title: Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice.
abstract: Neuroinflammation and neurodegeneration have been observed in the brain in type 1 diabetes (T1D). However, little is known about the mediators of these effects. In T1D mice with 12- and 35-wk duration of diabetes we examined two mechanisms of neurodegeneration, loss of the neuroprotective factors insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and changes in indoleamine 2,3-dioxygenase (IDO) expression in the brain, and compared the response to age-matched controls. Furthermore, levels of matrix metalloproteinase-2 (MMP-2), nucleoside triphosphate diphosphohydrolase-1 (CD39), and ionized calcium-binding adaptor molecule 1 (Iba-1) were utilized to assess inflammatory changes in astrocytes, microglia, and blood vessels. In the diabetic hypothalamus (HYPO), we observed 20% reduction in neuronal soma diameter (P<0.05) and reduced neuronal expression of IGFBP-3 (-32%, P<0.05) and IGF-I (-15%, P<0.05) compared with controls at 35 wk. In diabetic HYPO, MMP-2 expression was increased in astrocytes (46%, P<0.01), and IDO⁺ cell density rose by (62%, P<0.05). CD39 expression dropped by 30% (P<0.05) in microglia and blood vessels. With 10 wk of systemic treatment using minocycline, an anti-inflammatory agent that crosses the blood-brain barrier, MMP-2, IDO, and CD39 levels normalized (P<0.05). Our results suggest that increased IDO and early loss of CD39⁺ protective cells lead to activation of inflammation in sympathetic centers of the CNS. As a downstream effect, the loss of the neuronal survival factors IGFBP-3 and IGF-I and the neurotoxic products of the kynurenine pathway contribute to the loss of neuronal density observed in the HYPO in T1D.
authors.affiliation: Department of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Camperdown, New South Wales, Australia;
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida;
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida;
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.affiliation: Department of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Camperdown, New South Wales, Australia;
authors.forename: Samuel
authors.initials: S
authors.lastname: Adamson
authors.affiliation: Advanced Microscopy Facility, Bosch Institute, School of Medical Sciences, The University of Sydney, Camperdown, New South Wales, Australia; and.
authors.forename: Louise
authors.initials: L
authors.lastname: Cole
authors.affiliation: Department of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Camperdown, New South Wales, Australia;
authors.forename: Tailoi
authors.initials: T
authors.lastname: Chan-Ling
authors.affiliation: Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University, Indianapolis, Indiana mabgrant@iupui.edu.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004660:Encephalitis / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D007031:Hypothalamus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008911:Minocycline / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D018972:Insulin-Like Growth Factor Binding Protein 3; D009419:Nerve Tissue Proteins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D008911:Minocycline
keywords: brain; diabetes; inflammation; sympathetic nervous system