyelination were assessed by Luxol fast blue (LFB) staining. Our data revealed that reductions in MTR values observed during demyelination recover almost completely upon remyelination. The MTR values in demyelinated lesions were significantly higher in TUS-treated rats than in the LPC-only group after undergoing TUS. Form histological observation, TUS significantly reduced the size of demyelinated lesion 7 days after LPC administration. This study demonstrated that MTR was a sensitive and reproducible quantitative marker to assess remyelination process in vivo during TUS treatment. These findings might open new promising treatment strategies for demyelinating diseases such as multiple sclerosis.

Low-intensity pulsed ultrasound ameliorates glia-mediated inflammation and neuronal damage in experimental intracerebral hemorrhage conditions.

BACKGROUND: Intracerebral hemorrhage (ICH) is a condition associated with high morbidity and mortality, and glia-mediated inflammation is a major contributor to neurological deficits. However, there is currently no proven effective treatment for clinical ICH. Recently, low-intensity pulsed ultrasound (LIPUS), a non-invasive method, has shown potential for neuroprotection in neurodegenerative diseases. This study aimed to investigate the neuroprotective effects and potential mechanisms of LIPUS on glia-mediated inflammation in ICH. METHODS: This study used 289 mice to investigate the effects of LIPUS on ICH. ICH was induced by injecting bacterial collagenase (type VII-S; 0.0375 U) into the striatum of the mice. LIPUS was applied noninvasively for 3 days, including a 2-h-delayed intervention to mimic clinical usage. The study evaluated neurological function, histology, brain water content, hemoglobin content, MRI, and protein expression of neurotrophic factors, inflammatory molecules, and apoptosis. In vitro studies investigated glia-mediated inflammation by adding thrombin (10 U/mL) or conditioned media to primary and cell line cultures. The PI3K inhibitor LY294002 was used to confirm the effects of PI3K/Akt signaling after LIPUS treatment. RESULTS: LIPUS treatment improved neurological deficits and reduced tissue loss, edema, and neurodegeneration after ICH. The protective effects of LIPUS resulted from decreased glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling, which reduced cytokine expression and attenuated microglial activation-induced neuronal damage in vitro. CONCLUSIONS: LIPUS treatment improved neurological outcomes and reduced glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling after ICH. LIPUS may provide a non-invasive potential management strategy for ICH.

Neuroprotection by Abdominal Ultrasound in Lipopolysaccharide-Induced Systemic Inflammation.

Systemic inflammation is associated with intestinal inflammation and neuroinflammation by imbalancing the gut-brain axis. Low-intensity pulsed ultrasound (LIPUS) has neuroprotective and anti-inflammatory effects. This study explored LIPUS's neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation through transabdominal stimulation. Male C57BL/6J mice were intraperitoneally injected with LPS (0.75 mg/kg) daily for seven days, and abdominal LIPUS was applied to the abdominal area for 15 min/day during the last six days. One day after the last LIPUS treatment, biological samples were collected for microscopic and immunohistochemical analysis. Histological examination showed that LPS administration leads to tissue damage in the colon and brain. Transabdominal LIPUS stimulation attenuated colonic damage, reducing histological score, colonic muscle thickness, and villi shortening. Furthermore, abdominal LIPUS reduced hippocampal microglial activation (labeled by ionized calcium-binding adaptor molecule-1 [Iba-1]) and neuronal cell loss (labeled by microtubule-associated protein 2 [MAP2]). Moreover, abdominal LIPUS attenuated the number of apoptotic cells in the hippocampus and cortex. Altogether, our results indicate that abdominal LIPUS stimulation attenuates LPS-induced colonic inflammation and neuroinflammation. These findings provide new insights into the treatment strategy for neuroinflammation-related brain disorders and may facilitate method development through the gut-brain axis pathway.

Low-Intensity Pulsed Ultrasound Enhances Neurotrophic Factors and Alleviates Neuroinflammation in a Rat Model of Parkinson's Disease.

