Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Exogenous melatonin restrains neuroinflammation in high fat diet induced diabetic rats through attenuating indoleamine 2,3-dioxygenase 1 expression Adham M. Maher ⁎ , Samar R. Saleh, Nihal M. Elguindy, Hagar M. Hashem, Galila A. Yacout Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt ARTICLE INFO Keywords: Melatonin High-fat diet Type 2 diabetes mellitus Inflammation Hippocampus Chemical compounds studied in this article: 3,5-dichloro-2-hydroxybenzenesulfonate Melatonin Copper sulfate Potassium iodide Sodium potassium tartrate Phosphate buffer saline Sodium hydroxide Formalin Diethyl ether Triazole ABSTRACT Aim of the work: Neuroinflammation can arise from metabolic disturbances accompanying type 2 diabetes mellitus (T2DM) with an implication of indoleamine 2,3-dioxygenase 1 (IDO1). The antioxidant and anti-in- flammatory potentials of melatonin (Mel) can amend diabetic complications. Here, we examined the effect of exogenous melatonin on neuroinflammation in high fat diet (HFD)-induced T2DM rats. Main methods: Twenty-one adult male Sprague-dawley rats were divided in to three groups: control group: fed commercial standard rat chow, T2DM group: fed with HFD for 16 weeks, and T2DM-Mel group: received HFD for 8 weeks, followed by daily melatonin treatment (i.p injection 10 mg/kg in saline) for 8 weeks with continuous supply of HFD. After which, animals were submitted to euthanasia for brain and blood samples collection. Key findings: In T2DM-Mel group the diabetic profile was ameliorated, and the state of low-grade systemic inflammation was alleviated through lowering serum pro-inflammatory cytokines (TNF-α and IL-6) and leptin while increasing adiponectin. Melatonin improved brain oxidative stress by increasing total antioxidant capacity and reduced glutathione (GSH), whereas malondialdehyde was declined. Melatonin reduced acet- ylcholinesterase (AChE) activity in blood and brain and its hippocampal expression, also hippocampal inducible nitric oxide synthase (iNOS) expression was reduced, moreover IDO1 hippocampal expression was declined, furthermore recovered neuronal morphology following melatonin treatment was also clearly viewed in the hippocampus under the light microscope in T2DM-Mel rats. Significance: Melatonin can be considered as a promising solution in preventing neuroinflammation develop- ment in T2DM owing to its ability to render the oxidative stress and accompanied low-grade systemic in- flammation. 1. Introduction Melatonin (N-acetyl-5-methoxyindolamine), the pineal gland hor- mone [1], is well known for its anti-inflammatory [2], free radical scavenging and antioxidant properties within the brain and the whole body [3]. Also melatonin has a chronobiological effect through reg- ulating; metabolism, energy balance, glucose uptake, and serum lipid profile, as well as increasing the energy expenditure [4]. Melatonin is derived from the essential amino acid tryptophan (Trp), where its bioavailability is governed by the rate-limiting step enzyme in- doleamine 2,3-dioxygenase 1 (IDO1)[5]. IDO1 catabolizes Trp into Kynurenine, which is further metabolized in to the neurotoxic 3-hy- droxykynurenine and quinolinic acid [6]. An increase in IDO1 activity is associated with many inflammation-associated disorders such as type 2 diabetes mellitus (T2DM), suggesting a link between increased in- flammatory cytokines and IDO1 [7,8]. Diminished melatonin is correlated with loss of antioxidant protection and immunological and anti-inflammatory effects [9] jeopardizing the central nervous system to inflammation [10]. The pervasion of westernization, urbanization and mechanization is accompanied with changes in the diet by in- troducing high fat foods along with a sedentary lifestyle, this shift is also associated with both childhood and adult obesity [11]. Obesity is considered as a health disaster where its prevalence is escalating sig- nificantly in many nations worldwide [12]. Moreover obesity is asso- ciated with numerous adverse health consequences such as dyslipi- demia, insulin resistance (IR), T2DM, hypertension, and cardiovascular disease [13]. Type 2 diabetes mellitus is an intricated metabolic disease characterized by hyperglycemia caused by the low amounts of insulin produced from the pancreatic β-cells and/or defects in insulin uptake in the peripheral tissue which is known as peripheral IR. The metabolic disturbances associated with T2DM represented by hyperglycemia, hyperinsulinemia, and dyslipidemia participate in an elevated oxidative https://doi.org/10.1016/j.lfs.2020.117427 Received 31 December 2019; Received in revised form 24 January 2020; Accepted 9 February 2020 ⁎ Corresponding author. E-mail address: Adham.Mostafa@alexu.edu.eg (A.M. Maher). Life Sciences 247 (2020) 117427 Available online 15 February 2020 0024-3205/ © 2020 Elsevier Inc. All rights reserved. T