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 Scopus citations

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 - Jan 1 2015

Keywords

  • Brain
  • Diabetes
  • Inflammation
  • Sympathetic nervous system

ASJC Scopus subject areas

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

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