The neuropathology of Parkinson's disease (PD) involves a reduction of endogenous antioxidant enzyme systems, heightened oxidative stress and mitochondrial aberrations in the region of the substantia nigra. Similarly, neurotoxins commonly used to investigate PD pathology include 6-hydroxydopamine (6-OHDA), a powerful hydrogen peroxide (H₂0₂) pro-oxidant and 1-methyl-4-phenylpyridinium ion (MPP+), a mitochondrial complex I inhibitor that exerts detrimental effects on cellular energy production. Pyruvic acid is a neuronal metabolic energy fuel that can also rapidly undergo decarboxylation to diffuse H₂0₂ into H₂0. In this study, we investigated the effect of pyruvic acid against 6-OHDA, MPP+ and H₂0₂ toxicity in murine brain neuroblastoma cells. The results obtained indicated that the toxicity of 6-OHDA was inversely related to the autoxidative formation of H₂0₂. Pyruvic acid exhibited powerful non-enzymatic stoichiometric H₂0₂ trapping properties, and protected against both 6-OHDA and H₂0₂ toxicity. While both sodium pyruvate and pyruvate were highly protective against oxidative stress, pyruvate in its free acid form only was protective against MPP+, indicating a requirement for effective transport in order to fuel glycolysis. The protective properties of glucose were compared to pyruvic acid, and the data indicated that glucose did not exhibit antioxidant properties and was effective in blocking MPP+, but not 6-OHDA or H₂0₂ toxicity. On the other hand, pyruvic acid was protective against all three toxins, and unlike glucose, completely blocked MPP+ toxicity in a combination insult model with up to 500 μM of H₂0₂. Moreover, the data obtained indicate that pyruvic acid exerts powerful neuroprotective properties by providing simultaneous resistance to oxidative stress and mitochondrial insult. These protective effects are the result of a unique dual property of pyruvic acid with concurrent ability to serve as an effective neuronal energy substrate for glycolysis and to act as an exceptionally powerful antioxidant.