Jörg B. Schulz1, D. Ross Henshaw1, Donald Siwek2, Bruce G. Jenkins3, Robert J. Ferrante2, P. Ben Cipolloni2, Neil W. Kowall2, Bruce R. Rosen3, M. Flint Beal1
1Neurochemistry Laboratory, Neurology Service, and
2Geriatric Research Education and Clinical Center, Bedford VA Medical Center, and Departments of Neurology and Pathology, Boston University School of Medicine, Boston, Massachusetts, U.S.A.
3MGH-NMR Center, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, and
Tóm tắt
Abstract: Recent evidence has linked excitotoxicity with the generation of free radicals. We examined whether free radical spin traps can attenuate excitotoxic lesions in vivo. Pretreatment with N‐tert‐butyl‐α‐(2‐sulfophenyl)‐nitrone (S‐PBN) significantly attenuated striatal excitotoxic lesions in rats produced by N‐methyl‐d‐aspartate (NMDA), kainic acid, and α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐4‐propionic acid (AMPA). In a similar manner, striatal lesions produced by 1‐methyl‐4‐phenylpyridinium (MPP+), malonate, and 3‐acetylpyridine were significantly attenuated by either S‐PBN or α‐phenyl‐N‐tert‐butylnitrone (PBN) treatment. Administration of S‐PBN in combination with the NMDA antagonist MK‐801 produced additive effects against malonate and 3‐acetylpyridine toxicity. Malonate injections resulted in increased production of hydroxyl free radicals (•OH) as assessed by the conversion of salicylate to 2,3‐ and 2,5‐dihydroxybenzoic acid (DHBA). This increase was significantly attenuated by S‐PBN, consistent with a free radical scavenging effect. S‐PBN had no effects on malonate‐induced ATP depletions and had no significant effect on spontaneous striatal electrophysiologic activity. These results provide the first direct in vivo evidence for the involvement of free radicals in excitotoxicity and suggest that antioxidants may be useful in treating neurologic illnesses in which excitotoxic mechanisms have been implicated.
