Neuroprotective effects of alpha-lipoic acid and its positively charged amide analogue

Elevated levels of extracellular glutamate have been linked to reactive oxy gen species mediated neuronal damage and brain disorders. Lipoic acid is a potent antioxidant that has previously been shown to exhibit neuroprotectio n in clinical studies. A new positively charged water soluble lipoic acid a mide analog, 2-(N,N-dimethylamine) ethylamido lipoate . HCl (LA-plus), with a better cellular reduction and retention of the reduced form was develope d. This novel antioxidant was tested for protection against glutamate induc ed cytotoxicity in a HT4 neuronal cell line. Glutamate treatment for 12 h r esulted in significant release of LDH from cells to the medium suggesting c ytotoxicity. Measurement of intracellular peroxides showed marked (up to 20 0%) increase after 6 h of glutamate treatment. Compared to lipoic acid, LA- plus was more effective in (1) protecting cells against glutamate induced c ytotoxicity, (2) preventing glutamate induced loss of intracellular GSH, an d (3) disallowing increase of intracellular peroxide level following the gl utamate challenge. The protective effect of LA-plus was found to be indepen dent of its stereochemistry, The protective function of this antioxidant wa s synergistically enhanced by selenium. These results demonstrate that LA-p lus is a potent protector of neuronal cells against glutamate-induced cytot oxicity and associated oxidative stress. (C) 1999 Elsevier Science Inc.