Low-intensity pulsed ultrasound (LIPUS) has also been reported to improve behavioral functions in Parkinson's disease (PD) animal models; however, the effect of LIPUS stimulation on the neurotrophic factors and neuroinflammation has not yet been addressed. PD rat model was built by injection of 6-hydroxydopamine (6-OHDA) in 2 sites in the right striatum. The levels of neurotrophic factors and lipocalin-2 (LCN2)-induced neuroinflammation were quantified using a western blot. Rotational test and cylinder test were conducted biweekly for 8 weeks. When the 6-OHDA + LIPUS and 6-OHDA groups were compared, the locomotor function of the 6-OHDA + LIPUS rats was significantly improved. After LIPUS stimulation, the tyrosine hydroxylase staining density was significantly increased in the striatum and substantia nigra pars compacta (SNpc) of lesioned rats. Unilateral LIPUS stimulation did not increase brain-derived neurotrophic factor in the striatum and SNpc of lesioned rats. In contrast, unilateral LIPUS stimulation increased glial cell line-derived neurotrophic factor (GDNF) protein 1.98-fold unilaterally in the SNpc. Additionally, LCN2-induced neuroinflammation can be attenuated following LIPUS stimulation. Our data indicated that LIPUS stimulation may be a potential therapeutic tool against PD via enhancement of GDNF level and inhibition of inflammatory responses in the SNpc of the brain.

Ultrasound Neuromodulation Reduces Demyelination in a Rat Model of Multiple Sclerosis.

Microglia, astrocytes, and oligodendrocyte progenitor cells (OPCs) may serve as targets for remyelination-enhancing therapy. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to ameliorate myelin loss and inhibit neuroinflammation in animal models of brain disorders; however, the underlying mechanisms through which LIPUS stimulates remyelination and glial activation are not well-understood. This study explored the impacts of LIPUS on remyelination and resident cells following lysolecithin (LPC)-induced local demyelination in the hippocampus. Demyelination was induced by the micro-injection of 1.5 µL of 1% LPC into the rat hippocampus, and the treatment groups received daily LIPUS stimulation for 5 days. The therapeutic effects of LIPUS on LPC-induced demyelination were assessed through immunohistochemistry staining. The staining was performed to evaluate remyelination and Iba-1 staining as a microglia marker. Our data revealed that LIPUS significantly increased myelin basic protein (MBP) expression. Moreover, the IHC results showed that LIPUS significantly inhibited glial cell activation, enhanced mature oligodendrocyte density, and promoted brain-derived neurotrophic factor (BDNF) expression at the lesion site. In addition, a heterologous population of microglia with various morphologies can be found in the demyelination lesion after LIPUS treatment. These data show that LIPUS stimulation may serve as a potential treatment for accelerating remyelination through the attenuation of glial activation and the enhancement of mature oligodendrocyte density and BDNF production.

Ultrasound Stimulation Suppresses LPS-Induced Proinflammatory Responses by Regulating NF-κB and CREB Activation in Microglial Cells.

The purpose of this study was to investigate the effects and underlying mechanisms of low-intensity pulsed ultrasound (LIPUS) against lipopolysaccharide (LPS)-induced neuroinflammation. BV-2 microglia subjected to LPS administration (1 µg/mL) were treated with LIPUS stimulation. The levels of inflammatory mediators and brain-derived neurotrophic factor (BDNF) were quantified using the western blot. The results showed that LIPUS stimulation promoted the associated cAMP response element-binding protein (CREB)/BDNF expression in the LPS-treated microglia. Meanwhile, LIPUS treatment effectively suppressed the LPS-induced production of tumor necrosis factor-α, interleukin-1ß, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the microglial cells, in addition to inhibiting the LPS-induced expressions of toll-like receptor 4 and myeloid differentiation factor 88, as well as the LPS-induced activation of c-Jun N-terminal kinase and nuclear factor kappa B. Furthermore, LIPUS significantly decreased the Bax/Bcl-2 ratio in the microglia following LPS treatment. Our data indicated that LIPUS attenuated the proinflammatory responses as well as the decline in BDNF in LPS-treated microglia. This study provides a better understanding of how LIPUS stimulation regulates anti-inflammatory actions in microglia, providing further evidence suggesting that such stimulation may be regarded as a novel strategy for the treatment of neuroinflammation.

Low-Intensity Pulsed Ultrasound Attenuates LPS-Induced Neuroinflammation and Memory Impairment by Modulation of TLR4/NF-κB Signaling and CREB/BDNF Expression.

The purpose of this study was to investigate the restorative role of low-intensity pulsed ultrasound (LIPUS) against lipopolysaccharide (LPS)-induced neuroinflammation and memory impairments in a simulation of Alzheimer's disease. Mice subjected to LPS administration (250 µg/kg, i.p.) were treated with LIPUS daily for 7 days. The levels of brain-derived neurotrophic factor (BDNF) and inflammatory markers were estimated in brain tissue using western blot. After LIPUS treatment, the neuroprotective effects of LIPUS in mice were assessed by behavioral tests. LPS plus LIPUS-treated mice exhibited a significant increase in the average time spent in the target quadrant compared to the LPS-treated group. Compared with the LPS-treated group, LPS plus LIPUS-treated mice revealed a preference for the novel object. LIPUS treatment significantly attenuated LPS-induced increases in the expression of amyloid-beta (Aß) and amyloid precursor protein (APP) in the hippocampus region of LPS-treated mice. Furthermore, LIPUS significantly reduced the protein levels of TNF-α, IL-1ß, and IL-6 in the mice brain induced by LPS. LIPUS treatment induces neuroprotection by inhibiting the LPS-induced activation of TLR4/NF-κB inflammatory signaling and by enhancing the associated CREB/BDNF expression in LPS-treated mice. Our data showed that LIPUS attenuated LPS-induced memory impairment as well as amyloidogenesis via the suppression of neuroinflammatory activity and BDNF decline.

Ultrasound Enhances the Expression of Brain-Derived Neurotrophic Factor in Astrocyte Through Activation of TrkB-Akt and Calcium-CaMK Signaling Pathways.

Low-intensity pulsed ultrasound (LIPUS) stimulation has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in astrocytes of an in vitro model and rat brains of an in vivo model; however, their molecular mechanisms are still not well clarified. Here, we investigated the underlying mechanisms of BDNF enhancement by LIPUS in rat cerebral cortex astrocytes. After LIPUS stimulation in astrocytes, the protein and mRNA expressions were measured by western blot and RT-PCR, respectively. The concentration of intracellular calcium was determined spectrophotometrically. The results showed that LIPUS enhanced the phosphorylation of tropomyosin-related kinase B (TrkB) and Akt but had no effect on Erk1/2 phosphorylation. Additionally, LIPUS increased the intracellular concentration of calcium and enhanced the protein levels of calmodulin-dependent kinase (CaMK) II and CaMKIV. LIPUS also activated the phosphorylation of NF-κB-p65 but did not promote the activation of cAMP response element-binding protein (CREB). Taken together, our results suggest that LIPUS stimulation upregulates BDNF production in astrocytes through the activation of NF-κB via the TrkB/PI3K/Akt and calcium/CaMK signaling pathways. BDNF has emerged as a major molecular player in the regulation of neural circuit development and function. Therefore, LIPUS stimulation may play a crucial and beneficial role in neurodegenerative diseases.

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.

Quantitative assessment of cerebral glucose metabolic rates after blood-brain barrier disruption induced by focused ultrasound using FDG-MicroPET.

