Parapyruvate Induces Neurodegeneration in C57BL/6JNarl Mice via Inhibition of the α-Ketoglutarate Dehydrogenase Complex

Parapyruvate is a substance commonly found in commercial dietary supplements of calcium pyruvate (DSCP) that inhibits the α-ketoglutarate dehydrogenase complex (KGDHC) and has been shown to induce senescence in human Hs68 cells. However, it is unknown whether parapyruvate can induce neurodegeneration. In this study, the parapyruvate content in DSCP was converted to an equivalent dose for mice and administered to the C57BL/6JNarl mice at doses around the equivalent dose for 69 days, including 5, 50, and 500 mg/kg/day. The Morris water maze (MWM) task and the active avoidance test were conducted to assess the learning and memory ability in mice, and then brain tissues were collected for biochemical analyses. The results demonstrated that parapyruvate significantly impaired the learning and memory ability, decreased the KGDHC activity, and promoted the oxidative stress and acetylcholinesterase (AChE) activity in mice in a dose-dependent manner. Additionally, parapyruvate induced Tau and phosphorylated Tau (p-Tau) aggregation at dosages ≥5 mg/kg/day and increased the myelin basic protein (MBP) expression at a dosage of 500 mg/kg/day. These results suggest that the equivalent dose of parapyruvate can induce neurodegeneration in the C57BL/6JNarl mice.