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Analysis of Lymphocyte Extravasation Using an In Vitro Model of the Human Blood-brain Barrier
Published on: April 5, 2017
Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity
Gerty Schreibelt1, René J P Musters, Arie Reijerkerk
1Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
Abstract:
Reactive oxygen species (ROS) play an important role in various events underlying multiple sclerosis (MS) pathology. In the initial phase of lesion formation, ROS are known to mediate the transendothelial migration of monocytes and induce a dysfunction of the blood-brain barrier (BBB). In this study, we describe the beneficial effect of the antioxidant alpha-lipoic acid (LA) on these phenomena. In vivo, LA dose-dependently prevented the development of clinical signs in a rat model for MS, acute experimental allergic encephalomyelitis (EAE). Clinical improvement was coupled to a decrease in leukocyte infiltration into the CNS, in particular monocytes. Monocytes isolated from the circulation of LA-treated rats revealed a reduced migratory capacity to cross a monolayer of rat brain endothelial cells in vitro compared with monocytes isolated from untreated EAE controls. Using live cell imaging techniques, we visualized and quantitatively assessed that ROS are produced within minutes upon the interaction of monocytes with brain endothelium. Monocyte adhesion to an in vitro model of the BBB subsequently induced enhanced permeability, which could be inhibited by LA. Moreover, administration of exogenous ROS to brain endothelial cells induced cytoskeletal rearrangements, which was inhibited by LA. In conclusion, we show that LA has a protective effect on EAE development not only by affecting the migratory capacity of monocytes, but also by stabilization of the BBB, making LA an attractive therapeutic agent for the treatment of MS.
Insights
Alpha-lipoic acid (LA) reduces multiple sclerosis (MS) symptoms by decreasing monocyte migration and stabilizing the blood-brain barrier (BBB). This antioxidant shows promise as a therapeutic agent for MS treatment.
Area of Science:
- Neuroimmunology
- Oxidative Stress Research
Background:
- Reactive oxygen species (ROS) are implicated in multiple sclerosis (MS) pathology, particularly in monocyte migration and blood-brain barrier (BBB) dysfunction.
- Understanding the role of ROS in the early stages of MS lesion formation is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the therapeutic potential of alpha-lipoic acid (LA), an antioxidant, in mitigating MS-related pathology.
- To elucidate the mechanisms by which LA affects monocyte migration and BBB integrity in a rat model of MS.
Main Methods:
- Utilized an in vivo rat model of MS (experimental allergic encephalomyelitis - EAE) to assess LA's clinical effects.
- Employed in vitro models using rat brain endothelial cells and isolated monocytes to quantify migratory capacity and BBB permeability.
- Employed live cell imaging to visualize ROS production during monocyte-endothelial cell interactions.
Main Results:
- LA administration dose-dependently reduced clinical signs of EAE and decreased leukocyte infiltration into the central nervous system (CNS).
- LA treatment significantly inhibited monocyte migration across brain endothelial cells in vitro.
- LA protected against ROS-induced BBB dysfunction and cytoskeletal damage in brain endothelial cells.
Conclusions:
- Alpha-lipoic acid (LA) demonstrates protective effects against EAE development by modulating monocyte migration and enhancing BBB stability.
- LA emerges as a promising therapeutic candidate for multiple sclerosis (MS) due to its dual action on immune cell infiltration and barrier integrity.
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