Prostaglandin A(1) protects striatal neurons against excitotoxic injury inrat striatum

Prostaglandin A(1) (PGA(1)) reportedly inhibits NF-kappaB activation and in duces expression of heat shock proteins. Since both these effects could be neuroprotective, the therapeutic potential of PGA(1) in neurodegenerative d isorders, where excitotoxicity may contribute to pathogenesis, was evaluate d in rat striatal neurons exposed to the N-methyl-D-aspartate (NMDA) recept or agonist quinolinic acid (QA). Intrastriatal administration of PGA(1) (5- 80 nmol) attenuated QA (60 nmol)-induced internucleosomal DNA fragmentation . The inhibitory effects of a single dose of PGA(1) (80 nmol) on QA (60 nmo l)-induced DNA fragmentation were observed 12 to 48 h after treatment. PGA( 1) (80 nmol) also attenuated QA-induced DNA fragmentation when administered up to 4 h after QA exposure. PGA(1) significantly decreased the loss of D- 1 dopamine receptors and GAD(67) mRNA in QA-injected striatum as measured b y quantitative receptor autoradiography and in situ hybridization histochem istry, suggesting that it reduced the neuronal loss induced by QA. Protecti on of striatal neurons against QA-induced death by PGA(1) was further indic ated by Nissl staining 10 days after QA administration. PGA(1) (5-80 nmol) significantly inhibited QA-induced NF-kappaB activation by blocking inhibit ory kappaB-alpha degradation but had no effect on activator protein-1 bindi ng activity. PGA(1) (80 nmol) treatment substantially increased 70- and 72- kDa heat shock protein levels in striatum. These results indicate that PGA( 1) blunts NMDA receptor-mediated neuronal apoptosis by a mechanism possibly involving the up-regulation of neuroprotective heat shock proteins and inh ibition of NF-kappaB activation. In view of its potent neuroprotective acti vity, PGA(1) could prove useful in the treatment of certain neurodegenerati ve disorders related to excitotoxicity.