The goal of this study was to evaluate the pharmacokinetics of (18)F-2-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the expression of glucose transporter 1 (GLUT1) protein after blood-brain barrier (BBB) disruption of normal rat brains by focused ultrasound (FUS). After delivery of an intravenous bolus of ~37 MBq (1 mCi) (18)F-FDG, dynamic positron emission tomography scans were performed on rats with normal brains and those whose BBBs had been disrupted by FUS. Arterial blood sampling was collected throughout the scanning procedure. A 2-tissue compartmental model was used to estimate (18)F-FDG kinetic parameters in brain tissues. The rate constants Ki, K1, and k3 were assumed to characterize the uptake, transport, and hexokinase activity, respectively, of (18)F-FDG. The uptake of (18)F-FDG in brains significantly decreased immediately after the blood-brain barrier was disrupted. At the same time, the derived values of Ki, K1, and k3 for the sonicated brains were significantly lower than those for the control brains. In agreement with the reduction in glucose, Western blot analyses confirmed that focused ultrasound exposure significantly reduced the expression of GLUT1 protein in the brains. Furthermore, the effect of focused ultrasound on glucose uptake was transient and reversible 24h after sonication. Our results indicate that focused ultrasound may inhibit GLUT1 expression to decrease the glucose uptake in brain tissue during the period of BBB disruption.

Low-Intensity Pulsed Ultrasound Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity by Upregulating Neurotrophic Factors.

OBJECTIVE: Neonatal hypoxic-ischemic brain damage (HIBD) can have long-term implications on patients' physical and mental health, yet the available treatment options are limited. Recent research has shown that low-intensity pulsed ultrasound (LIPUS) holds promise for treating neurodegenerative diseases and traumatic brain injuries. Our objective was to explore the therapeutic potential of LIPUS for HIBD. METHODS: Due to the lack of a suitable animal model for neonatal HIBD, we will initially simulate the therapeutic effects of LIPUS on neuronal cells under oxidative stress and neuroinflammation using cell experiments. Previous studies have investigated the biologic responses following intracranial injection of 6-hydroxydopamine (6-OHDA). In this experiment, we will focus on the biologic effects produced by LIPUS treatment on neuronal cells (specifically, SH-SY5Y cells) without the presence of other neuroglial cell assistance after stimulation with 6-OHDA. RESULTS: We found that (i) pulsed ultrasound exposure, specifically three-intermittent sonication at intensities ranging from 0.1 to 0.5 W/cm², did not lead to a significant decrease in viability among SH-SY5Y cells; (ii) LIPUS treatment exhibited a positive effect on cell viability, accompanied by an increase in glial cell-derived neurotrophic factor (GDNF) levels and a decrease in caspase three levels; (iii) the administration of 6-OHDA had a significant impact on cell viability, resulting in a decrease in both brain cell-derived neurotrophic factor (BDNF) and GDNF levels, while concurrently elevating caspase three and matrix metalloproteinase-9 (MMP-9) levels; and (iv) LIPUS treatment demonstrated its potential to alleviate the changes induced by 6-OHDA, particularly in the levels of BDNF, GDNF, and tyrosine hydroxylase (TH). CONCLUSION: LIPUS treatment may possess partial therapeutic capabilities for SH-SY5Y cells damaged by 6-OHDA neurotoxicity. Our findings enhance our understanding of the effects of LIPUS treatment on cell viability and its modulation of key factors involved in the pathophysiology of HIBD and show the promising potential of LIPUS as an alternative therapeutic approach for neonates with HIBD.

Focused Ultrasound Stimulates the Prefrontal Cortex and Prevents MK-801-Induced Psychiatric Symptoms of Schizophrenia in Rats.

