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Modulation of the Blood-Brain Barrier by Sigma-1R Activation
Brailoiu, Eugen Barr, Jeffrey L. Wittorf, Hailey N. Inan, Saadet Unterwald, Ellen M. Brailoiu, Gabriela Cristina
Brailoiu, Eugen
Barr, Jeffrey L.
Wittorf, Hailey N.
Inan, Saadet
Unterwald, Ellen M.
Brailoiu, Gabriela Cristina
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Journal article
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2024-05-09
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Neural Sciences
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https://doi.org/10.3390/ijms25105147
Abstract
Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The role of Sigma-1R at the blood–brain barrier (BBB) is incompletely characterized. In this study, the effect of Sigma-1R activation was investigated in vitro on rat brain microvascular endothelial cells (RBMVEC), an important component of the blood–brain barrier (BBB), and in vivo on BBB permeability in rats. The Sigma-1R agonist PRE-084 produced a dose-dependent increase in mitochondrial calcium, and mitochondrial and cytosolic reactive oxygen species (ROS) in RBMVEC. PRE-084 decreased the electrical resistance of the RBMVEC monolayer, measured with the electric cell-substrate impedance sensing (ECIS) method, indicating barrier disruption. These effects were reduced by pretreatment with Sigma-1R antagonists, BD 1047 and NE 100. In vivo assessment of BBB permeability in rats indicates that PRE-084 produced a dose-dependent increase in brain extravasation of Evans Blue and sodium fluorescein brain; the effect was reduced by the Sigma-1R antagonists. Immunocytochemistry studies indicate that PRE-084 produced a disruption of tight and adherens junctions and actin cytoskeleton. The brain microcirculation was directly visualized in vivo in the prefrontal cortex of awake rats with a miniature integrated fluorescence microscope (aka, miniscope; Doric Lenses Inc.). Miniscope studies indicate that PRE-084 increased sodium fluorescein extravasation in vivo. Taken together, these results indicate that Sigma-1R activation promoted oxidative stress and increased BBB permeability.
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Brailoiu, E.; Barr, J.L.; Wittorf, H.N.; Inan, S.; Unterwald, E.M.; Brailoiu, G.C. Modulation of the Blood–Brain Barrier by Sigma-1R Activation. Int. J. Mol. Sci. 2024, 25, 5147. https://doi.org/10.3390/ijms25105147
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International Journal of Molecular Sciences, Vol. 25, Iss. 10
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