Vol. 297, Issue 1, 78-87, April 2001

Prostaglandin A₁ Protects Striatal Neurons against Excitotoxic Injury in Rat Striatum

Zheng-Hong Qin¹ , Yumei Wang¹ , Ren-Wu Chen, Xiaoxia Wang, Ming Ren, De-Maw Chuang and Thomas N. Chase

Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (Z.-H.Q., Y.W., T.N.C., X.W.); and Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (R.-W.C., M.R., D.-M.C.)

Prostaglandin A₁ (PGA₁) reportedly inhibits NF-B 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 GAD₆₇ 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-B activation by blocking inhibitory B- 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-B activation. In view of its potent neuroprotective activity, PGA₁ could prove useful in the treatment of certain neurodegenerative disorders related to excitotoxicity.