Bhardwaj Deepshikha, Youssef Ibrahim, Imphean Darren, Holmes Sydni K, Krishnan Venugopal, Estill-Terpack Sandi Jo, Diamond Marc, Chopra Rajiv, Bailey Rachel M, Shah Bhavya R
Transcranial Focused Ultrasound Lab, UTSW Medical Center, Dallas, TX, USA.
Neuroradiology and Neuro-intervention Section, Department of Radiology, UTSW Medical Center, Dallas, TX, USA.
Gene Ther. 2025 May 6. doi: 10.1038/s41434-025-00530-z.
Transcranial Magnetic Resonance Guided Focused Ultrasound can oscillate intravenously delivered microbubbles and transiently open the blood brain barrier (BBB) in a targeted brain region. However, high microbubble doses or Focused ultrasound pressures (FUS) leads to injury. So, we administered nitrous oxide (NO), an anesthetic gas to determine reduced need of FUS pressure and microbubble dose for opening BBB. Swiss Webster mice were treated with NO or medical air (MA) at varying FUS pressures, while the microbubble dose was kept constant and the vice-versa. Consequently, BBB opening was quantified by acoustic emissions and enhancement rate on T1-weighted MR. To compare the effect of NO on gene delivery, following BBB opening with either MA or NO, a viral vector expressing GFP was subsequently delivered. Additionally, Immunohistochemical studies quantified viral transfection efficacy and assessed acute cell injury. We observed that NO significantly potentiates acoustic emissions and enhancement rate on post-contrast MRI images, compared to MA at all measured pressures (0.39, 0.45, 0.67 MPa). Furthermore, NO reduces the microbubble dose to 0.02μl/kg and FUS pressures to 0.28 and 0.39 MPa for BBB disruption and enhanced viral gene delivery, respectively. Hence, NO potentiates microbubble oscillations, allowing reduced microbubble dose and FUS pressures and improved viral gene delivery.
经颅磁共振引导聚焦超声可使静脉注射的微泡振荡，并在目标脑区短暂打开血脑屏障（BBB）。然而，高剂量微泡或聚焦超声压力（FUS）会导致损伤。因此，我们给予一氧化二氮（NO）这种麻醉气体，以确定打开血脑屏障所需的FUS压力和微泡剂量是否能够降低。在不同的FUS压力下，对瑞士韦伯斯特小鼠给予NO或医用空气（MA），同时保持微泡剂量恒定，反之亦然。随后，通过声发射和T1加权磁共振成像上的增强率对血脑屏障的开放进行定量。为了比较NO对基因递送的影响，在用MA或NO打开血脑屏障后，随后递送一种表达绿色荧光蛋白（GFP）的病毒载体。此外，免疫组织化学研究对病毒转染效率进行了定量，并评估了急性细胞损伤。我们观察到，与在所有测量压力（0.39、0.45、0.67兆帕）下的MA相比，NO显著增强了对比后MRI图像上的声发射和增强率。此外，对于血脑屏障破坏和增强病毒基因递送，NO分别将微泡剂量降低至0.02μl/kg，将FUS压力降低至0.28和0.39兆帕。因此，NO增强了微泡振荡，从而降低了微泡剂量和FUS压力，并改善了病毒基因递送。