BACKGROUND AND HYPOTHESIS: Treatment of schizophrenia remains a major challenge. Recent studies have focused on glutamatergic signaling hypoactivity through N-methyl-D-aspartate (NMDA) receptors. Low-intensity pulsed ultrasound (LIPUS) improves behavioral deficits and ameliorates neuropathology in dizocilpine (MK-801)-treated rats. The aim of this study was to investigate the efficacy of LIPUS against psychiatric symptoms and anxiety-like behaviors. STUDY DESIGN: Rats assigned to 4 groups were pretreated with or without LIPUS for 5 days. The open field and prepulse inhibition tests were performed after saline or MK-801 (0.3 mg/kg) administration. Then, the neuroprotective effects of LIPUS on the MK-801-treated rats were evaluated using western blotting and immunohistochemical staining. STUDY RESULTS: LIPUS stimulation of the prefrontal cortex (PFC) prevented deficits in locomotor activity and sensorimotor gating and improved anxiety-like behavior. MK-801 downregulated the expression of NR1, the NMDA receptor, in rat medial PFC (mPFC). NR1 expression was significantly higher in animals receiving LIPUS pretreatment compared to those receiving only MK-801. In contrast, a significant increase in c-Fos-positive cells in the mPFC and ventral tegmental area was observed in the MK-801-treated rats compared to those receiving only saline; this change was suppressed by pretreatment with LIPUS. CONCLUSIONS: This study provides new evidence for the role of LIPUS stimulation in regulating the NMDA receptor and modulating c-Fos activity, which makes it a potentially valuable antipsychotic treatment for schizophrenia.

Ultrasound Alleviates Lipopolysaccharide-Induced Colonic Damage.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the intestinal tract. There is currently no effective cure for IBD. The aim of this study was to evaluate the protective effect of low-intensity pulsed ultrasound (LIPUS) on lipopolysaccharide (LPS)-induced intestinal damage in a C57BL/6 mouse model. Colonic inflammation was induced by LPS injection (0.75 mg/kg, i.p.) for 7 days. A 1.0 MHz ultrasound transducer was used with a duty cycle of 5% and a repetition frequency of 1 Hz. LIPUS was applied to the abdominal region for 15 min/day from days 1 to 6 at both intensity of 0.5 W/cm2 or 1.0 W/cm2. Colonic samples were collected for macroscopic and westerm blotting analysis. First, the optimal dose of LPS for experiments was investigated. Our results demonstrated that LIPUS alleviates colonic damage by reducing colon shortening and increasing the levels of tight junction proteins such as Occludin and ZO-1. These findings show that abdominal LIPUS stimulation may be a novel therapeutic strategy for IBD through enhancement of tight junction protein levels and attenuation of colonic length.

Application of transcranial brain stimulation in dementia.

The number of patients with dementia grows rapidly as the global population ages, which posits tremendous health-care burden to the society. Only cholinesterase inhibitors and a N-methyl-D-aspartate receptor antagonist have been approved for treating patients with Alzheimer's disease (AD), and their clinical effects remained limited. Medical devices serve as an alternative therapeutic approach to modulating neural activities and enhancing cognitive function. Four major brain stimulation technologies including deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial ultrasound stimulation (TUS) have been applied to AD in a clinical trial setting. DBS allows electrical stimulation at the specified nucleus but remains resource-demanding, and after all, an invasive surgery; whereas TMS and tDCS are widely available and affordable but less ideal with respect to localization. The unique physical property of TUS, on the other hand, allows both thermal and mechanical energy to be transduced and focused for neuromodulation. In the context of dementia, using focused ultrasound to induce blood-brain barrier opening for delivering drugs and metabolizing amyloid protein has drawn great attention in recent years. Furthermore, low-intensity pulsed ultrasound has demonstrated its neuroprotective effects in both in vitro and in vivo studies, leading to ongoing clinical trials for AD. The potential and limitation of transcranial brain stimulation for treating patients with dementia would be discussed in this review.

Ultrasound reduces inflammation by modulating M1/M2 polarization of microglia through STAT1/STAT6/PPARγ signaling pathways.

