Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia - Crucial roles of endothelial nitric oxide synthase
Kumiko Eguchi, Tomohiko Shindo, Kenta Ito, Tsuyoshi Ogata, Ryo Kurosawa, Yuta Kagaya, Yuto Monma, Sadamitsu Ichijo, Sachie Kasukabe, Satoshi Miyata, Takeo Yoshikawa, Kazuhiko Yanai, Hirofumi Taki, Hiroshi Kanai, Noriko Osumi, Hiroaki Shimokawa
Brain Stimulation 2018, 11, 959-973 · 10.1016/j.brs.2018.05.012
Abstract
Background Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved. Methods We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain. Results In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice. Conclusions These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism.
Abstract via europepmc.
Exposures
Exposure 1: Whole-brain LIPUS therapy
Target: whole brain or unfocused — “whole brain”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,875 | ✓✓✓ |
| Pulse duration (ms) | 0.0171 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 6,000 | ✓✓✓⚑ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 10.24% | |
| Sonication duration (s) | not reported |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Whole-brain LIPUS therapy (1.875 MHz, 6.0 kHz, 32 cycles per pulse) was applied to mouse models of vascular dementia (BCAS) and Alzheimer's disease (5XFAD), including eNOS-knockout mice; full device, session number, and treatment-schedule details are given only in Supplementary Methods, which were not available in the main text.
Flags from extraction
exposures[0].timing.pulse_repetition_frequency_hz— The abstract lists three numbers (1.875 MHz, 6.0 kHz, 32 cycles) without labeling them; 6.0 kHz is interpreted as the pulse repetition frequency based on common usage in this parameter format, but the paper does not explicitly name it as PRF.exposures[0].timing.pulse_duration_ms— Pulse duration was derived from the stated 32 cycles per pulse divided by the 1.875 MHz fundamental frequency (32/1,875,000 Hz = 0.017067 ms), per the allowed cycles-per-pulse-over-frequency conversion; the paper does not itself state a pulse duration in ms.n_subjects— Full methods (including group sizes) are in Supplementary Methods, not provided; main text gives many different per-figure n's (e.g., n=12-17, n=5-12, n=6, n=9-10, n=20-25) across different endpoints and models, with no single total.sham_type— Control mice 'underwent the same procedure without the LIPUS treatment', but the paper does not describe whether a transducer was present but inactive, or whether ultrasound was simply not applied; coded as 'other'.anaesthesia— Methods for whole-brain LIPUS delivery (including whether mice were anaesthetised or awake during sonication) are in Supplementary Methods, not provided in the main text.