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.
Keywords:
brain; diabetes; inflammation; sympathetic nervous system.
Copyright © 2015 the American Physiological Society.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Astrocytes / drug effects
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Astrocytes / immunology
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Astrocytes / metabolism
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Astrocytes / pathology
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Diabetes Mellitus, Type 1 / complications*
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Diabetes Mellitus, Type 1 / drug therapy
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Diabetes Mellitus, Type 1 / physiopathology
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Diabetic Neuropathies / immunology
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Diabetic Neuropathies / metabolism*
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Diabetic Neuropathies / pathology
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Diabetic Neuropathies / prevention & control
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Disease Progression
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Down-Regulation* / drug effects
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Encephalitis / complications*
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Encephalitis / immunology
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Encephalitis / metabolism
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Encephalitis / prevention & control
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Hypothalamus / drug effects
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Hypothalamus / immunology
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Hypothalamus / metabolism*
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Hypothalamus / pathology
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Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / metabolism
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor I / metabolism
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice, Inbred C57BL
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Microglia / drug effects
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Microglia / immunology
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Microglia / metabolism
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Microglia / pathology
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Minocycline / therapeutic use
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / metabolism*
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Neurons / drug effects
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Neurons / immunology
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Neurons / metabolism
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Neurons / pathology
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Sympathetic Nervous System / drug effects
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Sympathetic Nervous System / immunology
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Sympathetic Nervous System / metabolism*
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Sympathetic Nervous System / pathology
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Up-Regulation / drug effects
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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IDO1 protein, mouse
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Inflammation Mediators
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Insulin-Like Growth Factor Binding Protein 3
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Nerve Tissue Proteins
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insulin-like growth factor-1, mouse
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Insulin-Like Growth Factor I
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Minocycline