title: Changes in inflammatory processes associated with selective vulnerability following mild impairment of oxidative metabolism.
abstract: Abnormalities in oxidative metabolism and reductions of thiamine-dependent enzymes accompany many age-related neurodegenerative diseases. Thiamine deficiency (TD) produces a cascade of events including mild impairment of oxidative metabolism, activation of microglia, astrocytes and endothelial cells that leads to neuronal loss in select brain regions. The earliest changes occur in a small, well-defined brain region, the submedial thalamic nucleus (SmTN). In the present study, a micropunch technique was used to evaluate quantitatively the selective regional changes in mRNA and protein levels. To test whether this method can distinguish between changes in vulnerable and non-vulnerable regions, markers for neuronal loss (NeuN) and endothelial cells (eNOS) and inflammation (IL-1beta, IL-6 and TNF-alpha) in SmTN and cortex of control and TD mice were assessed. TD significantly reduced NeuN and increased CD11b, GFAP and ICAM-1 immunoreactivity in SmTN as revealed by immunocytochemistry. When assessed on samples obtained by the micropunch method, NeuN protein declined (-49%), while increased mRNA levels were observed for eNOS (3.7-fold), IL-1beta (43-fold), IL-6 (44-fold) and TNF-alpha (64-fold) in SmTN with TD. The only TD-induced change that occurred in cortex with TD was an increase in TNF-alpha (22-fold) mRNA levels. Immunocytochemical analysis revealed that IL-1beta, IL-6 and TNF-alpha protein levels increased in TD brains and colocalized with glial markers. The consistency of these quantitative results with immunocytochemical measurements validates the micropunch technique. The results demonstrate that TD induces quantitative, distinct inflammatory responses and oxidative stress in vulnerable and non-vulnerable regions that may underlie selective vulnerability.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.
authors.forename: Saravanan S
authors.initials: SS
authors.lastname: Karuppagounder
authors.forename: Qingli
authors.initials: Q
authors.lastname: Shi
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gibson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002470:Cell Survival; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004660:Encephalitis / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D020656:Posterior Thalamic Nuclei / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism / Q000473:pathology; D013831:Thiamine / Q000378:metabolism; D013832:Thiamine Deficiency / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D016207:Cytokines; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D013831:Thiamine