3-Nitropropionic acid toxicity in the striatum.
We examined the effects of chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) in doses ranging from 12 to 16 mg/kg/day for 30 days on striatal cytoarchitecture in rats. Administration of 3-NP at a dose of 16 mg/kg/day resulted in large lesions with a central necrotic core that was depleted of both neurons and glia. Glial fibrillary acidic protein (GFAP) gene expression was decreased in the lesion core, whereas the tissue surrounding this area showed a massive increase in signal intensity. Enkephalin and substance P mRNA expression in the striatum showed dose-dependent decreases following administration of 3-NP. A substantial decrease occurred even in animals treated with 3-NP at a dose of 12 mg/kg/day, in which there was little discernible neuronal loss and no increase in GFAP gene expression. In contrast to the decrease in enkephalin and substance P mRNA expression, somatostatin mRNA-expressing neurons were largely preserved. There was no preferential loss of [3H]naloxone patches in the rat striatum following chronic administration of 3-NP. In animals treated with 12-15 mg/kg/day neither the area nor binding density of the patches was changed. To study the effect of 3-NP on N-methyl-D-aspartate (NMDA)-gated Ca2+ channels we used in vivo administration of [3H]MK-801. Three hours after a single injection of 3-NP at a dose of 30 mg/kg there was a three- to fivefold increase in [3H]MK-801 binding in cortex and striatum as compared with saline-treated animals, consistent with an activation of NMDA receptors.
Wüllner
U
U
Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114.
Young
A B
AB
Penney
J B
JB
Beal
M F
MF
D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D001483:Base Sequence; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000235:genetics; D016291:Dizocilpine Maleate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006651:Histocytochemistry; D017403:In Situ Hybridization; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D014316:Tritium
D000959:Antihypertensive Agents; D004745:Enkephalins; D005904:Glial Fibrillary Acidic Protein; D008024:Ligands; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; D014316:Tritium; D013373:Substance P; D009270:Naloxone; D013004:Somatostatin; D016291:Dizocilpine Maleate; D004247:DNA; C015392:3-nitropropionic acid