Ghrelin ameliorates nerve growth factor Dysmetabolism and inflammation in STZ-induced diabetic rats
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ORIGINAL ARTICLE
Ghrelin ameliorates nerve growth factor Dysmetabolism and inflammation in STZ-induced diabetic rats Yuxing Zhao 1 & Zhaoxing Shen 1 & Dongling Zhang 1 & Huiqiong Luo 1 & Jinliang Chen 1 & Yue Sun 1 & Qian Xiao 1
Received: 21 April 2016 / Accepted: 23 March 2017 # Springer Science+Business Media New York 2017
Abstract Diabetic encephalopathy is characterized by cognitive impairment and neuroinflammation, deficient neurotrophic support, and neuronal and synaptic loss. Ghrelin, a 28 amino acid peptide, is associated with neuromodulation and cognitive improvement, which has been considered as a potential protective agent for several neurodegenerative diseases. Here we sought to investigate the role of ghrelin in preventing diabetic-related neuropathology. We found that ghrelin attenuated astrocytic activation and reduced levels of interleukin-6 and tumor necrosis factor-α in streptozotocin-induced diabetic rats. In addition, ghrelin inhibited p38 mitogen-associated protein kinase activation. The upregulation of nerve growth factor (NGF) precursor and matrix metalloproteinase (MMP)-9 and downregulation of mature NGF and MMP-7 in the diabetic brain were reversed by ghrelin. Treatment with ghrelin elevated synaptophysin expression and synaptic density in diabetic rats. Taken together, our results demonstrate that ghrelin ameliorates diabetes-related neurodegeneration by preventing NGF dysmetabolism and synaptic degeneration through regulating MMP levels as well as inhibiting neuroinflammation. Keywords Diabetes . Neurodegeneration . Nerve growth factor . Inflammation . Ghrelin
Abbreviations CNS Central nervous system DG Dentate gyrus * Qian Xiao [email protected] 1
Department of Geriatrics, the First Affiliated Hospital of Chongqing Medical University, No. 1 YouYi Road, YuZhong District, Chongqing 400016, China
DM GFAP GHS-R1a ICV MMP mNGF ProNGF p38 MAPK RT-PCR STZ SYN
Diabetes mellitus Glial fibrillary acidic protein Growth hormone secretagogue receptor 1a Intracerebral ventricular Matrix metalloproteinase Mature nerve growth factor Nerve growth factor precursor p38 mitogen-associated protein kinase Reverse-transcriptase polymerase chain reaction Streptozotocin Synaptophysin
Introduction It is well established that individuals with diabetes are at increased risk of developing cognitive impairment (McCrimmon et al. 2012; Reagan 2012). The neuropathological alterations in the central nervous system (CNS) of patients with diabetes have been considered as diabetic encephalopathy (Geijselaers et al. 2015). Chronic and persistent systemic low-grade inflammation, oxidative stress (Mastrocola et al. 2012; Díaz-Gerevini et al. 2014), deficient neurotrophic support, and synaptic loss (Ahmad 2013; Thomas et al. 2013; Reagan 2012) are among the suggested pathogeneses of diabetic encephalopathy. Astrocytes, the most abundant cells in the CNS, provide critical neurotrophic support to modulate neuronal activities under physiological conditions (Lior et al. 2014). Notably, astrocytes are susceptible to infla
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