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

Li-dong, Deng; Lin, Qi; Suo, Qian; Wu, Shukun; Mamtilahun, Muyassar; Shi, Rubing; Liu, Ze; Sun, Junfeng; Tang, Yaohui; Zhang, Zhijun; Yang, Guo‐Yuan; Wang, Jixian

doi:10.4103/1673-5374.335158

Cited by 19 publications

(7 citation statements)

References 43 publications

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“…The decrease in IgG deposition observed indirectly measures BBB function and suggests LIFU may function to prevent the accumulation of extracellular fluid. A decrease in edema following surgically induced ischemic stroke with LIFU treatment has been shown by multiple groups, further supporting this hypothesis [ 17 – 19 ].…”

Section: Discussionmentioning

confidence: 55%

“…These changes may play a central mechanistic role in the neuroprotective properties of LIFU under ischemic stroke conditions. The sustained vasodilation in the microvessels may also explain, at least in part, the increase in cerebral blood flow by roughly 20% seen in other studies at least 30 minutes posttranscranial focused ultrasound treatment [ 19 ]. Transcranial LIFU was applied to the cerebral vasculature, including the MCA-ACA pial collateral niche, after ischemic stroke using a 1.1 MHz single element transducer.…”

Section: Discussionmentioning

confidence: 98%

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Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke

et al. 2022

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Objective and Impact Statement. This study examined the efficacy and safety of pulsed, low-intensity focused ultrasound (LIFU) and determined its ability to provide neuroprotection in a murine permanent middle cerebral artery occlusion (pMCAO) model. Introduction. Focused ultrasound (FUS) has emerged as a new therapeutic strategy for the treatment of ischemic stroke; however, its nonthrombolytic properties remain ill-defined. Therefore, we examined how LIFU influenced neuroprotection and vascular changes following stroke. Due to the critical role of leptomeningeal anastomoses or pial collateral vessels, in cerebral blood flow restoration and tissue protection following ischemic stroke, we also investigated their growth and remodeling. Methods. Mice were exposed to transcranial LIFU (fundamental frequency: 1.1 MHz, sonication duration: 300 ms, interstimulus interval: 3 s, pulse repetition frequency: 1 kHz, duty cycle per pulse: 50%, and peak negative pressure: -2.0 MPa) for 30 minutes following induction of pMCAO and then evaluated for infarct volume, blood-brain barrier (BBB) disruption, and pial collateral remodeling at 24 hrs post-pMCAO. Results. We found significant neuroprotection in mice exposed to LIFU compared to mock treatment. These findings correlated with a reduced area of IgG deposition in the cerebral cortex, suggesting attenuation of BBB breakdown under LIFU conditions. We also observed increased diameter of CD31-postive microvessels in the ischemic cortex. We observed no significant difference in pial collateral vessel size between FUS and mock treatment at 24 hrs post-pMCAO. Conclusion. Our data suggests that therapeutic use of LIFU may induce protection through microvascular remodeling that is not related to its thrombolytic activity.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 98%

Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke

et al. 2022

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“…Researchers have confirmed that barrier function is disrupted when ZO-1 is knocked out. It was previously noted that many tight junction proteins are degraded after SCI [21]. ZO-1 was selected as a representative protein involved in BSCB structural stability in this study.…”

Section: Discussionmentioning

confidence: 99%

An inhibitor of claudin-5 interactions, M01, alleviates neuroinflammation and vasogenic edema after blood–spinal cord barrier dysfunction

Jin¹,

Cao

Chang

2023

NeuroReport

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Molecular docking modeling has confirmed that M01 (C 30 H 28 N 4 O 5 ) acts as a potent inhibitor of claudin-5. Our prior data indicated that claudin-5 is essential to the structural integrity of the blood-spinal cord barrier (BSCB). The aim of this study was to investigate the effect of M01 on the integrity of the BSCB and its effect on neuroinflammation and vasogenic edema after blood-spinal cord barrier dysfunction in in-vitro and in-vivo models. Transwell chambers were used to construct an in-vitro model of the BSCB. Fluorescein isothiocyanate (FITC)-dextran permeability and leakage assays were performed to validate the reliability of the BSCB model. Semiquantitative analysis of inflammatory factor expression and nuclear factor-κB signaling pathway protein levels was performed using western blotting. The transendothelial electrical resistance of each group was measured, and the expression of a tight junction protein ZO-1 was determined via immunofluorescence confocal microscopy. Rat models of spinal cord injury were established by the modified Allen's weight-drop method.Histological analysis was carried out by hematoxylin and eosin staining. Locomotor activity was evaluated with Footprint analysis and the Basso-Beattie-Bresnahan scoring system. The M01 (10 μM) reduced the release of inflammatory factors and degradation of ZO-1 and improved the integrity of the BSCB by reversing vasogenic edema and leakage. M01 may represent a new strategy for the treatment of diseases related to BSCB destruction.

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“…18 19 In vivo, LIFUS could induce angiogenesis to ameliorate infarction area in the acute stage of stroke, and inhibit brain oedema formation. [20][21][22] These studies intrigued us to explore which optimal parameter of LIFUS would be suitable for late-stage therapy for ischaemic stroke and its underlying mechanism.…”

Section: What This Study Addsmentioning

confidence: 99%

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

Qi,

Wang,

Deng

et al. 2024

Stroke Vasc Neurol

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BackgroundLow-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear.MethodsUltrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0–14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1.ResultsOptimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05).ConclusionOur results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

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

Cited by 19 publications

References 43 publications

Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke

Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke

An inhibitor of claudin-5 interactions, M01, alleviates neuroinflammation and vasogenic edema after blood–spinal cord barrier dysfunction

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice

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