The Cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat

Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination intwitcher

“…Cyclooxygenases (COXs) are the key enzymes for the production of PGs and are upregulated in the CNS in various neurodegenerative diseases, including Alzheimer's disease (Yermakova et al, 1999), Parkinson's disease (Teismann et al, 2003), prion disease (Walsh et al, 2000;Deininger et al, 2003), spinal cord injury (Schwab et al, 2000), and ischemia (Govoni et al, 2001). Several investigators have reported selective COX inhibitors to be neuroprotective (McGeer and McGeer, 1995;Stewart et al, 1997;Pasinetti, 1998;Lim et al, 2000;Govoni et al, 2001), suggesting that some classes of PGs may play important roles in neurodegeneration. Positive immunoreactivities for COX-1 and COX-2 are mostly observed in microglia (Pasinetti and Aisen, 1998;Yermakova et al, 1999;Walsh et al, 2000).…”

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

“…In particular, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after global ischemia, suggesting that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia (Candelario-Jalil et al, 2003). In the same way, SC-58236, a selective COX-2 inhibitor, dose-dependently prevented ischemia-induced eicosanoid formation and caused significant reduction of the damaged area, suggesting that selective inhibitors of COX-2 are neuroprotective (Govoni et al, 2001). Moreover, anoxic stress attenuates NMDA-induced pial arteriolar dilation via a mechanism involving actions of COX-derived reactive oxygen species, an effect protected by the selective COX-2 inhibitor NS-398 (Domoki et al, 2001).…”

“…In particular, focal ischemia induced in the frontoparietal region of rat brain is accompanied by formation of PGD2 peaking 60 to 90 min postischemia and declining thereafter. This effect is due to increased COX-2 and is characterized by morphological alterations with necrosis of neurons, glial cells, and blood vessels surrounded by a halo with pyknotic cells with cytoplasm swelling and vacuolization (Govoni et al, 2001). Many cell types within ischemic brain tissue have been shown to overexpress COX enzymes; however, in focal ischemic damage, the elevation of COX-2 was restricted to microglial cells, suggesting that the isozymes of COX are differentially regulated depending on the cellular source and the types of ischemic damage (Tomimoto et al, 2002).…”

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

“…Genetic deletion of COX-2 in laboratory animals decreases susceptibility to ischemic brain injury and N-methyl-Daspartate-mediated neurotoxicity (Iadecola et al, 2001), and COX-2 overexpression in transgenic mice increases susceptibility to ␤-amyloid-induced neurotoxicity (Kelley et al, 1999). A COX-2 selective NSAID reduces focal ischemic brain injury in a rat model, suggesting a role for COX-2 in stroke and a possible role of COX-2-selective inhibitors in stroke treatment (Govoni et al, 2001); however, pretreatment of mice with NS398 leads to markedly increased neuronal cell death in the hippocampus and increased mortality following kainate treatment. This latter finding suggests that inhibition of COX-2 induced by excitotoxins may be neuroprotective, but that inhibition of constitutive COX-2 expression may be deleterious in the event of a seizure (Baik et al, 1999).…”