Udilova Natalia, Kozlov Andrey V, Bieberschulte Werner, Frei Klemens, Ehrenberger Klaus, Nohl Hans
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, A-1210 Vienna, Austria.
Biochem Pharmacol. 2003 Jan 1;65(1):59-65. doi: 10.1016/s0006-2952(02)01452-1.
Caroverine, 1-(2-diethylaminoethyl)-3-(p-methoxy benzyl)-1,2-dihydro-2-quinoxalin-2-on-hydrochloride, is a class B calcium-channel-blocker and antiglutamatergic agent with significant effects on the brain function. Caroverine exhibits competitive AMPA antagonism, and at higher concentrations, noncompetitive NMDA antagonism. In clinical practice caroverine is used as a spasmolytic and otoneuroprotective agent. Since reactive oxygen species are supposed to be involved in the pathogenesis of inner ear diseases in which caroverine shows beneficial effects, the present study aimed to investigate the antioxidant properties of caroverine. Lipid peroxidation of liposomal membranes was suppressed in the presence of caroverine. In order to understand the mechanism of this antioxidant action of caroverine, we determined the rate constants both for a possible reaction with superoxide (O(2)(.-)) radicals from xanthine/xanthine oxidase and for a possible reaction with hydroxyl (.OH) radicals in Fenton system. Using a defined chemical reaction model O(2)(.-) scavenging was found to occur at a rather low rate constant only (3 x 10(2)M(-1)s(-1)). Thus, a reaction of caroverine with O(2)(.-) radicals is of marginal significance. In contrast, the reaction of caroverine with .OH radicals occurs at an extremely high rate constant (k=1.9 x 10(10)M(-1)s(-1)). The strong antioxidant activity of caroverine is therefore based both on the partial prevention and highly active scavenging of hydroxyl radicals.
卡罗维林，即1-(2-二乙氨基乙基)-3-(对甲氧基苄基)-1,2-二氢-2-喹喔啉酮盐酸盐，是一种B类钙通道阻滞剂和抗谷氨酸能药物，对脑功能有显著影响。卡罗维林表现出竞争性的AMPA拮抗作用，在较高浓度时，还表现出非竞争性的NMDA拮抗作用。在临床实践中，卡罗维林用作解痉剂和耳神经保护剂。由于活性氧被认为参与了卡罗维林显示出有益作用的内耳疾病的发病机制，本研究旨在探讨卡罗维林的抗氧化特性。在卡罗维林存在的情况下，脂质体膜的脂质过氧化受到抑制。为了了解卡罗维林这种抗氧化作用的机制，我们测定了其与黄嘌呤/黄嘌呤氧化酶产生的超氧阴离子（O(2)(.-)）自由基可能发生反应的速率常数，以及与芬顿体系中的羟基（.OH）自由基可能发生反应的速率常数。使用一个确定的化学反应模型发现，卡罗维林清除O(2)(.-)自由基的速率常数相当低（3×10(2)M(-1)s(-1)）。因此，卡罗维林与O(2)(.-)自由基的反应意义不大。相比之下，卡罗维林与.OH自由基的反应速率常数极高（k = 1.9×10(10)M(-1)s(-1)）。因此，卡罗维林的强抗氧化活性既基于对羟基自由基的部分预防，也基于对其的高效清除。
