PubMed · 11269118
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R Koike. 2000. [Relapsing polychondritis].. https://pubmed.ncbi.nlm.nih.gov/11269118/
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The effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in treating neuropathic pain caused by nerve injury has been controversial. In the present study, 4 weeks following partial sciatic nerve ligation, a single intrathecal injection of the cyclooxygenase (COX)-1 preferring inhibitor ketorolac (50 microg) significantly attenuated tactile allodynia for 6 days. The COX-2 preferring inhibitor, NS-398 (60 microg) significantly reversed tactile allodynia 2 h following injection but this anti-allodynic effect did not last greater than 24 h. Surprisingly, the non-selective COX inhibitor, piroxicam (60 microg) was without effect. These data agree with previous studies suggesting that spinal prostaglandin synthesis is important in the maintenance of hypersensitivity states following nerve injury. They differ from results in other models by suggesting that both COX isoenzymes are important in this spinal process, and for the first time demonstrate a remarkably long duration of action from a single intrathecal injection of ketorolac. Inhibition of spinal COX may be an important mechanism of action in treating some patients with neuropathic pain following peripheral nerve injury.
Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent colorectal tumorigenesis in humans and in rodents. In vitro and in vivo studies indicate that one of their principal antineoplastic avenues is the induction of apoptosis. We have shown previously that NS-398, which selectively inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1, induces apoptosis of colorectal tumour cells and elevates COX-2 protein expression. Here, we have determined that the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway mediates these effects of NS-398. Treatment of HT29 colorectal carcinoma cells with 75 microM NS-398 caused activation of ERK-1/-2 but not of the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. This was apparent at 24 hr and maintained at 72 hr. U0126, a specific inhibitor of the ERK-activating kinases MEK-1/-2, prevented the activation of ERK induced by NS-398 and blocked the increase in COX-2 protein expression seen when HT29 cells were treated with NS-398 alone. The activation of ERK by NS-398 preceded and accompanied a decrease in attached cell yield and an increase in apoptosis. U0126 dose-dependently protected HT29 cells from these antiproliferative effects of NS-398, indicating an antiproliferative role for sustained ERK-1/-2 activation in response to this NSAID. These results point to a key role for the MEK/ERK signalling pathway in mediating the effects of a COX-2-selective NSAID on colorectal carcinoma cells.