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

Ping Hu, Jeffrey S. Thinschmidt, Sergio Caballero, Samuel Adamson, Louise Cole, Tailoi Chan-Ling, Maria B. Grant

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E688-E698
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume308
Issue number8
DOIs
StatePublished - 2015

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Insulin-Like Growth Factor Binding Protein 3
Matrix Metalloproteinase 2
Type 1 Diabetes Mellitus
Insulin-Like Growth Factor I
Hypothalamus
Brain
Microglia
Astrocytes
Blood Vessels
Kynurenine
Minocycline
Carisoprodol
Blood-Brain Barrier
Nucleosides
Anti-Inflammatory Agents
Cell Count
Inflammation
Calcium

Keywords

  • Brain
  • Diabetes
  • Inflammation
  • Sympathetic nervous system

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. / Hu, Ping; Thinschmidt, Jeffrey S.; Caballero, Sergio; Adamson, Samuel; Cole, Louise; Chan-Ling, Tailoi; Grant, Maria B.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 308, No. 8, 2015, p. E688-E698.

Research output: Contribution to journalArticle

Hu, Ping ; Thinschmidt, Jeffrey S. ; Caballero, Sergio ; Adamson, Samuel ; Cole, Louise ; Chan-Ling, Tailoi ; Grant, Maria B. / Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 308, No. 8. pp. E688-E698.
@article{7143b954ddf0430a9b47d0a688c599a6,
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.",
keywords = "Brain, Diabetes, Inflammation, Sympathetic nervous system",
author = "Ping Hu and Thinschmidt, {Jeffrey S.} and Sergio Caballero and Samuel Adamson and Louise Cole and Tailoi Chan-Ling and Grant, {Maria B.}",
year = "2015",
doi = "10.1152/ajpendo.00504.2014",
language = "English (US)",
volume = "308",
pages = "E688--E698",
journal = "American Journal of Physiology",
issn = "0193-1857",
publisher = "American Physiological Society",
number = "8",

}

TY - JOUR

T1 - Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice

AU - Hu, Ping

AU - Thinschmidt, Jeffrey S.

AU - Caballero, Sergio

AU - Adamson, Samuel

AU - Cole, Louise

AU - Chan-Ling, Tailoi

AU - Grant, Maria B.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Brain

KW - Diabetes

KW - Inflammation

KW - Sympathetic nervous system

UR - http://www.scopus.com/inward/record.url?scp=84929625899&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929625899&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00504.2014

DO - 10.1152/ajpendo.00504.2014

M3 - Article

C2 - 25714673

AN - SCOPUS:84929625899

VL - 308

SP - E688-E698

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0193-1857

IS - 8

ER -