抗炎与抗氧化特性：二者有关联吗？
Anti-inflammatory and anti-oxidant properties: Is there a link?
作者信息
Valeeva I Kh, Titarenko A F, Khaziakhmetova V N, Ziganshina L E
机构信息
Kazan State Medical University, Central Research Laboratory, Kazan, Russia.
Kazan Federal University, Department of Basic and Clinical Pharmacology, Kazan, Russia.
出版信息
Int J Risk Saf Med. 2015;27 Suppl 1:S67-8. doi: 10.3233/JRS-150693.
BACKGROUND
It is believed that the anti-inflammatory activity of medicines is closely related to their antioxidant activity. However, in clinical practice rigorous evidence-based medicine approach fails to reveal important effects of antioxidants on patient important outcomes in inflammatory disorders, as has been shown by a number of Cochrane reviews [1-3].
OBJECTIVE
To evaluate anti-inflammatory and antioxidant effects of newly developed pharmacological agents: dimephosphone and its structural analogues ephorane and mephoprane, and xymedon, in comparison with prednisolone and etidronate in experimental animal model of adjuvant arthritis.
METHODS
Experiments were conducted in 64 white mongrel rats of both sexes weighing 180-200 g, which were divided into 8 groups 8 rats each (4 males and 4 females each), kept under standard vivarium conditions with certified feeding ration (kombikorm). The study was approved by the local ethics committee. We induced adjuvant arthritis by administration under the plantar aponeurosis of the left hind paw of 0.1 ml of Freund's adjuvant (Sigma) in rats of 7 study groups. The groups were as follows: 1st group - intact animals (control); 2nd group - animals to whom the solvent (distilled water) was administered with intra-gastric tube in corresponding volume (control of the model); 3rd - 8th study groups, in which animals were administered with study agents each at a dose of 1 mmol/kg body weight: dimephosphone, ephorane, mephoprane, xymedon, etindronate and prednisolone. The intensity of the modeled arthritis was determined by measurements of paw volumes with plethysmometer (UgoBasile). We calculated the difference in rat paw volume before the administration (baseline) and after administration of Freund's adjuvant at 3, 7, 11, 15, 20, 27, 31, 38, 41 days. The development of secondary arthritis was documented by the increase in volume of both hind and fore paws and tails. On the 41st day of the experiment the animals were sacrificed under light ether anesthesia and exsanguinated. The blood was used to determine the activity of catalase and peroxidase, the content of the total, reduced and oxidized glutathione, the level of ceruloplasmin, conjugated dienes of unsaturated fatty acids (DC), TBA-interacting products (MDA), and the total antioxidant activity of serum (AOA). The results were processed statistically using the Student's t-test.
RESULTS
The primary reaction to the Freund's adjuvant in a form of swelling of the ankle joint of the left hind paw was observed at 24 hours after its injection. External clinical manifestations of the modeled disease were more pronounced on the third day: local inflammatory reaction (redness, swelling, ulceration) was seen in all the animals at the injection site with the increase of the paw volume. On the 11th day of the experiment 20% of the animals developed secondary arthritis. The study agents dimephosphone, ephorane, and prednisone exerted anti-inflammatory effect decreasing the volume of left hind paws by 45%, 46% и 27% respectively on the 40th day of experiment. Mephoprane did not affect the primary inflammatory response to the Freund's adjuvant (rats' left hind paws), however it reduced the volume of the contralateral right paw (secondary arthritis) by 90% on the 20th day of the experiement. This ant-inflammatory effect was accompanied by documented antioxidant activity in case of dimephosphone, ephorane, prednisolone, but not mephoprane. Dimephosphone reduced the levels of lipid peroxidation products in rats blood by 46% (DC) and by 25% (MDA). Ephorane also reduced the levels of lipid peroxidation products in the blood by 46% (DC) and by 25% (MDA), increasing the level of glutathione by nearly half, both the total and the reduced form. Prednisolone reduced the level of lipid peroxidation products in blood by 61% (DC), but not the TBA-interacting products. Mefopran did not affect the blood level of lipid peroxidation products. Xymedon and etidronate showed no anti-inflammatory effect. Xymedon demonstrated anti-oxidant properties, decreasing the blood levels of lipid peroxidation products, while etidronate seemed to behave in pro-oxidant mode, increasing the blood levels of lipid peroxidation products.
