Possible roles of COX-1 in learning and memory impairment induced by traumatic brain injury in mice

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.

Role of p21CIP1 as a determinant of SC-560 response in human HCT116 colon carcinoma cells

SC-560, a strucutral analogue of celecoxib, induces growth inhibition in a wide range of human cancer cells in a cyclooxygenase (COX)-independent manner. Since SC-560 suppresses the growth of cancer cells mainly by inducing cell cycle arrest, we sought to examine the role of p21CIP1, a cell cycle regulator protein, in the cellular response against SC-560 by using p21(+/+)and p21(-/-)isogenic HCT116 colon carcinoma cells. In HCT116 (p21(+/+)) cells, SC-560 dose-dependently induced growth inhibition and cell cycle arrest at the G1 phase without significant apoptosis induction. SC-560-induced cell cycle arrest was accompanied by upregulation of p21CIP1. However, the extent of SC-560-induced accumulation at the G1 phase was approximately equal in the p21(+/+)and the p21(-/-)cells. Nonetheless, the growth inhibition by SC-560 was increased in p21(-/-)cells than p21(+/+)cells. SC-560-induced reactive oxygen species (ROS) generation did not differ between p21(+/+)and p21(-/-)cells but the subsequent activaton of apoptotic caspase cascade was more pronounced in p21(-/-)cells compared with p21(+/+)cells. These results suggest that p21CIP1 blocks the SC-560-induced apoptotic response of HCT116 cells. SC-560 combined with other therapy that can block p21 CIP1 expression or function may contribute to the effective treatment of colon cancer.

Effects of Cyclooxygenase Inhibitors on Neuropathic Pain following Spinal Nerve Ligation in Rats / 대한마취과학회지

BACKGROUND: The facilitatory effect of spinal prostaglandins (PGs) on nociceptive transmission suggests that early PG synthesis after nerve injury could be important in the development of allodynia. METHODS: The aim of this study is to examine the effects of diclofenac (nonselective COX inhibitor), SC-560 (selective COX-1 inhibitor), and NS-398 (selective COX-2 inhibitor) on mechanical allodynia and thermal hyperalgesia in the neuropathic pain model. The rats underwent right L5 spinal nerve ligation (SNL) and were assigned to three COX inhibitor groups to be injected intraperitoneally with different administration dosages (0.2 mg, 1 mg, 5 mg) 30 minutes before, and at 1, 2, and 3 days after SNL. The withdrawal threshold of both hindpaws in response to mechanical stimulation was measured by dynamic plantar anesthesiometer and the withdrawal ratio of right to left hindpaw was calculated. The thermal stimulation applied to both hindpaws by the plantar test was calculated different administration dosages were compared with the vehicle group. RESULTS: There were no differences in mechanical allodynia among the lower dosage groups (0.2 mg) until 14 days after SNL. However, 1 mg of NS-398 decreased mechanical allodynia compared with the vehicle group at 14 days after SNL, and 5 mg of NS-398 decreased mechanical allodynia at 3 days after SNL. However, there was no difference in thermal hyperalgesia between the groups. CONCLUSIONS: These results suggest that intraperitoneal administration of COX inhibitor (especially selective COX-2 inhibitor) after nerve ligation injury can attenuate the development of mechanical allodynia.

Peripheral Analgesic Effects of NSAIDs and Expressions of Cyclooxygenase-1 and Cyclooxygenase-2 in Acute Arthritic Model in Rats / 대한마취과학회지

