الفهرس 
AcknowledgementOnly 14 pages are availabe for public view
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Abstract
The established correlation between obesity and cognitive impairment portrays pharmacological products aimed at both disorders as important therapeutic advance. Modulation of dysregulated adipokines and neurotransmitters is hence a critical aspect of the assessment of the in-use drugs. At the cellular level, repairments in brain barrier integrity and cognitive flexibility are the main checkpoints. The aim of this study was to investigate whether melatonin and histidine, alone or in combination, could produce weight loss, meanwhile improve the cognitive processes as secondary effect. In this study, obese rat model was established by feeding (HFD) composed of 25% fats (soybean oil) for 8 weeks, accompanied by melatonin (10 mg/kg), histidine (780 mg/kg), and a combination of both in conventional and nanoform, duloxetine (Dul) is used as positive control in this study (10 mg/kg). At the end of the study, the spatial learning and memory were assessed via Morris water maze (MWM) test. Serum was used to investigate liver function, lipid profile; adiposity hormonal profile (Leptin and adiponectin) and regulatory cytokines (Interleukin-4). Hippocampus was isolated, histology and ultrastructure were examined. High performance liquid chromatography was applied to determine neuronal monoamines and their metabolites (Norepinephrine, dopamine, serotonin, 5-Hydroxyindoleacetic acid); excitatory and inhibitory amino acids (aspartate,glutamate, gamma-aminobutyric acid, glycine); oxidative stress markers (malondialdehyde, reduced glutathione, oxidized glutathione, (nitrates + nitrites), 8-hydroxy-2-deoxyguanosine) and neuronal cell energy. Real time polymerase chain reaction was used to evaluate the levels of brain derived neurotrophic factor(BDNF) and zonula occluden-1(ZO-1). The results revealed that HFD group had a significant-increase in body weight and exhibited low performance inMWM cognitive test. Coadministration of histidine in the nano form increased the level of zonula occluden-1; an indicator of improving the brain barrier integrity, along with adjusting the adipokines and neurotransmitters levels, which had a positive impact on learning tasks. Co-treatment with melatonin resulted in an increase in the level ofBDNF marking ameliorated synaptic anomalies and learning disabilities, while reducing weight gain. On the other hand, the combination of melatonin and histidine reinstated the synaptic plasticity as well as brain barrier junctions, as demonstrated by increased levels of BDNFand zonula occluden-1, positively affecting weight loss and the intellectual function.