CONCLUSIONS
The effects of studied agents on the intensity of inflammation and lipid peroxidation were inconsistent. The results of the study did not show a clear link between anti-inflammatory and anti-oxidant activity. Further research in potential anti-inflammatory activity of new drugs exhibiting antioxidant properties needs to be done before recommending their use in clinical practice.
背景
人们认为药物的抗炎活性与其抗氧化活性密切相关。然而，正如多项Cochrane综述[1-3]所示，在临床实践中，严格的循证医学方法未能揭示抗氧化剂对炎症性疾病患者重要结局的重要影响。
目的
在佐剂性关节炎实验动物模型中，评估新开发的药物二膦酸酯及其结构类似物艾弗烷、美福烷和二甲麦角新碱，与泼尼松龙和依替膦酸相比的抗炎和抗氧化作用。
方法
实验选用64只体重180-200 g的白色杂种大鼠，雌雄各半，分为8组，每组8只（雌雄各4只），在标准饲养条件下，给予经认证的饲料（康比可）饲养。该研究经当地伦理委员会批准。对7个研究组的大鼠，在左后爪足底腱膜下注射0.1 ml弗氏佐剂（Sigma）诱导佐剂性关节炎。分组如下：第1组——正常动物（对照组）；第2组——经胃管给予相应体积溶剂（蒸馏水）的动物（模型对照组）；第3-8研究组，动物分别给予研究药物，剂量均为1 mmol/kg体重：二膦酸酯、艾弗烷、美福烷、二甲麦角新碱、依替膦酸和泼尼松龙。用体积描记器（UgoBasile）测量爪体积，以确定模型关节炎的强度。计算在给予弗氏佐剂前（基线）以及在第3、7、11、15、20、27、31、38、41天给予弗氏佐剂后大鼠爪体积的差异。通过后爪、前爪和尾巴体积的增加记录继发性关节炎的发展情况。在实验第41天，动物在轻度乙醚麻醉下处死并放血。取血测定过氧化氢酶和过氧化物酶活性、总谷胱甘肽、还原型谷胱甘肽和氧化型谷胱甘肽含量、铜蓝蛋白水平、不饱和脂肪酸共轭二烯（DC）、TBA相互作用产物（MDA）以及血清总抗氧化活性（AOA）。结果采用Student's t检验进行统计学处理。
结果
注射弗氏佐剂24小时后，观察到以左后爪踝关节肿胀形式出现的对弗氏佐剂的初始反应。建模疾病的外部临床表现在第三天更为明显：所有动物注射部位均出现局部炎症反应（发红、肿胀、溃疡），同时爪体积增大。在实验第11天，20%的动物出现继发性关节炎。研究药物二膦酸酯、艾弗烷和泼尼松龙发挥了抗炎作用，在实验第40天，左后爪体积分别减少了45%、46%和27%。美福烷对弗氏佐剂引起的初始炎症反应（大鼠左后爪）没有影响，但在实验第20天，它使对侧右爪（继发性关节炎）体积减少了90%。这种抗炎作用伴随着二膦酸酯、艾弗烷、泼尼松龙的抗氧化活性记录，但美福烷没有。二膦酸酯使大鼠血液中脂质过氧化产物水平降低了46%（DC）和25%（MDA）。艾弗烷也使血液中脂质过氧化产物水平降低了46%（DC）和25%（MDA），同时使总谷胱甘肽和还原型谷胱甘肽水平增加了近一半。泼尼松龙使血液中脂质过氧化产物水平降低了61%（DC），但对TBA相互作用产物没有影响。美福普对血液中脂质过氧化产物水平没有影响。二甲麦角新碱和依替膦酸没有抗炎作用。二甲麦角新碱具有抗氧化特性，降低了血液中脂质过氧化产物水平，而依替膦酸似乎表现为促氧化模式，增加了血液中脂质过氧化产物水平。
结论
所研究药物对炎症强度和脂质过氧化的影响不一致。该研究结果未显示抗炎和抗氧化活性之间存在明确联系。在推荐将具有抗氧化特性的新药用于临床实践之前，需要对其潜在的抗炎活性进行进一步研究。
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