The neuroprotective efficacy of antioxidant molecules against iodoacetate (IAA) neurotoxicity in rat cerebellar granule cell (CGC) cultures is investigated. In the absence of MK-801, (S)-Trolox displays marginal neuroprotective effects. In the presence of MK-801 (10 μM), the neuroprotective efficacy of (S)-Trolox is greatly enhanced, giving rise to a recovery in MTT-reductase activity equivalent to 80–100% of control cultures. (S)-Trolox displays EC50 value of 78 μM. The fluorescence increase in IAA-stimulated DCFH-DA-loaded cultures is inhibited in a dose-dependent manner by the antioxidants (S)-Trolox with an IC50 value of 97 μM. The antioxidant (S)-Trolox demonstrate apotent and specific neuroprotective action in an in vitro model of neurodegeneration induced by inhibition of the glycolytic enzyme GAPDH.