Ketoacids as antioxidants in human astrocytes exposed to oxidative and aluminum stress.

Abstract

Aluminum (Al), the most abundant metal in the earth’s crust, has been implicated in a number of neurological diseases. Its increased bioavailability has been associated with increased toxicity in humans. Increased lipid accumulation occurs as a result of disruption in carnitine homeostasis due to the shunting of α-ketoglutarate (αKG) towards reactive oxygen species (ROS) detoxification. The purpose of this study was to elucidate the role of ketoacids such as oxaloacetate (OAA) and αKG in combating oxidative stress in astrocytes. The present study has shown the ability of ketoacids such as αKG and OAA to sequester ROS in the astrocytes and restore normal lipid levels as observed through fluorescence microscopy. The non-enzymatic decarboxylation of αKG and OAA into succinate and malonate respectively as observed in the HPLC studies point to the role of these ketoacids in ROS detoxification. Furthermore, the tricarboxylic acid (TCA) cycle activity which is diminished under oxidative stress as gauged by the activity of NAD-ICDH, was found to be restored to normal levels in the stressed cells upon recovery with OAA. Expression of apolipoprotein E, an essential biomolecule in lipid and β-amyloid metabolism, was found to be down-regulated under aluminum stress, an observation that was reversed by OAA recovery. Hence it appears that the ketoacids play a critical role in quelling ROS in human astrocytes.