title: Vascular factors are critical in selective neuronal loss in an animal model of impaired oxidative metabolism.
abstract: Thiamine deficiency (TD) models the cellular and molecular mechanisms by which chronic oxidative deficits lead to death of select neurons in brain. Region- and cell-specific oxidative stress and vascular changes accompany the TD-induced neurodegeneration. The current studies analyzed the role of oxidative stress in initiating these events by testing the role of intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS) in the selective neuronal loss that begins in the submedial thalamic nucleus of mice. Oxidative stress to microvessels is known to induce eNOS and ICAM-1. TD increased ICAM-1 immunoreactivity in microvessels within the submedial nucleus and adjacent regions 1 day prior to the onset of neuronal loss. On subsequent days, the pattern of ICAM-1 induction overlapped that of neuronal loss, and of induction of the oxidative stress marker heme oxygenase-1 (HO-1). The intensity and extent of ICAM-1 and HO-1 induction progressively spread in parallel with the neuronal death in the thalamus. Targeted disruption of ICAM-1 or eNOS gene, but not the neuronal NOS gene, attenuated the TD-induced neurodegeneration and HO-1 induction. TD induced ICAM-1 in eNOS knockout mice, but did not induce eNOS in mice lacking ICAM-1. These results demonstrate that in TD, an ICAM-1-dependent pathway of eNOS induction leads to oxidative stress-mediated death of metabolically compromised neurons. Thus, TD provides a useful model to help elucidate the role of ICAM-1 and eNOS in the selective neuronal death in diseases in which oxidative stress is implicated.
authors.affiliation: Weill Medical College of Cornell University at Burke Medical Research Institute, White Plains, New York 10605, USA.
authors.forename: N Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: P L
authors.initials: PL
authors.lastname: Huang
authors.forename: H S
authors.initials: HS
authors.lastname: Chun
authors.forename: A
authors.initials: A
authors.lastname: Fabian
authors.forename: G E
authors.initials: GE
authors.lastname: Gibson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001522:Behavior, Animal; D015415:Biomarkers; D001812:Blood-Brain Barrier / Q000502:physiology; D001835:Body Weight; D017353:Gene Deletion; D005838:Genotype; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D007074:Immunoglobulin G / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000276:immunology; D009474:Neurons / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis / Q000276:immunology; D013788:Thalamus / Q000098:blood supply / Q000201:enzymology; D013832:Thiamine Deficiency / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D007074:Immunoglobulin G; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse