eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain.
Wernicke's encephalopathy is a cerebral disorder caused by thiamine (vitamin B(1)) deficiency (TD). Neuropathologic consequences of TD include region-selective neuronal cell loss and blood-brain barrier (BBB) breakdown. Early increased expression of the endothelial isoform of nitric oxide synthase (eNOS) occurs selectively in vulnerable brain regions in TD. We hypothesize that region-selective eNOS induction in TD leads to altered expression of tight junction proteins and BBB breakdown. In order to address this issue, TD was induced in C57BL/6 wild-type (WT) and eNOS(-/-) mice by feeding a thiamine-deficient diet and treatment with the thiamine antagonist pyrithiamine. Pair-fed control mice were fed the same diet with additional thiamine. In medial thalamus of TD-WT mice (vulnerable area), increased heme oxygenase-1 and S-nitrosocysteine immunostaining was observed in vessel walls, compared to pair-fed control-WT mice. Concomitant increases in IgG extravasation, decreases in expression of the tight junction proteins occludin, zona occludens-1 and zona occludens-2, and up-regulation of matrix metalloproteinase-9 in endothelial cells were observed in the medial thalamus of TD-WT mice. eNOS gene deletion restored these BBB alterations, suggesting that eNOS-derived nitric oxide is a major factor leading to cerebrovascular alterations in TD. However, eNOS gene deletion only partially attenuated TD-related neuronal cell loss, suggesting the presence of mechanisms additional to BBB disruption in the pathogenesis of these changes.
Beauchesne
Elizabeth
E
Neuroscience Research Unit, Saint-Luc Hospital CHUM, Montreal, Quebec, Canada.
Desjardins
Paul
P
Hazell
Alan S
AS
Butterworth
Roger F
RF
D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000502:physiology*; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000473:pathology / Q000502:physiology; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011745:Pyrithiamine / Q000633:toxicity; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013787:Thalamic Nuclei / Q000473:pathology / Q000502:physiology*; D013832:Thiamine Deficiency / Q000378:metabolism / Q000503:physiopathology*
D000963:Antimetabolites; D007074:Immunoglobulin G; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011745:Pyrithiamine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020780:Matrix Metalloproteinase 9