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eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain.
- Source :
-
Journal of neurochemistry [J Neurochem] 2009 Oct; Vol. 111 (2), pp. 452-9. Date of Electronic Publication: 2009 Aug 17. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Antimetabolites toxicity
Disease Models, Animal
Frontal Lobe pathology
Frontal Lobe physiology
Immunoglobulin G metabolism
Male
Matrix Metalloproteinase 9 metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Degeneration chemically induced
Nerve Degeneration metabolism
Oxidative Stress physiology
Pyrithiamine toxicity
Reactive Nitrogen Species metabolism
Reactive Oxygen Species metabolism
Thalamic Nuclei pathology
Thiamine Deficiency metabolism
Blood-Brain Barrier physiology
Nerve Degeneration physiopathology
Nitric Oxide Synthase Type III genetics
Nitric Oxide Synthase Type III metabolism
Thalamic Nuclei physiology
Thiamine Deficiency physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 111
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19686244
- Full Text :
- https://doi.org/10.1111/j.1471-4159.2009.06338.x