INTRODUCTION: Activated microglia can be polarized to the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. Low-intensity pulsed ultrasound (LIPUS) can attenuate pro-inflammatory responses in activated microglia. OBJECTIVE: This study aimed to investigate the effects of LIPUS on M1/M2 polarization of microglial cells and the regulatory mechanisms associated with signaling pathways. METHODS: BV-2 microglial cells were stimulated by lipopolysaccharide (LPS) to an M1 phenotype or by interleukin-4 (IL-4) to an M2 phenotype. Some microglial cells were exposed to LIPUS, while others were not. M1/M2 marker mRNA and protein expression were measured using real-time polymerase chain reaction and western blot, respectively. Immunofluorescence staining was performed to determine inducible nitric oxide synthase (iNOS)-/arginase-1 (Arg-1)- and CD68-/CD206-positive cells. RESULTS: LIPUS treatment significantly attenuated LPS-induced increases in inflammatory markers (iNOS, tumor necrosis factor-α, interleukin-1ß, and interleukin-6) as well as the expression of cell surface markers (CD86 and CD68) of M1-polarized microglia. In contrast, LIPUS treatment significantly enhanced the expression of M2-related markers (Arg-1, IL-10, and Ym1) and membrane protein (CD206). LIPUS treatment prevented M1 polarization of microglia and enhanced or sustained M2 polarization by regulating M1/M2 polarization through the signal transducer and activator of transcription 1/STAT6/peroxisome proliferator-activated receptor gamma pathways. CONCLUSIONS: Our findings suggest that LIPUS inhibits microglial polarization and switches microglia from the M1 to the M2 phenotype.

Transabdominal ultrasound alleviates LPS-induced neuroinflammation by modulation of TLR4/NF-κB signaling and tight junction protein expression.

AIM: Inflammatory bowel disease (IBD) may be a risk factor in the development of brain inflammation. It has been demonstrated noninvasive neuromodulation through sub-organ ultrasound stimulation. The purpose of this study was to investigate whether abdominal low-intensity pulsed ultrasound (LIPUS) alleviates lipopolysaccharide (LPS)-induced cortical inflammation via inhibition of colonic inflammation. MATERIALS AND METHODS: Colonic and cortical inflammation was induced in mice by LPS (0.75 mg/kg, i.p. injection) for 7 days, followed by application of LIPUS (0.5 and 1.0 W/cm2) to the abdominal area for 6 days. Biological samples were collected for Western blot analysis, gelatin zymography, colon length measurement, and histological evaluation. KEY FINDINGS: LIPUS treatment significantly attenuated LPS-induced increases in IL-6, IL-1ß, COX-2, and cleaved caspase-3 expression in the colon and cortex of mice. Moreover, LIPUS significantly increased the levels of tight junction proteins in the epithelial barrier in the mouse colon and cortex with LPS-induced inflammation. Compared to the group treated only with LPS, the LIPUS-treated groups showed decreased muscle thickness and increased crypt length and colon length. Furthermore, LIPUS treatment reduced inflammation by inhibiting the LPS-induced activation of TLR4/NF-κB inflammatory signaling in the brain. SIGNIFICANCE: We found that LIPUS alleviated LPS-induced colonic and cortical inflammation through abdominal stimulation of mice. These results suggest that abdominal LIPUS stimulation may be a novel therapeutic strategy against neuroinflammation via enhancement of tight junction protein levels and inhibition of inflammatory responses in the colon.

Dopant triggered atomic configuration activates water splitting to hydrogen.

Finding highly efficient hydrogen evolution reaction (HER) catalysts is pertinent to the ultimate goal of transformation into a net-zero carbon emission society. The design principles for such HER catalysts lie in the well-known structure-property relationship, which guides the synthesis procedure that creates catalyst with target properties such as catalytic activity. Here we report a general strategy to synthesize 10 kinds of single-atom-doped CoSe2-DETA (DETA = diethylenetriamine) nanobelts. By systematically analyzing these products, we demonstrate a volcano-shape correlation between HER activity and Co atomic configuration (ratio of Co-N bonds to Co-Se bonds). Specifically, Pb-CoSe2-DETA catalyst reaches current density of 10 mA cm-2 at 74 mV in acidic electrolyte (0.5 M H2SO4, pH ~0.35). This striking catalytic performance can be attributed to its optimized Co atomic configuration induced by single-atom doping.

Boron neutron capture therapy for glioblastoma multiforme: enhanced drug delivery and antitumor effect following blood-brain barrier disruption induced by focused ultrasound.

