Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid.
The neuroprotective properties of two cyclooxygenase-2 (COX-2) specific inhibitors, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398) and o-(acetoxy-phenyl)hept-2-ynyl2 sulfide (APHS) were examined in vitro using a mixed cortical neuronal culture system. Each of these inhibitors conferred a concentration-dependent neuroprotective effect against an excitotoxic assault induced by NMDA. Neuroprotection was observed when the COX-2 inhibitor was added before or even 1-3 hours after NMDA, which was coincident with an NMDA-induced increase of COX-2 transcripts in neurons. To test whether these COX-2 inhibitors confer neuroprotection by inhibiting biosynthesis of prostanoids that may contribute toward excitotoxicity, two NMDA-induced prostanoids, PGE(2) and PGF(2alpha), were tested for their ability to reverse the neuroprotective properties of APHS. APHS-mediated neuroprotection was overcome by the concentration-dependent (as low as 100 nM) administration of a synthetic analog of PGE2, 17-phenyl-trinor-PGE(2) (17-pt-E(2)), which is a relatively specific agonist for the EP1 and EP3 prostaglandin receptors; however, PGF(2alpha) had no significant effect on neuroprotection conferred by APHS. In the absence of APHS, neuroprotection was observed with either prostanoid. PGE(2) may in some instances contribute toward excitotoxicity, and the inhibition of synthesis of this prostanoid may in part explain the neuroprotective properties of these COX-2 inhibitors.
Carlson
Noel G
NG
Salt Lake City VA-Geriatrics Research, Education and Clinical Center, Salt Lake City, Utah, USA. Noel.carlson@med.va.gov
D000114:Acetylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000480:Alkynes; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology*; D046508:Culture Techniques; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013440:Sulfides / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
D000480:Alkynes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009578:Nitrobenzenes; D011073:Polyamines; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D013440:Sulfides; D013449:Sulfonamides; C112390:o-(acetoxyphenyl)hept-2-ynyl sulfide; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C054801:N'-(3-aminopropyl)homospermidine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D000114:Acetylene