Carboxyfullerenes as neuroprotective?agents
Journal
National Academy of Sciences
Journal Volume
94
Journal Issue
17
Pages
9434-9439
Date Issued
1997
Date
1997
Author(s)
Dugan, Laura L. et al.
Turetsky, Dorothy M.
Du, Cheng
Lobner, Doug
Wheeler, Mark
Almli, C. Robert
Shen, Clifton K. F.
Choi, Dennis W.
Lin, T.-S.
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), α-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 μM, 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 Aβ1-42 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.
SDGs
Other Subjects
alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid; amyloid beta protein; carboxylic acid derivative; free radical; fullerene derivative; glucose; malonic acid derivative; n methyl dextro aspartic acid; n methyl dextro aspartic acid receptor; neuroprotective agent; oxygen; scavenger; superoxide dismutase; amyotrophic lateral sclerosis; animal cell; animal experiment; apoptosis; article; controlled study; drug synthesis; electron spin resonance; intraperitoneal drug administration; isomer; mouse; nerve cell necrosis; neuroprotection; nonhuman; priority journal; transgenic mouse; Animals; Brain; Carboxylic Acids; Cell Membrane; Free Radicals; Humans; Mice; Neuroprotective Agents; Animalia; Lethrinidae; Mus musculus
Type
journal article
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