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

et al. 2018

Clin Exp Pharma Physio

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The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are the drugs of choice for the pharmacotherapy of hyperlipidemia as well as for reducing atherosclerotic cardiovascular risk. 1 Statins inhibit the HMG-CoA reductase enzyme and therefore suppress the conversion of HMG-CoA into mevalonate-the first step in cholesterol biosynthesis. Following this step, low-density lipoprotein-cholesterol synthesis is lowered in hepatocytes, which consequently leads to a reduced blood cholesterol level. Despite this long known potent lipid-lowering effect, statins also possess lipid-independent pharmacological effects or pleiotropic effects. 2 Recently, there has been an increased interest in evaluating the potential use of statins for treating numerous neurological disorders. 3,4 Several pre-clinical and clinical trials substantiate the neuroprotective effect of statins in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's, multiple sclerosis, epilepsy, spinal cord injury, depression, cognitive dysfunction, and stroke. 3-6 Possible reasons behind the neuroprotective effect of statins may be attributed to their anti-inflammatory, antioxidant, anti-apoptotic, and anti-excitotoxicity activities. 7 Interestingly, of all the statins, rosuvastatin is comparatively the most potent. It exhibits greater affinity for the active site of HMG-CoA reductase as evident in STELLAR, DISCOVERY and the Discovery Belux studies. 8 Although statins contain both hydrophilic and lipophilic moieties, the hydrophilic nature of rosuvastatin is more prominent. 9 Rosuvastatin possesses an atypical N-methyl N-linked sulphonamide moiety along with a wholly substituted pyrimidine nucleus. Further, X-ray crystallography studies have revealed that rosuvastatin had the most number of protein-ligand interactions when compared to any other member of this family (Figure 1). 10 It is metabolized slowly by hepatic enzymes, particularly CYP2C19 and CYP2C9 and its duration of action and plasma half-life are higher than any other statin. 11 Escalating evidence suggests that rosuvastatin, apart from its hypolipidaemic effects, exerts multiple beneficial pleiotropic immunomodulatory, anti-inflammatory, anti-apoptotic and anti-excitotoxic actions. 12 These pleiotropic, cholesterol-independent effects include increase in endothelial NO synthase (NOS) and tissue-type plasminogen Summary Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, and one of the most popular antihyperlipidemic medications have been found to possess pharmacodynamic activities much different from its usual indication. Recent research studies have revealed the efficacy of rosuvastatin in attenuating neuroinflammation, reducing the progression of Alzheimer's disease, providing protection against cerebral ischaemia and spinal cord injury as well as ameliorating epilepsy.Mechanisms behind the neuroprotective potential of rosuvastatin can be attributed to its pleiotropic effects, independent of its abili...

Section: Introductionsupporting

confidence: 60%

Unfolding the pleiotropic facades of rosuvastatin in therapeutic intervention of myriads of neurodegenerative disorders

Husain

et al. 2018

Clin Exp Pharma Physio

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“…Then, the rats were treated daily for 5 weeks (weeks 7–11) with the drugs along with HFSD. The dose of VitD was 500 IU/kg/day; PO [ 37 ], while that for RSV was 15mg/kg/day; PO [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

Vitamin D and rosuvastatin alleviate type-II diabetes-induced cognitive dysfunction by modulating neuroinflammation and canonical/noncanonical Wnt/β-catenin signaling

et al. 2022

Background Type-II diabetes mellitus (T2DM) is a major risk factor for cognitive impairment. Protecting the brain environment against inflammation, and neurodegeneration, as well as preservation of the BBB veracity through modulating the crosstalk between insulin/AKT/GSK-3β and Wnt/β-catenin signaling, might introduce novel therapeutic targets. Purpose This study aimed at exploring the possible neuroprotective potential of vitamin D3 (VitD) and/or rosuvastatin (RSV) in T2DM-induced cognitive deficits. Methods T2DM was induced by a high-fat sucrose diet and a single streptozotocin (STZ) dose. Diabetic rats were allocated into a diabetic control and three groups treated with RSV (15 mg/kg/day, PO), VitD (500 IU/kg/day, PO), or their combination. Results Administration of VitD and/or RSV mitigated T2DM-induced metabolic abnormalities and restored the balance between the anti-inflammatory, IL 27 and the proinflammatory, IL 23 levels in the hippocampus. In addition, they markedly activated both the canonical and noncanonical Wnt/β-catenin cassettes with stimulation of their downstream molecular targets. VitD and/or RSV upregulated insulin and α7 nicotinic acetylcholine (α7nACh) receptors gene expression, as well as blood-brain barrier integrity markers including Annexin A1, claudin 3, and VE-cadherin. Also, they obliterated hippocampal ApoE-4 content, Tau hyperphosphorylation, and Aβ deposition. These biochemical changes were reflected as improved behavioral performance in Morris water maze and novel object recognition tests and restored hippocampal histological profile. Conclusion The current findings have accentuated the neuroprotective potential of VitD and RSV and provide new incentives to expand their use in T2DM-induced cognitive and memory decline. This study also suggests a superior benefit of combining both treatments over either drug alone.

“…[33][34][35] Pellets of high cholesterol diet were prepared freshly by adding 1.56% cholesterol and 10% coconut oil in standard diet pellets and dried at room temperature. [36,37] The composition of HCD has been validated in the first part of the study that consisted of HCD in different concentrations of cholesterol. 1).…”

Section: Validation Of Docking Protocolmentioning

confidence: 99%

Exploring effects of Simvastatin on coagulation mediators to alleviate the advancement of high cholesterol diet triggered neurodegeneration

Hasan

J Biochem & Molecular Tox

et al. 2023

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The objectives of our study were to investigate the possible effect of Simvastatin in ameliorating high cholesterol diet (HCD)-induced neurodegeneration and to also investigate its possible action on coagulation mediators. In silico and in vitro studies were performed to evaluate the impact of Simvastatin on prime coagulation mediators. HCD was used to induce neuropathology in wistar rats and histopathological and immunohistochemical studies were performed to evaluate the efficacy of Simvastatin in preventing the advancement of neurodegeneration in obese rats.Biochemical analyses were used to estimate changes in lipid profile, oxidative stress, inflammatory and coagulation markers. Simvastatin showed good theoretical affinity to coagulation proteins, significantly reversed changes in inflammatory and coagulation biomarkers which were induced by HCD. Enhanced fibrinolytic activity of Simvastatin was revealed through in vitro analysis. Immunohistoanalysis showed raised level of Nrf2. Histopathological studies also supported neuroprotective potential of Simvastatin in HCD fed rats. Simvastatin demonstrated reduced hypercoagulation, enhanced fibrinolysis and reversed neurodegeneration in HCD exposed rats suggesting its potential role in preventing the progression of neurodegeneration in obesity.