eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain.

Abstract

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.

• Authors: Elizabeth Beauchesne, Paul Desjardins, Alan S Hazell, Roger F Butterworth
• Journal: Journal of neurochemistry (J Neurochem) Vol. 111 Issue 2 Pg. 452-9 (Oct 2009) ISSN: 1471-4159 [Electronic] England
• PMID: 19686244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites
• Immunoglobulin G
• Reactive Nitrogen Species
• Reactive Oxygen Species
• Pyrithiamine
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Matrix Metalloproteinase 9

Topics

• Animals
• Antimetabolites (toxicity)
• Blood-Brain Barrier (physiology)
• Disease Models, Animal
• Frontal Lobe (pathology, physiology)
• Immunoglobulin G (metabolism)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nerve Degeneration (chemically induced, metabolism, physiopathology)
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Oxidative Stress (physiology)
• Pyrithiamine (toxicity)
• Reactive Nitrogen Species (metabolism)
• Reactive Oxygen Species (metabolism)
• Thalamic Nuclei (pathology, physiology)
• Thiamine Deficiency (metabolism, physiopathology)