There is substantial evidence that oxidative injury plays a role in many types of cytotoxic insults, and that the role of free radical damage may be especially prominent in neurological disease states, such as stroke, trauma and neurodegenerative disorders such as Parkinson's disease. Recently, the applicant reported that water-soluble derivatives of C60 were highly effective neuroprotective agents capable of rescuing cortical neurons from a broad range of insults, including excitotoxicity induced by NMDA or AMPA, apoptosis produced by growth factor withdrawal or application of A-Beta (1-42), and neuronal death following oxygen-glucose deprivation. In addition, intraperitoneal administration of these compounds to a mouse model of familial ALS delayed both the onset of motor deterioration and death. Electron paramagnetic resonance spectroscopic studies confirmed that these water-soluble malonic acid derivatives of C60 retain the potent free radical scavenging capabilities of native C60 with the ability to eliminate both hydroxyl and superoxide radicals. Based on these observations, the applicants believe that neuroprotection provided by these antioxidants reflects their ability to scavenge not only hydroxyl radical but superoxide radical (O2-) at concentrations in the micromolar range. This application proposes to test the specific hypothesis that superoxide radical scavenging by C60 derivatives is a critical determinant of neuroprotective efficacy by C60 derivatives. They plan to study mechanisms of neuroprotection by generating C60 derivatives substituted with similar functional groups, but possessing differing degrees of O2- scavenging ability. The rank-order potency of derivatives will be compared for both neuroprotection and superoxide scavenging to see if these properties correlate. In addition, using Sod2mlucsf mice, which have a specific impairment in the ability to eliminate mitochondrial O2-, they will test the protective efficacy of these agents on neurons cultured from these mice, and in neonatal mice. The broader goals of this proposal are: 1) to develop these molecules as tools to study the role of O2- as both signaling molecule and neurotoxin, 2) to continue exploration of the contribution of mitochondrial O2- to neuronal cell death, 3) and to begin to define structure-function relationships for these promising compounds as a necessary step towards pre-clinical trials.
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