Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity.
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.
Schreibelt
Gerty
G
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
Musters
René J P
RJ
Reijerkerk
Arie
A
de Groot
Lody R
LR
van der Pol
Susanne M A
SM
Hendrikx
Esther M L
EM
Döpp
Ed D
ED
Dijkstra
Christine D
CD
Drukarch
Benjamin
B
de Vries
Helga E
HE
D000208:Acute Disease; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D008063:Thioctic Acid