Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory

Abstract

Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, ABHD3, but also that the up-regulation of LEP gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (ob/ob), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX.hippocampal leptin | mild exercise | astaxanthin | antioxidant | spatial memory P ositive lifestyle changes including physical activity and diet are believed to be beneficial for promoting brain health and slowing cognitive decline of Alzheimer's disease (AD). Exercise is an important factor in improving hippocampus-related cognition by enhancing adult hippocampal neurogenesis (AHN) in rodents (1). Although dietary supplements such as docosahexaenoic acid (DHA) and epicatechin (EGCG) have been shown to potentiate the effects of voluntary exercise on memory function (2-4), voluntary exercise alone, not in combination with EGCG, improves AHN and memory functions (5, 6). However, previous animal studies were limited in their applicability to clinical trials because of the uncertainty concerning exercise intensity. To translate our mild exercise (ME) animal model to humans, we developed a quantitative evaluation system based on lactate threshold (LT) and showed that ME has beneficial effects on AHN and spatial memory in animals (7, 8) and on hippocampal memory function in young humans (9). This raises the question of whether, for translation to humans, a combined intervention of dietary supplements and ME could enhance memory function and neuronal plasticity.While mechanisms of exercise-enhanced hippocampal function are not fully understood, several molecular factors includin...

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

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Hypothesized Mechanisms Through Which Exercise May Attenuate Memory Interference

“…Exercise has been shown to produce structural and functional changes within the brain [16]. In human studies, structural changes are measured as increased hippocampal and prefrontal cortex (PFC) volume and white matter integrity, potentially mediated via neurogenesis, brain-derived neurotrophic factor (BDNF) [16,17] and other related mechanisms [18]. These neuronal changes lead to neuroplasticity, increased efficiency of BDNF uptake, and upregulated transcription and signaling cascades [15].…”

Stereochemistry of Astaxanthin Biosynthesis in the Marine Harpacticoid Copepod Tigriopus Californicus

“…This carotenoid, sourced from chemical synthesis mainly, is used to support the healthy growth of farmed salmon and trout [ 7 , 8 ], and is also essential for these species to acquire the characteristic reddish hue that is crucial for customer acceptance [ 9 ]. On the other hand, astaxanthin from microalgae origin is marketed for direct human consumption in capsules [ 10 ], as experiments in murine models suggest that this carotenoid may be beneficial in cognition [ 11 ], cardiac function [ 12 ], and inflammation [ 13 ]. Nevertheless, a recent meta-analysis of the randomized placebo-controlled trials conducted with astaxanthin suggests that more work is needed to confirm these benefits in humans [ 14 ].…”