BACKGROUND: Theoretically, an NSAID that inhibits COX-2 selectively should decrease inflammation but not influence normal physiologic functions and thus should cause fewer side effects. In the present study, to investigate the extent of peripheral nociception and inflammation of COX-1 and COX-2, diclofenac (non-selective COX inhibitor), SC-560 (selective COX-1 inhibitor) and NS-398 (selective COX-2 inhibitor) were injected intra-articularly on acute arthritic model in rats and COX-1 and COX-2 mRNA expression were measured by reverse transcription polymerase chain reaction (RT-PCR). METHODS: Arthritis was induced with 2% lambda-carrageenan into the right knee joint cavity under enflurane anesthesia (2-4%). Four and a half hours after the carrageenan injection, diclofenac, SC-560 or NS-398 was injected intra-articularly. The weight loads, diameters of knee joints and body weights were measured. The expressions of COX-1 and COX-2 were investigated in the inflammatory control group by RT-PCR. RESULTS: The weight loads predominantly increased and the diameters of the knee joints decreased in the diclofenac group, but not in the SC-560 and NS-398 groups. After the induction of arthritis, COX-1 and COX-2 mRNA expression increased with peak response at 9 and 6 hours after the induction, respectively. CONCLUSIONS: These results suggested that the non-selective COX inhibitor, diclofenac, which was injected intra-articularly, showed effective analgesic and anti-inflammatory effects in acute arthritic rats, and that the expressions of COX-1 and COX-2 mRNA were increased after induction of arthritis.

Peripheral Analgesic and Anti-inflammatory Effects of Diclofenac, SC-560 and NS-398 on Acute Arthritic Model in Rats / 대한마취과학회지

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are generally attributed to suppression cyclooxygenase enzymes, leading to decreased products of the arachidonic acid cascade. Since the discovery of two isoenzymes of cyclooxygenase, inhibition of cyclooxygenase-2 has been suggested to be responsible for therapeutic effects of NSAIDs without side effects. In the present study, to investigate the extent to peripheral nociception and inflammation of cyclooxygenase-1 and cyclooxygenase-2, diclofenac (non-selective inhibitor), SC-560 (selective cyclooxygenase-1 inhibitor) and NS-398 (selective cyclooxygenase-2 inhibitor) are injected intra-articularly on acute arthritic model in rats. METHODS: Arthritis was induced with 2% lamda-carrageenan (suspended in 50microliter normal saline) into the right knee joint cavity under enflurane anesthesia (2-4%). Before and after the injection, rats were allowed to walk freely through a pathway constructed to record weight load by means of 8 weight sensors (strain gauge type) attached to 8 plates which function independently. The weight load, diameter of both knee joints and weight of rat were measured at each test. At 4 hours and 30 minutes, diclofenac, SC-560 and NS-398 dissolved in 10% dimethyl sulfoxide were injected intra-articularly (50microgram/50microliter). RESULTS: The weight loads increased in diclofenac group at 6 and 9 hours and in NS-398 group at 24 and 48 hours after induction of arthritis. The diameter ratio decreased in diclofenac group at 12 hours after induction of arthritis. CONCLUSIONS: These results suggest that peripheral nociception and inflammation in acute model of arthritis in rats are likely related with both cyclooxygenase-1 and cyclooxygenase-2 pathways.

Relationship between antitumor effect of valdecoxib and COX-2 expression / 第三军医大学学报

Objective To evaluate the inhibitory effect of valdecoxib on the growth of the cancer cell lines and involvement of COX-2 in this inhibition. Methods Western blotting and immunocytochemistry were used to detect the expression of COX-2. MTT assay was used to determine inhibitory effect of the drugs on the cell growth. The content of PGE_ 2 in cell medium was determined with PGE_ 2 ELISA kit. Results ①Clone 26 cells expressed high levels of COX-2, whereas BGC-823,HGC-27 and SK-OV-3 cell had no COX-2 expression. ②Valdecoxib inhibited the growth of BGC-823, HGC-27, SK-OV-3 and clone 26 cells, with a IC_ 50 of 110.7, 99.2, 113.3, 117.6 ?mol/L, respectively. ③The inhibitory effect of these drugs on BGC-823 and clone 26 cell was in the descending order of valdecoxib, SC-560 and indomethacin. ④PGE_ 2 did not antagonize the effect of valdecoxib, SC-560 and indomethacin on BGC-823 and clone 26 cells. ⑤The inhibitory effect of valdecoxib and indomethacin on the growth of clone 26 cells was not compatible with that on PGE_ 2 . Conclusion The inhibitory effect of valdecoxib on cell growth is not related to its effect on COX-2.