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.

Research highlights▶ Thiamine deficiency (TD) in the rat results in a focal increase in caveolin-1 gene and protein expression. ▶ Increase in caveolin-1 occurs concomitantly with breakdown of the blood–brain barrier (BBB) in TD. ▶ Oxidative stress plays a major role in the up-regulation of caveolin-1 in TD. ▶ Oxidative stress is a major contributor to BBB breakdown, possibly via its effect on the caveolin-1 pathway in TD.