Document Detail


3-Acetylpyridine produces age-dependent excitotoxic lesions in rat striatum.
MedLine Citation:
PMID:  7929644     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The effects of 3-acetylpyridine (3-AP) were studied in rat striatum. Striatal injections of 3-AP produced dose-dependent lesions. The lesion size was significantly increased in 4- and 12-month-old rats compared to 1-month-old rats. Coinjection of the competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovaleric acid (APV) or systemic administration of the noncompetitive NMDA antagonist MK-801, the competitive NMDA antagonist LY274614, or the glutamate release inhibitor lamotrigine partially but significantly attenuated striatal lesion volume. Consistent with an NMDA receptor-mediated excitotoxic effect, histologic studies showed that 3-AP lesions result in relative sparing of NADPH-diaphorase neurons. Using freeze clamp, 3-AP resulted in a marked depletion of ATP. Two-dimensional water-suppressed proton chemical shift magnetic resonance imaging showed a striatal depletion of the neuronal marker N-acetylaspartate but no focal increase in lactate during the first 3 h after intrastriatal 3-AP injections. Pretreatment with fructose-1,6-biphosphate attenuated the lesion volume significantly, which may be due to its ability to serve as a substrate for glycolytic metabolism, with resulting ATP production. The results of the present studies support the hypothesis that 3-AP produces an impairment of energy metabolism due to its substitution for niacinamide in the formation of NAD(P). Furthermore, 3-AP toxicity may involve a secondary excitotoxic mechanism mediated by NMDA receptors.
Authors:
J B Schulz; D R Henshaw; B G Jenkins; R J Ferrante; N W Kowall; B R Rosen; M F Beal
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  14     ISSN:  0271-678X     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  1994 Nov 
Date Detail:
Created Date:  1994-11-21     Completed Date:  1994-11-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1024-9     Citation Subset:  IM    
Affiliation:
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Aging / physiology*
Animals
Corpus Striatum / drug effects*,  pathology
Dose-Response Relationship, Drug
Energy Metabolism / drug effects
Male
N-Methylaspartate / antagonists & inhibitors
Neurotoxins / pharmacology
Pyridines / pharmacology*
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
NINDS 16367/DS/DS NIH HHS; NS 10828/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Neurotoxins; 0/Pyridines; 350-03-8/3-acetylpyridine; 56-65-5/Adenosine Triphosphate; 6384-92-5/N-Methylaspartate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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