Prevention of glutamate excitotoxicity in motor neurons by 5,6-dihydrocyclopenta-1,2-dithiole-3-thione: implication to the development of neuroprotective drugs

Glutamate-induced excitotoxicity and oxidative damage are believed to play an important role in the development of a number of central nerve system disorders. Nuclear-factor erythroid 2-related factor 2 (Nrf2) is a master transcriptional regulator of many cytoprotective genes.We report herein that 5,6-dihydrocyclopenta-1,2-dithiole-3-thione (CPDT), which was previously shown to induce several Nrf2 target genes in non-nervous cells and tissues, significantly activates Nrf2 and Nrf2 target genes in rat spinal cord explants. More importantly, such activation is accompanied by complete inhibition of glutamate-induced motor neuron death in these explants. Further studies show that CPDT inhibits glutamate-induced intracellular Ca2+ rise, loss of mitochondrial transmembrane potential and depletion of tissue glutathione. CPDT did not appear to modulate glutamate transport or to interfere with glutamate interaction with postsynaptic receptors. Taken together, our studies have identified CPDT as a promising neuroprotective agent and suggest that pharmacological activation of Nrf2 signaling is an important strategy for protection against glutamate-induced excitotoxicity.