Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice.

Hu, P; Thinschmidt, JS; Caballero, S; Adamson, S; Cole, L; Chan-Ling, T; Grant, MB

Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice.

Hu, P Thinschmidt, JS Caballero, S Adamson, S Cole, L

Chan-Ling, T Grant, MB

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Publisher:: AMER PHYSIOLOGICAL SOC
Publication Type:: Journal Article
Citation:: Am J Physiol Endocrinol Metab, 2015, 308, (8), pp. E688-E698
Issue Date:: 2015-04-15

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Field	Value	Language
dc.contributor.author	Hu, P
dc.contributor.author	Thinschmidt, JS
dc.contributor.author	Caballero, S
dc.contributor.author	Adamson, S
dc.contributor.author	Cole, L https://orcid.org/0000-0001-9206-9272
dc.contributor.author	Chan-Ling, T
dc.contributor.author	Grant, MB
dc.date.accessioned	2024-01-16T04:10:59Z
dc.date.available	2015-02-13
dc.date.available	2024-01-16T04:10:59Z
dc.date.issued	2015-04-15
dc.identifier.citation	Am J Physiol Endocrinol Metab, 2015, 308, (8), pp. E688-E698
dc.identifier.issn	0193-1849
dc.identifier.issn	1522-1555
dc.identifier.uri	http://hdl.handle.net/10453/174572
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER PHYSIOLOGICAL SOC
dc.relation.ispartof	Am J Physiol Endocrinol Metab
dc.relation.isbasedon	10.1152/ajpendo.00504.2014
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Endocrinology & Metabolism
dc.subject.classification	31 Biological sciences
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.classification	42 Health sciences
dc.subject.mesh	Animals
dc.subject.mesh	Anti-Inflammatory Agents, Non-Steroidal
dc.subject.mesh	Astrocytes
dc.subject.mesh	Diabetes Mellitus, Type 1
dc.subject.mesh	Diabetic Neuropathies
dc.subject.mesh	Disease Progression
dc.subject.mesh	Down-Regulation
dc.subject.mesh	Encephalitis
dc.subject.mesh	Hypothalamus
dc.subject.mesh	Indoleamine-Pyrrole 2,3,-Dioxygenase
dc.subject.mesh	Inflammation Mediators
dc.subject.mesh	Insulin-Like Growth Factor Binding Protein 3
dc.subject.mesh	Insulin-Like Growth Factor I
dc.subject.mesh	Macrophages
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Microglia
dc.subject.mesh	Minocycline
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Neurons
dc.subject.mesh	Sympathetic Nervous System
dc.subject.mesh	Up-Regulation
dc.subject.mesh	Hypothalamus
dc.subject.mesh	Astrocytes
dc.subject.mesh	Microglia
dc.subject.mesh	Neurons
dc.subject.mesh	Sympathetic Nervous System
dc.subject.mesh	Macrophages
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Encephalitis
dc.subject.mesh	Diabetic Neuropathies
dc.subject.mesh	Diabetes Mellitus, Type 1
dc.subject.mesh	Disease Progression
dc.subject.mesh	Minocycline
dc.subject.mesh	Insulin-Like Growth Factor I
dc.subject.mesh	Insulin-Like Growth Factor Binding Protein 3
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Anti-Inflammatory Agents, Non-Steroidal
dc.subject.mesh	Inflammation Mediators
dc.subject.mesh	Down-Regulation
dc.subject.mesh	Up-Regulation
dc.subject.mesh	Male
dc.subject.mesh	Indoleamine-Pyrrole 2,3,-Dioxygenase
dc.subject.mesh	Animals
dc.subject.mesh	Anti-Inflammatory Agents, Non-Steroidal
dc.subject.mesh	Astrocytes
dc.subject.mesh	Diabetes Mellitus, Type 1
dc.subject.mesh	Diabetic Neuropathies
dc.subject.mesh	Disease Progression
dc.subject.mesh	Down-Regulation
dc.subject.mesh	Encephalitis
dc.subject.mesh	Hypothalamus
dc.subject.mesh	Indoleamine-Pyrrole 2,3,-Dioxygenase
dc.subject.mesh	Inflammation Mediators
dc.subject.mesh	Insulin-Like Growth Factor Binding Protein 3
dc.subject.mesh	Insulin-Like Growth Factor I
dc.subject.mesh	Macrophages
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Microglia
dc.subject.mesh	Minocycline
dc.subject.mesh	Nerve Tissue Proteins
dc.subject.mesh	Neurons
dc.subject.mesh	Sympathetic Nervous System
dc.subject.mesh	Up-Regulation
dc.title	Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice.
dc.type	Journal Article
utslib.citation.volume	308
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access	*
dc.date.updated	2024-01-16T04:10:57Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	308
utslib.citation.issue	8

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.

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http://hdl.handle.net/10453/174572