Hu, PingThinschmidt, Jeffrey S.Caballero, SergioAdamson, SamuelCole, LouiseChan-Ling, TailoiGrant, Maria B.2016-08-182016-08-182015-04-15Hu, P., Thinschmidt, J. S., Caballero, S., Adamson, S., Cole, L., Chan-Ling, T., & Grant, M. B. (2015). Loss of survival factors and activation of inflammatory cascades in brain sympathetic centers in type 1 diabetic mice. American Journal of Physiology - Endocrinology and Metabolism, 308(8), E688–E698. http://doi.org/10.1152/ajpendo.00504.20141522-1555https://hdl.handle.net/1805/10727Neuroinflammation 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.en-USPublisher PolicyDiabetes Mellitus, Type 1complicationsDiabetic NeuropathiesmetabolismEncephalitisHypothalamusNerve Tissue ProteinsSympathetic Nervous SystemArticle