1,3-butanediol administration as an alternative strategy to calorie restriction for neuroprotection – Insights into modulation of stress response in hippocampus of healthy rats

Ketogenic diet has a wide range of beneficial effects but presents practical limitations due to its low compliance, hence dietary supplements have been developed to induce ketosis without nutrient deprivation. The alcohol 1,3- butanediol (BD) is a promising molecule for its ability to induce ketosis, but its effects on brain have been investigated so far only in disease models, but never in physiological conditions. To support BD use to preserve brain health, the analysis of its activity is mandatory. Therefore, we investigated, in healthy rats, the effect of a fourteen-days BD-administration on the hippocampus, an area particularly vulnerable to oxidative and inflammatory damage. Since BD treatment has been reported to reduce energy intake, results were compared with those obtained from rats undergoing a restricted dietary regimen, isoenergetic with BD group (pair fed, PF). Reduced pro-inflammatory signaling pathways and glial activation were revealed in hippocampus of BD treated rats in comparison to control (C) and PF groups. ROS content and the extent of protein oxidative damage were lower in BD and PF groups than in C. Interestingly, higher amounts of nuclear factor erythroid 2-related factor 2 (Nrf2), decreased level of lipid hydroperoxides, lower susceptibility to oxidative insult, higher amounts of superoxide dismutase-2, glutathione reductase and glutathione peroxidase (GPx), and increased GPx activity were observed in BD animals. BD administration, but not dietary restriction, attenuated endoplasmic reticulum stress, reduced autophagic response activation, and was associated with an increase of both the neurotrophin BDNF and presynaptic proteins synaptophysin and synaptotagmin. Our results highlight that BD plays a neuroprotective role in healthy conditions, thus emerging as an effective strategy to support brain function without the need of implementing ketogenic nutritional interventions.