Carboxyfullerenes as Potent Neuroprotective Agents

A pioneering study published in the Proceedings of the National Academy of Sciences (Dugan et al., 1997) investigated the neuroprotective potential of water-soluble carboxylic acid C60 derivatives, specifically two regioisomers (C3 and D3 symmetry) with three malonic acid groups per molecule. Using electron paramagnetic resonance (EPR) analysis, both isomers demonstrated equipotent free radical scavenging in solution. However, in cellular models, the C3 regioisomer outperformed the D3 isomer in preventing excitotoxic neuronal death in cultured cortical neurons exposed to N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or oxygen-glucose deprivation. The C3 derivative’s superior efficacy, likely due to its polar nature and enhanced ability to penetrate lipid membranes, fully blocked even rapidly triggered NMDA receptor-mediated toxicity at 100 μM—a feat unmatched by other free radical scavengers tested. The C3 isomer also reduced apoptotic neuronal death triggered by serum deprivation or exposure to Aβ1–42 protein, implicated in Alzheimer’s disease. In vivo, continuous infusion of the C3 derivative in transgenic mice with the human mutant G93A superoxide dismutase gene (a model for familial amyotrophic lateral sclerosis) delayed both mortality and functional decline. These findings highlight polar carboxyfullerenes, particularly the C3 regioisomer, as promising therapeutic candidates for acute and chronic neurodegenerative diseases, offering robust antioxidant and neuroprotective effects.

Link to research study