Impact Of 3-hydroxybutyrate And Its Derivatives On Physiological Functions Of Hippocampal Neurons And Synthesis And Characterization Of A Fluorescent 3-HB Probe

Ketone bodies produced in the liver during long-term starvation or fasting are used as the alternative fuels for body organs. 3-hydroxybutyric acid (3-HB) is one of the ketone bodies produced during ketosis. Past studies (e.g., Zou et al., 2009) on animal models suggested that 3-HB might improve learning and spatial memory. In order to explore the mechanism underlying the 3-HB-induced memory improvement, we investigated various physiological and metabolic functions of hippocampal neuronal cells cultured with 3-HB or 3-HBME. To further study how 3-HB bind with and enter mammalian cells, we synthesized a novel 3-HB fluorescent probe. The small fluorophore 7-amino-4-methylcoumarin (AMC) was chemically conjugated to 3-HB via a zero-length cross linking reaction. The synthesized 3-HB fluorescent probe was used to monitor the endocytosis of 3-HB into rabbit smooth muscle cells. Competition assay with native 3-HB revealed a possible receptor binding competition on cell cytoplasm with the synthesized 3-HB-AMC conjugates. 3-HB and 3-HBME were found to improve mitochondrial respiration and viability of cultured hippocampal neurons under low-glucose conditions. We concluded that 3-HB and 3-HBME protect cells through preserving cellular metabolic functions under pathophysiological stresses. This protection might support the recent finding regarding the improved animal learning and spatial memory conferred by 3-HB.