Klinische Neurophysiologie 2011; 42(03): 172-176
DOI: 10.1055/s-0031-1285903
Nachwuchspreis Neurosonologie
Georg Thieme Verlag KG Stuttgart · New York

Ultraschall-induzierte Blut-Hirn-Schranken-Öffnung

Ultrasound-Induced Opening of the Blood-Brain Barrier
A. Alonso
1   Neurologische Klinik, Universitätsmedizin Mannheim
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
25. August 2011 (online)

Zusammenfassung

Einleitung:

Eine reversible Öffnung der Blut-Hirn-Schranke (BBB) mittels Ultraschall stellt einen neuen Therapieansatz zur Behandlung von ZNS-Erkrankungen dar. In der vorliegenden Studie wurden sekundär auftretende Bioeffekte der Ultraschall-induzierten BBB-Öffnung untersucht.

Methoden:

Wistar Ratten wurden mit 1 MHz-Ultraschall in Kombination mit intravenösen Mikrobläschen behandelt. Pathologische Stressantworten wurden mittels Immunfluoreszenz analysiert.

Ergebnisse und Diskussion:

In den beschallten Arealen zeigte sich eine Zunahme der Ubiquitinexpression in Neuronen, während Hsp 70 und Hsc 70 keine Expressionsänderung aufwiesen. Eine Apoptose konnte nur in wenigen Neuronen beobachtet werden. Nach Ultraschall-Applika­tion kam es vorwiegend in Astrozyten zu einer transienten Größenzunahme von gap junctional Plaques. Diese Umverteilung deutet auf einen Reaktionsmechanismus zur Erhaltung der Homöostase hin.

Abstract

Introduction:

Ultrasound-induced reversible blood-brain barrier (BBB) opening is a promising new strategy for the treatment of CNS diseases. In the present study, we examined secondary bioeffects following ultrasound-mediated opening of the BBB.

Methods:

Wistar rats were insonated with 1 MHz ultrasound in combination with microbubbles. Stress pathways were analysed by immunofluorescence.

Results and Discussion:

In insonated areas, we observed an increase in ubiquitin expression in neurons while no change in Hsp 70 and Hsc 70 expression could be demonstrated. Apoptosis occurred only in a few neuronal cells. Insonation led to an increase in gap junctional plaque sizes predominantly in astrocytes. This reorganisation may be a regulatory mechanism to maintain homeostasis.

 
  • Literatur

  • 1 Pardridge WM. The blood-brain barrier: bottleneck in brain drug ­development. NeuroRx 2005; 2: 3-14
  • 2 Meairs S, Alonso A. Ultrasound, microbubbles and the bloodbrain barrier. Prog Biophys Mol Biol 2007; 93: 354-362
  • 3 Hynynen K, McDannold N, Vykhodtseva N et al. Noninvasive MR ­imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 2001; 220: 640-646
  • 4 Sheikov N, McDannold N, Sharma S et al. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol 2008; 34: 1093-1104
  • 5 Treat LH, McDannold N, Vykhodtseva N et al. Targeted delivery of ­doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer 2007; 121: 901-907
  • 6 Yang FY, Fu WM, Yang RS et al. Quantitative evaluation of focused ultrasound with a contrast agent on blood-brain barrier disruption. Ultrasound Med Biol 2007; 33: 1421-1427
  • 7 Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67: 425-479
  • 8 Sohl G, Maxeiner S, Willecke K. Expression and functions of neuronal gap junctions. Nat Rev Neurosci 2005; 6: 191-200
  • 9 Alonso A, Reinz E, Fatar M et al. Neurons but not glial cells overexpress ubiquitin in the rat brain following focused ultrasound-induced opening of the blood-brain barrier. Neuroscience 2010; 169: 116124
  • 10 Kumon RE, Aehle M, Sabens D et al. Spatiotemporal effects of sonoporation measured by real-time calcium imaging. Ultrasound Med Biol 2009; 35: 494-506
  • 11 Wallraff A, Kohling R, Heinemann U et al. The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci 2006; 26: 5438-5447
  • 12 Seo H, Sonntag KC, Kim W et al. Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS One 2007; 2 (02) e238
  • 13 Vykhodtseva N, McDannold N, Martin H et al. Apoptosis in ultrasound-produced thresold lesions in the rabbit brain. Ultrasound Med Biol 2001; 27: 111-117
  • 14 Marcuccilli CJ, Mathur SK, Morimoto RI et al. Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock. J Neurosci 1996; 16: 478-485
  • 15 Chen S, Brown IR. Translocation of constitutively expresses heat shock protein Hsc70 to synapse-enriched areas of the cerebral cortex after hyperthermic stress. J Neurosci Res 2007; 85: 402-409
  • 16 Alonso A, Reinz E, Jenne JW et al. Reorganisation of gap junctions after focused ultrasound blood-brain barrier opening in the rat brain. J Cereb Blood Flow Metab 2010; 30: 1394-1402
  • 17 Leykauf K, Salek M, Bomke J et al. Ubiquitin protein ligase Nedd4 binds to connexin43 by a phosphorylation-modulated process. J Cell Sci 2006; 119: 3634-3642
  • 18 Hossain MZ, Peeling J, Sutherland GR et al. Ischemia-induced cellular redistribution of the astrocytic gap junctional protein connexin43 in rat brain. Brain Res 1994; 652: 311-322
  • 19 Hunter AW, Barker RJ, Zhu C et al. Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell 2005; 6: 5686-5698
  • 20 O’Brien JJ, Li W, Pan F et al. Coupling between A-type horizontal cells is mediated by connexin 50 gap junctions in the rabbit retina. J Neurosci 2006; 26: 11624-11636
  • 21 Li X, Olson C, Lu S et al. Neuronal connexin36 association with zonula occludens-1 protein (ZO-1) in mouse brain and interaction with the first PDZ domain of ZO-1. Eur J Neurosci 2004; 19: 2132-2146