Blood brain barrier precludes the cerebral arteries to intravenously-injected antisense oligonucleotide.
European Journal of Pharmacology. 2015-01-01; 747: 141-149
DOI: 10.1016/j.ejphar.2014.11.027
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1. Eur J Pharmacol. 2015 Jan 15;747:141-9. doi: 10.1016/j.ejphar.2014.11.027. Epub
2014 Dec 13.
Blood brain barrier precludes the cerebral arteries to intravenously-injected
antisense oligonucleotide.
Boursereau R(1), Donadieu A(1), Dabertrand F(2), Dubayle D(3), Morel JL(4).
Author information:
(1)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France.
(2)University of Vermont, Department of Pharmacology, UVM College of Medicine,
Burlington, VT, USA. Electronic address: .
(3)Centre de Neurophysique, Physiologie, Pathologie, CNRS UMR 8119, Faculté des
Sciences fondamentales et Biomédicales, Université Paris Descartes, 45, rue des
Saints-Pères, 75006 Paris, France. Electronic address:
.
(4)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France. Electronic address: .
Alternative splicing of the ryanodine receptor subtype 3 (RyR3) produces a short
isoform (RyR3S) able to negatively regulate the ryanodine receptor subtype 2
(RyR2), as shown in cultured smooth muscle cells from mice. The RyR2 subtype has
a crucial role in the control of vascular reactivity via the fine tuning of
Ca(2+) signaling to regulate cerebral vascular tone. In this study, we have shown
that the inhibition of RyR3S expression by a specific antisense oligonucleotide
(asRyR3S) was able to increase the Ca(2+) signals implicating RyR2 in cerebral
arteries ex vivo. Moreover, we tried to inhibit the expression of RyR3S in vivo.
The asRyR3S was complexed with JetPEI and injected intravenously coupled with
several methods known to induce a blood brain barrier disruption. We tested
solutions to induce osmotic choc (mannitol), inflammation (bacteria
lipopolysaccharide and pertussis toxin), vasoconstriction or dilatation
(sumatriptan, phenylephrine, histamine), CD73 activation (NECA) and lipid
instability (Tween80). All tested technics failed to target asRyR3 in the
cerebral arteries wall, whereas the molecule was included in hepatocytes or
cardiomyocytes. Our results showed that the RyR3 alternative splicing could have
a function in cerebral arteries ex vivo; however, the disruption of the blood
brain barrier could not induce the internalization of antisense oligonucleotides
in the cerebral arteries, in order to prove the function of RYR3 short isoform in
vivo.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejphar.2014.11.027
PMID: 25510229 [Indexed for MEDLINE]