Ketone beta-hydroxybutyrate up-regulates BDNF expression through NF-κB as an adaptive response against ROS, which may improve neuronal bioenergetics and enhance neuroprotection (P3.090)

Objective: The objective of this study was to investigate whether and how ketones activate adaptive neuronal stress response signaling pathways through brain derived neurotrophic factor (BDNF) to bolster neuronal bioenergetics and mediate neuroprotection. Background: During fasting and exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB and ketogenic diets can protect neurons against excitotoxicity and oxidative stress during epilepsy and neurodegenerative disorders, but the underlying mechanisms are unclear. Since BDNF signaling has also been linked to beneficial effects of fasting and exercise on neuroprotection, we investigated whether and how 3OHB induces BDNF expressions to improve bioenergetics and stress resistance. Design/Methods: After primary culture of cortical and hippocampal neurons was maintained with or without 3OHB for 24 hours, BDNF expression, ROS levels, and oxidative mitochondrial capacity were measured. Experiments were repeated after treatments with ROS scavengers and NF-kB inhibitors to identify the targets that mediate ketone-dependent BDNF upregulation. Then, in the presence or absence of inhibitor for BDNF receptor (TrkB), neurons pre-incubated with or without ketone media were assessed for capacity of mitochondrial oxidative phosphorylation and survival after kainic acid treatment. Results: ROS was significantly increased in neurons after 6 hours of ketone incubation. However, after 24 hours, neurons show improved efficiency in ATP productions, upregulated expressions of antioxidant enzyme SOD2, and enhanced resistance to excitotoxicity. These effects were significantly abolished in neurons after treatment with TrkB inhibitor. More interestingly, ROS scavengers or blocking ROS-dependent NF-kB activation significantly decreased ketone-dependent BDNF-upregulation in neurons, suggesting that ROS may have increased BDNF expressions to improve mitochondrial respiration as adaptive responses. Conclusions: 3OHB initially generates ROS and poses oxidative stress. However, ROS appears to trigger adaptive responses against oxidative stress by upregulating BDNF through NF-kB activation, which can improve mitochondrial oxidative capacity and ultimately enhance neuroprotection. Study Supported by: Intramural Research Program of the National Institute on Aging. Disclosure: Dr. Kim has nothing to disclose. Dr. Marosi has nothing to disclose. Dr. Mattson has nothing to disclose.