The ketone metabolite β-hydroxybutyrate (βOHB), is reported to be neuroprotective after spinal cord injury (SCI) in rats, but the underlying mechanism remains unknown. The present study aims to investigate effects of βOHB on suppression of oxidative stress and inhibition of class I histone deacetylases (HDACs) in in vivo and in vitro models. Rats were fed with ketogenic diet (KD) or standard diet (SD) for 3 weeks. A C5 hemi-contusion injury was applied to these animals on the 14th day of experiment, and spinal cord samples were harvested on the 1st, 3rd and 7th days after SCI, respectively. The blood ketone levels were significantly higher in the KD groups. KD reduced oxidative stress markers and reactive oxygen species (ROS) products, downregulated the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)2 and NOX4, and upregulated the expression of forkhead box group O (FOXO)3a, mitochondrial superoxide dismutase (MnSOD), and catalase after SCI. The in vitro study, performed on PC12 cells, indicated that βOHB inhibited HO-induced ROS production, decreased NOX2 and NOX4 protein levels, and upregulated FOXO3a, MnSOD, and catalase levels in a dose-dependent manner, which was consistent with the in vivo results. The ketone metabolite βOHB inhibited HDAC1, HDAC2, and HDAC3 activity, but not HDAC8 in SCI rats and PC12 cells. Depletion of HDAC1 or HDAC2 with small interfering RNA (siRNA) attenuated HO-induced ROS production and protein carbonylation and elevated FOXO3a protein levels, meanwhile reducing NOX2 and NOX4 protein expression in PC12 cells. Our results indicate that the ketone metabolite βOHB attenuates oxidative stress in SCI by inhibition of class I HDACs, and selected suppression of HDAC1 or HDAC2 regulates FOXO3a, NOX2, and NOX4 expression. Therefore, the ketone metabolite βOHB may be a novel promising therapeutic agent for SCI.
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