Abstract
Therapeutic treatment options for central nervous system diseases are greatly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), in conjunction with circulating microbubbles, can be used to induce a targeted and transient increase in BBB permeability, providing a unique approach for the delivery of drugs from the systemic circulation into the brain. While preclinical research has demonstrated the utility of FUS, there remains a large gap in our knowledge regarding the impact of sonication on BBB gene expression. This work is focused on investigating the transcriptional changes in dorsal hippocampal rat microvessels in the acute stages following sonication. Microarray analysis of microvessels was performed at 6 and 24 hrs post-FUS. Expression changes in individual genes and bioinformatic analysis suggests that FUS may induce a transient inflammatory response in microvessels. Increased transcription of proinflammatory cytokine genes appears to be short-lived, largely returning to baseline by 24 hrs. This observation may help to explain some previously observed bioeffects of FUS and may also be a driving force for the angiogenic processes and reduced drug efflux suggested by this work. While further studies are necessary, these results open up intriguing possibilities for novel FUS applications and suggest possible routes for pharmacologically modifying the technique.
Highlights
Over the past 15 years, focused ultrasound (FUS) has emerged as a viable method for noninvasively inducing targeted and transient increases in BBB permeability
The composition of laser capture microdissection (LCM) collected microvessels was assessed by semiquantitative polymerase chain reaction (PCR) in a separate cohort of rats not receiving FUS
The expression of Pecam[1], Map[2], and Gfap was compared between LCM collected microvessels and LCM collected whole tissue as a measure of endothelial cell (EC), mature neuron, and astrocyte content, respectively (Fig. 2e–g)
Summary
Over the past 15 years, focused ultrasound (FUS) has emerged as a viable method for noninvasively inducing targeted and transient increases in BBB permeability. On of the main goals of this technique is to aid in drug delivery to the brain, a feat that continues to hinder the development of effective treatments for many neurological disorders[1]. This particular effect of FUS is achieved by intravenously administering a microbubble (MB) contrast agent at the onset of sonication. The work described here is focused on the study of brain microvessels, as this is the site of increased permeability following FUS and experiences the largest magnitude of stress during sonication[2]. A detailed characterization of the brain microvascular response to FUS treatment will aid in clinical translation, providing a tool in the treatment of neurological diseases
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