Journal of Neuroscience, Vol 8, 3901-3908, Copyright © 1988 by Society for Neuroscience
Systemic approaches to modifying quinolinic acid striatal lesions in rats
MF Beal, NW Kowall, KJ Swartz, RJ Ferrante and JB Martin
Neurology Service, Massachusetts General Hospital, Boston 02114.
Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian
brain that reproduces many of the histologic and neurochemical features of
Huntington's disease (HD). In the present study we have examined the
ability of a variety of systemically administered compounds to modify
striatal QA neurotoxicity. Lesions were assessed by measurements of the
intrinsic striatal neurotransmitters substance P, somatostatin,
neuropeptide Y, and GABA. Histologic examination was performed with Nissl
stains. The antioxidants ascorbic acid, beta-carotene, and alpha-
tocopherol administered s.c. for 3 d prior to striatal QA lesions had no
significant effect. Other drugs were administered i.p. 1/2 hr prior to QA
striatal lesions. The following were ineffective in blocking QA
excitotoxicity: allopurinol, 50 and 100 mg/kg; ketamine, 75 mg/kg;
nimodipine, 2.4, and 10 mg/kg; baclofen, 10 mg/kg; 2-amino-5-
phosphonovalerate, 50 mg/kg; and 2-amino-7-phosphonoheptanoate, 50 mg/kg.
Oral taurine administration for 4 weeks resulted in significantly increased
levels of brain taurine but had no significant effect in blocking QA
neurotoxicity. Systemic administration of the noncompetitive
N-methyl-D-aspartate (NMDA) antagonist MK-801 resulted in a dose-responsive
protection against QA toxicity, with complete block at a dose of 4 mg/kg.
If the pathogenesis of HD involves QA or another excitotoxin acting at the
NMDA receptor, it is possible that MK- 801 could retard the degenerative
process.
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