Effect of Astaxanthin on Hippocampal Neuroinflammation in Aging Mice Fed a High-Fat Diet

Abstract Research into neuroprotective strategies aimed at correcting diet- and aging-related hippocampal dysfunction is of high relevance given the increasing prevalence of the Western diet and global population aging. This study investigated the effects of a long-term high-fat diet (HFD) and the antioxidant astaxanthin (AST) on the hippocampal state during aging in mice. Aging was shown to be accompanied by the impairment of long-term memory and the development of chronic neuroinflammation in the hippocampus. HFD had a moderate effect on hippocampal alterations compared to animals fed a standard diet (SD). The age-related dynamics of microglial activity, assessed by Iba1 immunoreactivity, was characterized by its increase in the hippocampal CA1 and CA3 regions and dentate gyrus (DG) at 12 months, followed by a decrease at 15 months. Dietary AST supplementation led to improved passive avoidance performance and exerted a duration-dependent effect: when administered for less than 6 months, AST promoted the suppression of pro-inflammatory activity, as evidenced by the downregulation of NF-κB expression in the hippocampus. However, longer continuous AST administration, conversely, led to the upregulation of NF-κB expression. These results indicate the ambiguous effects of HFD on the brain and emphasize the importance of optimizing the timing of antioxidant administration for protecting the hippocampus from neuroinflammation.