| Amtolmetin guacyl (AMG) that was successfully explored and went on the market in Italian in 1993, and went on sale in American in 2001 has been a novel nonsteroidal anti-inflammatory drug (NSAID), but it doesn't go on the market in our country at present. AMG and its metabolisms that were MED5 and Tolmetin (TOL) possess antiinflammatory and antinociceptive actions. AMG is a non-selective cyclooxygenase (COX) inhibitor and could inhibit synthesis of prostaglandins (PGs).To investigate analgesic and gastroprotective effects of AMG and its mechanisms of action, the different animal models were used in this experiment. The principal contents were divided into some sections as follows:1 The analgesic effects of AMGAMG(75,150,300 mg kg-1) showed significant analgesic effects in the tail-immersion, hot plate, acetic acid test and formalin test (second phase 15-30min) in mice. AMG(50,100,200 mg kg-1) strikingly demonstrated analgesic effects in the rat formalin test (second phase 15-30min) and chronic constriction injury. All data showed that AMG had significant analgesic effects in peripheral and central nervous system in a dose-dependent manner.2 The analgesic mechanisms of AMG2.1 Antioxidative effect of AMGAMG (ig 75,150, 300 mg kg-1) significnatly reduced MDA level in serum and increased SOD level in serum after 30 and 60min in acetic acid test in mice. All this showed that AMG might cause analgesic effect by antioxidation.2.2 The effect of nitric oxide on analgesia of AMGThe NO2- contents in seurm, and spinal cord and brain homogenate in hot plate,formalin and acetic acid test of mice were higher than those in the normal group(P<0.05, P<0.01) . Not only did AMG (150, 300 mg kg-1) significantly reduce NOSlevel in spinal cord & brain homogenate, but also AMG (75,150,300 mg kg-1) notablylower NO2- contents in spinal cord & brain homogenate in same experiment.The number of writhing within 15min in the AMG+L-Arg group was strikingly more than that in the AMG group in the acetic acid test of mice, while the number in the AMG +L-NAME group was notably fewer than that in the AMG group (F<0.05) in the same test. Moreover, the AMG, L-NAME and AMG+L-NAME groups significantly reduced NO2- contents in spinal cord & brain homogenate, but the L-Arg and AMG+L-Arg+LNAME groups elevated those in the acetic acid test of mice.Compared with the AMG group, the AMG+L-NAME group significantly decreased the accumulative licking time, but the AMG+L-Arg group strikingly elongated it in the formalin test of mice (second phase 15-30min) (P<0.05). The data certified that L-Arg could reduce antinociceptive action of AMG, and that L-NAME could enhance analgesic effect of AMG.In the spinal cord & brain tissue sections, immunohistochemistry staining showed that nNOS positive expression neurons were strong staining in cytoplasms (brown) and light staining in nuclei (blue), and that c-Fos positive expression neurons were strong staining in nuclei (dark brown) and light staining in cytoplasms (light brown). The number of nNOS & c-Fos positive expression neurons and their average optical density in the AMG (100,200 mg kg-1) groups were significantly fewer than those in the modelgroup in the rat formalin models (P<0.05, P<0.01). All this demonstrated that AMG strikingly inhibited nNOS & c-Fos protein positive expression, and that AMG might give rise to analgesia by depressing nNOS & c-Fos protein positive expression in spinal cord or encephalon level.AMG(50,100, 200 mg kg-1 )not only obviously inhibited nNOS mRNA expression in spinal cord by RT-PCR, but also significantly prevented nNOS protein in spinal cord by western-blot in the rat formalin models. Thus AMG could exert analgesic effect by inhibiting nNOS activity in spinal cord.2.3 Influence of AMG on TNF- a level in blood, and spinal cord and sciatic nerve homogenate of rat CCICompared with model group, AMG (50,100,200 mg kg-1) groups obviously alleviated TNF- a level in serum, and simultaneously AMG (100, 200 mg kg-1) groups significantly decreased TNF...
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