AIM: This study investigated whether the efficacy of boron neutron capture therapy was enhanced by means of intravenous administration of boronophenylalanine (BPA) with blood-brain barrier disruption induced by focused ultrasound (FUS). MATERIALS & METHODS: BPA was administered, followed by pulsed FUS, and the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. Growth of the firefly luciferase-labeled glioma cells was monitored through noninvasive biophotonic imaging. Finally, the brain tissue was histologically examined after sacrifice. RESULTS: Compared with the nonsonicated tumor group, animals treated with an injection of 500 mg/kg of BPA followed by FUS exhibited not only significantly increased accumulation of the drug at the sonicated tumor site, but also a significantly elevated tumor-to-normal brain drug ratio (p < 0.05). DISCUSSION: The data demonstrated that FUS significantly enhances the tumor-to-normal brain drug ratio in the sonicated tumor and subsequently the efficacy of boron neutron capture therapy.

Anti-inflammatory and Neuroprotective Effects of Transcranial Ultrasound Stimulation on Parkinson's Disease.

Low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive neuromodulation tool for deep brain stimulation. Here, we investigated the impact of LIPUS, including neuroprotective effects, on the pathology of Parkinson's disease (PD) in an animal model. Sprague-Dawley rats were injected with 6-hydroxydopamine (6-OHDA) at two sites in the right striatum. LIPUS (1 MHz, 5% duty cycle, 1-Hz pulse repetition frequency, 15 min/d) stimulation was then applied to some of the rats (the 6-OHDA + LIPUS group) beginning 2 wk after the 6-OHDA administration, while the remaining rats (the 6-OHDA group) received no LIPUS stimulation. The 6-OHDA-induced inflammatory responses and expressions of neurotrophic factors were quantified with immunofluorescence activity. The safety of LIPUS was assessed using hematoxylin and eosin and Nissl staining. LIPUS treatment significantly inhibited 6-OHDA-induced glial activation and the phosphorylation of nuclear factor-κB p65 in the substantia nigra pars compacta. Further study revealed that LIPUS effectively preserved the levels of neurotrophic factors, dopamine transporter and tight junction proteins of the blood-brain barrier in the 6-OHDA + LIPUS group compared with the 6-OHDA group. These results indicate that LIPUS acts via multiple neuroprotective mechanisms in the PD rat model and suggest that LIPUS can be viewed as a potential treatment for PD.

Transcranial Ultrasound Stimulation Reverses Behavior Changes and the Expression of Calcium-Binding Protein in a Rodent Model of Schizophrenia.

Cognitive dysfunctions are a core feature of schizophrenia that may be linked to abnormalities in gamma-aminobutyric-acid (GABA)ergic neurons. Traditional antipsychotics show poor efficacy in treating cognitive symptoms. The purpose of this study was to investigate the restorative role of transcranial ultrasound stimulation (TUS) in counteracting dizocilpine (MK-801)-induced cognitive deficits and GABAergic interneuron dysfunction in a simulation of schizophrenia. Some rats subjected to MK-801 administration were treated with low-intensity pulsed ultrasound (LIPUS) daily for 5 days, while other rats subjected to MK-801 administration received no LIPUS treatment. After LIPUS treatment, the neuroprotective effects of LIPUS in the LIPUS-treated rats were assessed through behavioral analysis, western blotting, and histological observations. Compared with the MK-801-treated group, the MK-801 plus LIPUS-treated rats revealed a preference for novel objects. The MK-801 plus LIPUS-treated rats also exhibited a significant decrease in swim times compared to the MK-801-treated rats. LIPUS stimulation significantly increased hippocampal levels of CB and PV and restored the cell densities of PV + and CB + in the cingulate cortex in the MK-801 plus LIPUS-treated group. In addition, LIPUS stimulation rebalanced the BDNF levels in the hippocampus and medial prefrontal cortex. Our findings indicate that LIPUS improves cognitive deficits and ameliorates neuropathology in MK-801-treated rats. These results suggest that LIPUS may constitute a potential novel therapeutic approach for the treatment of schizophrenia.