3-Acetylpyridine produces age-dependent excitotoxic lesions in rat striatum.
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.
Schulz
J B
JB
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
Henshaw
D R
DR
Jenkins
B G
BG
Ferrante
R J
RJ
Kowall
N W
NW
Rosen
B R
BR
Beal
M F
MF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009498:Neurotoxins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009498:Neurotoxins; D011725:Pyridines; C010835:3-acetylpyridine; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate