Neuroprotective strategies for treatment of lesions produced by mitochondrial toxins: implications for neurodegenerative diseases.

Neuronal death in neurodegenerative diseases may involve energy impairment leading to secondary excitotoxicity, and free radical generation. Potential therapies for the treatment of neurodegenerative diseases therefore include glutamate release blockers, excitatory amino acid receptor antagonists, agents that improve mitochondrial function, and free radical scavengers. In the present study we examined whether these strategies either alone or in combination had neuroprotective effects against striatal lesions produced by mitochondrial toxins. The glutamate release blockers lamotrigine and BW1003C87 significantly attenuated lesions produced by intrastriatal administration of 1-methyl-4-phenylpyridinium. Lamotrigine significantly attenuated lesions produced by systemic administration of 3-nitropropionic acid. Memantine, an N-methyl-D-aspartate antagonist, protected against malonate induced striatal lesions. We previously found that coenzyme Q10 and nicotinamide, and the free radical spin trap n-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) dose-dependently protect against lesions produced by intrastriatal injection of malonate. In the present study we found that the combination of MK-801 (dizocipiline) with coenzyme Q10 exerted additive neuroprotective effects against malonate. Lamotrigine with coenzyme Q10 was more effective than coenzyme Q10 alone. The combination of nicotinamide with S-PBN was more effective than nicotinamide alone. These results provide further evidence that glutamate release inhibitors and N-acetyl-D-aspartate antagonists can protect against secondary excitotoxic lesions in vivo. Furthermore, they show that combinations of agents which act at sequential steps in the neurodegenerative process can produce additive neuroprotective effects. These findings suggest that combinations of therapies to improve mitochondrial function, to block excitotoxicity and to scavenge free radicals may be useful in treating neurodegenerative diseases.