Systemic approaches to modifying quinolinic acid striatal lesions in rats.
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.
Beal
M F
MF
Neurology Service, Massachusetts General Hospital, Boston 02114.
Kowall
N W
NW
Swartz
K J
KJ
Ferrante
R J
RJ
Martin
J B
JB
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives; D000493:Allopurinol / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D006816:Huntington Disease / Q000139:chemically induced / Q000503:physiopathology*; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D011725:Pyridines / Q000037:antagonists & inhibitors*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013373:Substance P / Q000378:metabolism; D013654:Taurine / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D000596:Amino Acids; D000975:Antioxidants; D003986:Dibenzocycloheptenes; D009478:Neuropeptide Y; D010455:Peptides; D011725:Pyridines; D011805:Quinolinic Acids; C029993:somatostatin-like peptides; D013654:Taurine; D013373:Substance P; D009553:Nimodipine; D000493:Allopurinol; D007649:Ketamine; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D017378:Quinolinic Acid; D001418:Baclofen; D014633:Valine; C031231:2-amino-7-phosphonoheptanoic acid