Hyperlipidemia Downregulate Brain Antioxidant Defense Enzymes and Neurotrophins in Rats: Assessment of the Modulatory Potential of EPA+DHA and Zerumbone

Abstract

Background: Oxidative stress (OS) plays a vital role in the pathogenesis of cognitive disorders. In this study, brain antioxidant defense dysregulation as a consequence of hyperlipidemia, and the efficacy of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), and zerumbone (Z) in their modulation are assessed. Methods and results: Male Wistar rats are fed control, high-fat (HF), HF + fish oil (HF+F), HF + zerumbone (HF+Z), and HF + fish oil + zerumbone (HF+F+Z) diet for 60 days. Markers of OS, antioxidant enzymes, monoamine oxidase, nuclear factor (erythroid-derived 2)-like 2 (NRF-2), nitric oxide-2 (NOS-2), inter cellular adhesion molecule-1 (ICAM-1), and neurotrophins are measured. Hyperlipidemia increases OS, decreases antioxidant enzyme activity, increases monoamine oxidase activity, increases NOS-2 and ICAM-1 expression, decreases NRF-2 activation, decreases nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels in the brain compared to control. While EPA+DHA and zerumbone significantly (p < 0.05) restores the perturbations induced by hyperlipidemia. Conclusion: It is concluded that hyperlipidemia cause OS by decreasing the activity of brain antioxidant enzymes via the downregulation of NRF-2. The reduced brain neurotrophins in hyperlipidemia indicate its potential risk on cognitive attributes. EPA+DHA, together with zerumbone, positively modulates hyperlipidemia induced brain dysfunction thereby offering promising therapeutic strategy.

Differential proteomic analysis of mouse cerebrums with high-fat diet (HFD)-induced hyperlipidemia

“…Besides the cardiovascular and metabolic disorders, hyperlipidemia has also been reported to affect brain functions ( Pappolla et al, 2003 ; Rahman et al, 2005 ; Thirumangalakudi et al, 2008 ; Cao et al, 2015 ; Ettcheto et al, 2015 ; Paul & Borah, 2017 ; Eriksson et al, 2017 ; Wang et al, 2018 ; Uppin et al, 2020 ; Dimache et al, 2021 ; Feringa & vander Kant, 2021 ). Cao et al (2015) reported that hyperlipidemia exacerbated cerebral injury of middle cerebral artery occlusion/reperfusion rats via oxidative stress, inflammation and neuronal apoptosis.…”

“…The blood brain barrier (BBB) was observed to be compromised in hyperlipidemic animals and subsequently led to increased levels of total cholesterol (TC), total triglyceride (TG) and low-density lipoprotein (LDL)-cholesterol, and decreased high-density lipoprotein (HDL)-cholesterol in the brain ( Paul & Borah, 2017 ; Wang et al, 2018 ). There have been accumulating evidence that abnormal lipid metabolism may contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer’s diseases (AD) and Parkinson’s diseases and the suggested mechanisms included impairment of BBB, amyloid deposition, pathological Tau accumulation, neuroinflammation and oxidative stress in the brain ( Pappolla et al, 2003 ; Rahman et al, 2005 ; Thirumangalakudi et al, 2008 ; Ettcheto et al, 2015 ; Paul & Borah, 2017 ; Eriksson et al, 2017 ; Uppin et al, 2020 ; Dimache et al, 2021 ; Feringa & vander Kant, 2021 ). However, not all of the research in the field found this association.…”

Zerumbone Exhibit Protective Effect against Zearalenone Induced Toxicity via Ameliorating Inflammation and Oxidative Stress Induced Apoptosis

“…Whenever a tissue injury occurs due to oxidate stress, the body releases antioxidant enzymes such as SOD, CAT, and GSH, which scavenge ROS in the liver [42]. Studies have shown that ZER prevents tissue injury by curbing the production of ROS [43][44][45]. The same mechanism is followed when paracetamol's cytotoxicity results in liver injury due to ROS generation [46].…”

Research advances in the influence of lipid metabolism on cognitive impairment

“…It is reported that hyperlipidemia can reduce the activity of free radical scavengers, which would lead to a massive accumulation of lipid peroxides, thus accelerating the development of atherosclerosis. Meanwhile, the reduction of cerebral blood flow causes cerebral ischemia and hypoxia, and ultimately leads to brain damage and CI 16,17 . Moreover, it has been confirmed in recent studies that abnormally expressed LDL‐C, apolipoprotein A (Apo A), and apolipoprotein B (Apo B) have a close relationship with CI 18–20 .…”