The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 {1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E 2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.Cyclooxygenase (prostaglandin G͞H synthase) is the first committed step in the production of prostaglandins and thromboxanes. Two forms of the cyclooxygenase enzyme have been cloned. Cyclooxygenase-1 (COX1) is constitutively expressed in many tissues including platelets, gastrointestinal mucosa, and kidney (1-3). The inducible form, cyclooxygenase-2 (COX2), is primarily expressed in leukocytes and brain (4). Its expression is induced by cytokines and inhibited by glucocorticoids, and it is an important mediator of cell injury in inflammation (5-7). Transcription of COX2 mRNA does not require new protein synthesis; therefore, it is an immediate early gene (6). The rat brain COX2 is identical to the nonnervous system COX2 (8). Its mRNA expression is rapidly induced by synaptic activity but blocked by the N-methyl-Daspartate receptor antagonist MK801 (8). This finding suggests that COX2 transcription is induced by increased intraneuronal Ca 2ϩ . COX2 is found in dendrites of neurons that receive excitatory input (9). Thus, COX2 may produce rapid neuronal responses to synaptic activity.Neuronal excitation and increased intracellular calcium, two stimuli that induce expression of COX2, are also important in the pathophysiology of neuronal death in ischemia and a variety of neurodegenerative diseases (10, 11). In nonneural cells, COX2 activity mediates inflammatory injury (12); however, COX2 overexpression may prevent apoptosis in intestinal epithelium (13). What role COX2 expression and activity have in mediating injury after global ischemia in brain is unknown. To address this question, the expression of COX2 mRNA and protein was studied in rat brain after global ischemia, and the effect of treatment with a selective inhibitor of COX2 {SC58125; 1-[(4-methylsulfonyl)phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} on hippocampal neuronal survival and prostaglandin E 2 (PGE 2 ) concentrations was determined. METHODSAnimal M...

Hen's egg yolk contains at least two antigen-binding subclasses of IgG, derived from the hen serum and transmitted t o the chick. IgM and IeA. absent in volkInstitute of Animal Physiology, Babraham, and in newly hatched chick serum, were detected in the white of unembrvonated Cambridge+

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Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), are active prostaglandin metabolites exerting a variety of biological effects that may be important in the pathogenesis of neurological diseases. Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain specific deubiquitinating enzyme whose aberrant function has been linked to neurodegenerative disorders. We report that [15d-PGJ 2 ] detected by quadrapole mass spectrometry (MS) increases in rat brain after temporary focal ischemia, and that treatment with 15d-PGJ 2 induces accumulation of ubiquitinated proteins and exacerbates cell death in normoxic and hypoxic primary neurons. 15d-PGJ 2 covalently modifies UCH-L1 and inhibits its hydrolase activity. Pharmacologic inhibition of UCH-L1 exacerbates hypoxic neuronal death while transduction with a TAT-UCH-L1 fusion protein protects neurons from hypoxia. These studies indicate UCH-L1 function is important in hypoxic neuronal death and excessive production of CyPGs after stroke may exacerbate ischemic injury by modification and inhibition of UCH-L1.