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Carboxyfullerenes as neuroprotective agents
L L Dugan1, D M Turetsky, C Du
1Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Summary
Novel water-soluble C60 derivatives act as potent free radical scavengers and protect neurons from excitotoxicity. The C3 isomer shows promise for treating neurodegenerative diseases like amyotrophic lateral sclerosis.
Area of Science:
- Organic Chemistry
- Neuroscience
- Biochemistry
Background:
- Neurodegenerative diseases are a growing health concern.
- Free radical scavenging is a potential therapeutic strategy.
- Fullerenes are being explored for their biological activities.
Purpose of the Study:
- To synthesize and characterize water-soluble C60 derivatives.
- To evaluate their efficacy as free radical scavengers.
- To assess their neuroprotective potential against various insults.
Main Methods:
- Synthesis of C3 and D3 regioisomers of carboxylic acid C60 derivatives.
- Electron paramagnetic resonance (EPR) analysis for free radical scavenging.
- In vitro neuronal cultures exposed to excitotoxins (NMDA, AMPA) and oxygen-glucose deprivation.
- In vivo studies using a transgenic mouse model of amyotrophic lateral sclerosis (ALS).
Main Results:
- Both C3 and D3 isomers were equipotent free radical scavengers.
- Both isomers inhibited excitotoxic neuronal death, with the C3 isomer being more effective.
- The C3 derivative fully blocked NMDA receptor-mediated toxicity and reduced apoptotic neuronal death.
- Continuous infusion of the C3 derivative delayed death and functional deterioration in a mouse model of ALS.
Conclusions:
- Polar carboxylic acid C60 derivatives exhibit significant neuroprotective properties.
- The C3 regioisomer demonstrates potential therapeutic value for acute and chronic neurodegenerative diseases.
- These findings open avenues for developing novel fullerene-based therapeutics for neurological disorders.