Agomelatine improves streptozotocin-induced diabetic nephropathy through melatonin receptors/SIRT1 signaling pathway.

INTRODUCTION: Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Agomelatine, a melatonin receptor agonist, has a potent anti-inflammatory activity. The current study aimed to determine the ameliorative anti-inflammatory effect of agomelatine against DN. METHODS: We used 10 % fructose with streptozotocin (STZ) to induce DN in male Wistar rats. Diabetic rats were treated with agomelatine in presence or absence of melatonin receptor antagonist (luzindole) or Sirtuin1 (SIRT1) inhibitor (EX527). SIRT1 expression was measured by qRT-PCR and immunohistochemical analysis. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), 5'adenosine monophosphate-activated protein kinase (AMPK), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA. Histological assessment was performed using hematoxylin and eosin-stained renal sections. RESULTS: Fructose and STZ treatment induced diabetes, insulin resistance, and renal damage accompanied by reduced SIRT1 expression, increased NFκB activation, and decreased AMPK phosphorylation in the kidney. Agomelatine treatment improved kidney histology and function and upregulated SIRT1 expression (2-fold). Inhibition of melatonin receptors and SIRT1 activity increased NFκB phosphorylation (2.13 and 1.98-folds, respectively), reduced AMPK activation (0.51 and 0.53-folds, respectively), increased inflammatory markers ICAM-1 (2.16 and 2.23-folds, respectively), VCAM-1 (2.19 and 2.26-folds, respectively), and MCP-1(2.84 and 3.12-folds, respectively), and inhibited the ameliorative effect of agomelatine on kidney structure and function. CONCLUSION: Our findings reveal the ameliorative anti-inflammatory activity of agomelatine against STZ-induced DN and this effect is SIRT1- and melatonin receptor-dependent. Therefore, agomelatine may be beneficial to prevent the development of ESRD from diabetes mellitus.

Melatonin Attenuates Methamphetamine-Induced Alteration of Amyloid ß Precursor Protein Cleaving Enzyme Expressions via Melatonin Receptor in Human Neuroblastoma Cells.

Alzheimer's disease (AD) is the most prominent neurodegenerative disease represented by the loss of memory and cognitive impairment symptoms and is one of the major health imperilments among the elderly. Amyloid (Aß) deposit inside the neuron is one of the characteristic pathological hallmarks of this disease, leading to neuronal cell death. In the amyloidogenic processing, the amyloid precursor protein (APP) is cleaved by beta-secretase and γ-secretase to generate Aß. Methamphetamine (METH) is a psychostimulant drug that causes neurodegeneration and detrimental cognitive deficits. The analogy between the neurotoxic and neurodegenerative profile of METH and AD pathology necessitates an exploration of the underlying molecular mechanisms. In the present study, we found that METH ineluctably affects APP processing, which might contribute to the marked production of Aß in human neuroblastoma cells. Melatonin, an indolamine produced and released by the pineal gland as well as other extrapineal, has been protective against METH-induced neurodegenerative processes, thus rescuing neuronal cell death. However, the precise action of melatonin on METH has yet to be determined. We further propose to investigate the protective properties of melatonin on METH-induced APP-cleaving secretases. Pretreatment with melatonin significantly reversed METH-induced APP-cleaving secretases and Aß production. In addition, pretreatment with luzindole, a melatonin receptor antagonist, significantly prevented the protective effect of melatonin, suggesting that the attenuation of the toxic effect on METH-induced APP processing by melatonin was mediated via melatonin receptor. The present results suggested that melatonin has a beneficial role in preventing Aß generation in a cellular model of METH-induced AD.