CARBOXYFULLERENES AS NEUROPROTECTIVE AGENTS

Two regioisomers with C-3 or D-3 symmetry of water-soluble carboxylic acid C-60 derivatives, containing three malonic acid groups per molecu le, were synthesized and found to be equipotent free radical scavenger s in solution as assessed by EPR analysis, Both compounds also inhibit ed the excitotoxic death of cultured cortical neurons induced qv expos ure to N-methyl-D-aspartate (NMDA), lpha-amino-3-hydroxy-5-methyl-4-is oxazolepropionic acid (AMPA), or oxygen-glucose deprivation, but the C -3 regioisomer was more effective than the D-3 regioisomer, possibly r eflecting its polar nature and attendant greater ability to enter lipi d membranes, At 100 mu M, the C-3 derivative fully blocked even rapidl y triggered, NMDA receptor-mediated toxicity, a form of toxicity with limited sensitivity to ail other classes of free radical scavengers we have tested, The C-3 derivative also reduced apoptotic neuronal death induced by either serum deprivation or exposure to A beta(1-42) prote in, Furthermore, continuous infusion of the C-3 derivative in a transg enic mouse carrying the human mutant (G93A) superoxide dismutase gene responsible for a form of familial amyotrophic lateral sclerosis, dela yed both death and functional deterioration, These data suggest that p olar carboxylic acid C-60 derivatives may hare attractive therapeutic properties in several acute or chronic neurodegenerative diseases.