α-Lipoic Acid Reduces Ceramide Synthesis and Neuroinflammation in the Hypothalamus of Insulin-Resistant Rats, While in the Cerebral Cortex Diminishes the β-Amyloid Accumulation

Abstract

Background Oxidative stress underlies metabolic diseases and cognitive impairment; thus, the use of antioxidants may improve brain function in insulin-resistant conditions. We are the first to evaluate the effects of α-lipoic acid (ALA) on redox homeostasis, sphingolipid metabolism, neuroinflammation, apoptosis, and β-amyloid accumulation in the cerebral cortex and hypothalamus of insulin-resistant rats. Methods The experiment was conducted on male cmdb/outbred Wistar rats fed a high-fat diet (HFD) for 10 weeks with intragastric administration of ALA (30 mg/kg body weight) for 4 weeks. Pro-oxidant and pro-inflammatory enzymes, oxidative stress, sphingolipid metabolism, neuroinflammation, apoptosis, and β-amyloid level were assessed in the hypothalamus and cerebral cortex using colorimetric, fluorimetric, ELISA, and HPLC methods. Statistical analysis was performed using three-way ANOVA followed by the Tukey HSD test. Results ALA normalizes body weight, food intake, glycemia, insulinemia, and systemic insulin sensitivity in HFD-fed rats. ALA treatment reduces nicotinamide adenine dinucleotide phosphate (NADPH) and xanthine oxidase activity, increases ferric-reducing antioxidant power (FRAP) and thiol levels in the hypothalamus of insulin-resistant rats. In addition, it decreases myeloperoxidase, glucuronidase, and metalloproteinase-2 activity and pro-inflammatory cytokines (IL-1β, IL-6) levels, while in the cerebral cortex ALA reduces β-amyloid accumulation. In both brain structures, ALA diminishes ceramide synthesis and caspase-3 activity. ALA improves systemic oxidative status and reduces insulin-resistant rats’ serum cytokines, chemokines, and growth factors. Conclusion ALA normalizes lipid and carbohydrate metabolism in insulin-resistant rats. At the brain level, ALA primarily affects hypothalamic metabolism. ALA improves redox homeostasis by decreasing the activity of pro-oxidant enzymes, enhancing total antioxidant potential, and reducing protein and lipid oxidative damage in the hypothalamus of HFD-fed rats. ALA also reduces hypothalamic inflammation and metalloproteinases activity, and cortical β-amyloid accumulation. In both brain structures, ALA diminishes ceramide synthesis and neuronal apoptosis. Although further study is needed, ALA may be a potential treatment for patients with cerebral complications of insulin resistance.

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“…AGEs induce NADPH oxidase (NOX) to produce ROS by activation of the receptor for advanced glycation end products (RAGE), as well as to stimulate the formation of cytotoxic β-amyloid (βA) and ceramide, inducing neuronal death. βA, through AGEs signaling, can contribute to the phosphorylation of mitogen-activated protein kinase (MAPK) and, thus, to the atrophy of synapses ( 11 – 13 ). Therefore, it should be no surprise that 11% of people with diabetes meet the criteria for a diagnosis of depression, and 31% report a history of depressive symptoms ( 14 ).…”

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“…intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1) 7 . AGE also promote ceramide synthesis and β-amyloid (βA) accumulation, leading to neuronal death via apoptosis and necrosis 8 , 9 . Interestingly, βA can mediate the phosphorylation of mitogen-activated protein kinase (MAPK) via AGE signalling.…”