Prostaglandin A(1) protects striatal neurons against excitotoxic injury in rat striatum.
Prostaglandin A(1) (PGA1) reportedly inhibits NF-kappaB activation and induces expression of heat shock proteins. Since both these effects could be neuroprotective, the therapeutic potential of PGA1 in neurodegenerative disorders, where excitotoxicity may contribute to pathogenesis, was evaluated in rat striatal neurons exposed to the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid (QA). Intrastriatal administration of PGA1 (5-80 nmol) attenuated QA (60 nmol)-induced internucleosomal DNA fragmentation. The inhibitory effects of a single dose of PGA1 (80 nmol) on QA (60 nmol)-induced DNA fragmentation were observed 12 to 48 h after treatment. PGA1 (80 nmol) also attenuated QA-induced DNA fragmentation when administered up to 4 h after QA exposure. PGA1 significantly decreased the loss of D1 dopamine receptors and GAD(67) mRNA in QA-injected striatum as measured by quantitative receptor autoradiography and in situ hybridization histochemistry, suggesting that it reduced the neuronal loss induced by QA. Protection of striatal neurons against QA-induced death by PGA1 was further indicated by Nissl staining 10 days after QA administration. PGA1 (5-80 nmol) significantly inhibited QA-induced NF-kappaB activation by blocking inhibitory kappaB-alpha degradation but had no effect on activator protein-1 binding activity. PGA1 (80 nmol) treatment substantially increased 70- and 72-kDa heat shock protein levels in striatum. These results indicate that PGA1 blunts NMDA receptor-mediated neuronal apoptosis by a mechanism possibly involving the up-regulation of neuroprotective heat shock proteins and inhibition of NF-kappaB activation. In view of its potent neuroprotective activity, PGA1 could prove useful in the treatment of certain neurodegenerative disorders related to excitotoxicity.
Qin
Z H
ZH
Experimental Therapeutics Branch, National Institute of Neurodegenerative Disorders and Stroke, National Institutes of Health, Bldg. 10, 10 Center Drive, Bethesda, MD 20892-1406, USA.
Wang
Y
Y
Chen
R W
RW
Wang
X
X
Ren
M
M
Chuang
D M
DM
Chase
T N
TN
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009707:Nucleosomes / Q000187:drug effects; D011454:Prostaglandins A / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D009707:Nucleosomes; D011454:Prostaglandins A; D017378:Quinolinic Acid; C100573:prostaglandin A1