Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

Ibraheem Husain,Mohd Akhtar,Tushar Madaan,Malik Zainul Abdin,Mohammad Islamuddin,Abul Kalam Najmi

doi:10.1080/13510002.2018.1492774

Abstract

ABSTRACTObjective: The objectives of our study were to investigate the possible effect of rosuvastatin in ameliorating high salt and cholesterol diet (HSCD)-induced cognitive impairment and to also investigate its possible action via the Nrf2-ARE pathway.Methods: In silico studies were performed to check the theoretical binding of rosuvastatin to the Nrf2 target. HSCD was used to induce cognitive impairment in rats and neurobehavioral studies were performed to evaluate the efficacy of rosuvastatin in enhancing cognition. Biochemical analyses were used to estimate changes in oxidative markers. Western blot and immunohistochemical analyses were done to check Nrf2 translocation. TUNEL and caspase 3 tests were performed to evaluate reversal of apoptosis by rosuvastatin.Results: Rosuvastatin showed good theoretical affinity to Nrf2, significantly reversed changes in oxidative biomarkers which were induced by HSCD, and also improved the performance of rats in the neurobehavioral test. A rise in nuclear translocation of Nrf2 was revealed through immunohistochemical analysis and western blot. TUNEL staining and caspase 3 activity showed attenuation of apoptosis.Discussion: We have investigated a novel mechanism of action for rosuvastatin (via the Nrf2–ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment.

Highlights

Dementia is a neurological disorder that is associated with progressive loss of memory and difficulties in language, behavior, and cognition [1]
The docked ligand (PCT and RSV) displayed acceptable docking scores and binding free energy for nuclear factor erythroid 2-related factor 2 (Nrf2). These reports strongly suggest that the recognition of key structural features of RSV template will be helpful in designing and synthesizing new analogues with improved Nrf2 activity
Nrf2 works by binding to the antioxidant response element (ARE) and regulating various genes which are responsible for anti-oxidative, antiinflammatory and mitochondrial protection actions

Summary

Introduction

Dementia is a neurological disorder that is associated with progressive loss of memory and difficulties in language, behavior, and cognition [1]. Modern western food habits – especially those consisting of high salt and cholesterol diet (HSCD) – are one of the major risk factors for cognitive impairment. Such high-energy, high-saturated diets are commonly associated with progressive deterioration in learning and memory [4]. Numerous longitudinal & cross-sectional correlational studies have concluded that increased consumption of food containing high levels of saturated lipids and fats leads to greater susceptibility for diseases such as dementia and have indicated to cause impairment in memory retrieval speed as well as prospective memory [5]. Metabolic syndrome caused by HSCD is a major risk factor for cognitive decline [8]

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Conclusion