Up-regulation of caveolin-1 and blood-brain barrier breakdown are attenuated by N-acetylcysteine in thiamine deficiency.
Wernicke's encephalopathy is a cerebral metabolic disorder caused by thiamine (vitamin B1) deficiency (TD). Neuropathologic consequences of TD include region-selective neuronal cell loss and blood-brain barrier (BBB) breakdown. Caveolin-1 is involved in the regulation of tight junction proteins and BBB permeability, and is modulated by oxidative stress, a feature of vulnerable brain regions in TD. We hypothesized that TD-related oxidative stress alters BBB integrity via induction of the caveolin-1 pathway. TD was induced in C57BL6 mice by treatment with a thiamine-deficient diet and administration of the thiamine antagonist pyrithiamine, in the absence or presence of the antioxidant N-acetylcysteine (NAC). A significant and focal increase in both caveolin-1 gene and protein expression was detected in the thalamus of thiamine-deficient mice, concomitant with IgG extravasation. Reduction of oxidative stress by NAC, as shown by normalization of reduced glutathione levels and attenuation of endothelial heme oxygenase-1 and nitric oxide synthase expression, resulted in prevention of the up-regulation of caveolin-1 in TD. Normalization of caveolin-1 levels by NAC was accompanied by a reduction in BBB breakdown, indicated by decreased IgG extravasation, normalization of occludin levels and prevention of matrix metalloproteinase-9 up-regulation. These findings demonstrate a role for caveolin-1 in TD pathogenesis, and suggest that oxidative stress contributes to BBB alterations in TD via modulation of this pathway.
Beauchesne
Elizabeth
E
Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Desjardins
Paul
P
Butterworth
Roger F
RF
Hazell
Alan S
AS
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology*; D051242:Caveolin 1 / Q000096:biosynthesis*; D018450:Disease Progression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D015398:Signal Transduction / Q000502:physiology; D013832:Thiamine Deficiency / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation / Q000502:physiology*
D051242:Caveolin 1; D018696:Neuroprotective Agents; D000111:Acetylcysteine