Article

Carboxyfullerenes as neuroprotective agents

Laura L. DuganDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Dorothy M. TuretskyDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Cheng DuDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Doug LobnerDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Mark E. WheelerDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130C. Robert AlmliDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Clifton Kwang-Fu ShenDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Tien‐Yau LuhDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Dennis W. ChoiDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130Tien‐Sung LinDepartments of Neurology and Occupational Therapy, and the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO 63110; Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, People’s Republic of China; and Department of Chemistry, Washington University, St. Louis, MO 63130

1997en

ABI

Abstract

Two regioisomers with C3 or D3 symmetry of water-soluble carboxylic acid C60 derivatives, containing three malonic acid groups per molecule, were synthesized and found to be equipotent free radical scavengers in solution as assessed by EPR analysis. Both compounds also inhibited the excitotoxic death of cultured cortical neurons induced by exposure to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or oxygen-glucose deprivation, but the C3 regioisomer was more effective than the D3 regioisomer, possibly reflecting its polar nature and attendant greater ability to enter lipid membranes. At 100 microM, the C3 derivative fully blocked even rapidly triggered, NMDA receptor-mediated toxicity, a form of toxicity with limited sensitivity to all other classes of free radical scavengers we have tested. The C3 derivative also reduced apoptotic neuronal death induced by either serum deprivation or exposure to Abeta1-42 protein. Furthermore, continuous infusion of the C3 derivative in a transgenic mouse carrying the human mutant (G93A) superoxide dismutase gene responsible for a form of familial amyotrophic lateral sclerosis, delayed both death and functional deterioration. These data suggest that polar carboxylic acid C60 derivatives may have attractive therapeutic properties in several acute or chronic neurodegenerative diseases.

Identifiers

DOI: 10.1073/pnas.94.17.9434

Citations and references

Cited by 30 references

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