Matsumoto K, Yobimoto K, Huong N T, Abdel-Fattah M, Van Hien T, Watanabe H
Department of Pharmacology, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Japan.
Brain Res. 1999 Aug 21;839(1):74-84. doi: 10.1016/s0006-8993(99)01715-1.
We investigated the effect of psychological stress on lipid peroxidation activity in the mouse brain, the mechanism underlying the psychological stress-induced change in the activity, and the effects of anxiolytic and anxiogenic drugs on the activity in psychologically-stressed animals. Psychological stress exposure using a communication box paradigm for 2-16 h significantly increased the content of thiobarbituric acid reactive substance (TBARS), an index of lipid peroxidation activity, in the brain, and the effect was maximal after peaked by a 4-h stress exposure. In the animals stressed for over 4 h, the increased brain TBARS content lasted for 30 min after the stress exposure, while no significant increase of the TBARS content was observed in the liver or serum. Trolox (67.6 mg/kg, i.p.), an antioxidant drug, but not monoamine oxidase inhibitors, clorgyline (2.5-5 mg/kg, i.p.) or 5-(4-benzylphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-o ne (1-5 mg/kg, i.p.), significantly suppressed the effect of psychological stress. The non-selective nitric oxide (NO) synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10-100 mg/kg, i.p.) and the selective neuronal NOS inhibitor 7-nitroindazole (25 and 50 mg/kg, i.p.), but not the inducible NOS inhibitor aminoguanidine (1-100 mg/kg, i.p.), dose dependently suppressed the psychological stress-induced enhancement of lipid peroxidation in the brain. L-Arginine (300 mg/kg, i.p.), a substrate of NOS, antagonized the effect of L-NAME. Measurements of NO metabolites revealed a significant increase of NO production in the brains of stressed mice. The benzodiazepine (BZD) receptor agonist diazepam (0.05-0.5 mg/kg, i.p.), the 5-HT(1A) receptor agonists (+/-)-8-hydroxy-di-propylaminotetralin and buspirone (0.1-1 mg/kg, i. p.), but not the 5-HT(3) receptor agonist MDL72222, dose-dependently suppressed the psychological stress-induced enhancement of brain lipid peroxidation. In contrast, the administration of anxiogenic drugs, FG7142 (an inverse BZD agonist: 1-10 mg/kg, i.p.) and 1-(3-chlorophenyl)piperazine (a mixed 5-HT(2A/2B/2C) agonist: 0.1-1 mg/kg, i.p.), potentiated it. The effects of diazepam and FG7142 were abolished by the BZD receptor antagonist flumazenil (10 mg/kg, i.p.). These results indicate that psychological stress causes oxidative damage to the brain lipid via enhancing constitutive NOS-mediated production of NO, and that drugs with a BZD or 5-HT(1A) receptor agonist profile have a protective effect on oxidative brain membrane damage induced by psychological stress.
我们研究了心理应激对小鼠大脑脂质过氧化活性的影响、心理应激诱导该活性变化的潜在机制，以及抗焦虑和致焦虑药物对处于心理应激状态动物的该活性的影响。使用通讯箱范式进行2 - 16小时的心理应激暴露显著增加了大脑中硫代巴比妥酸反应性物质（TBARS，脂质过氧化活性指标）的含量，且在4小时应激暴露达到峰值后效果最为明显。在应激超过4小时的动物中，大脑中TBARS含量的增加在应激暴露后持续30分钟，而在肝脏或血清中未观察到TBARS含量的显著增加。抗氧化药物曲洛克斯（67.6毫克/千克，腹腔注射）可显著抑制心理应激的影响，而单胺氧化酶抑制剂氯吉兰（2.5 - 5毫克/千克，腹腔注射）或5 - (4 - 苄基苯基)-3-(2 - 氰基乙基)-(3H)-1,3,4 - 恶二唑 - 2 - 酮（1 - 5毫克/千克，腹腔注射）则无此作用。非选择性一氧化氮（NO）合酶（NOS）抑制剂N(G)-硝基 - L - 精氨酸甲酯（L - NAME，10 - 100毫克/千克，腹腔注射）和选择性神经元NOS抑制剂7 - 硝基吲唑（25和50毫克/千克，腹腔注射），而非诱导型NOS抑制剂氨基胍（1 - 100毫克/千克，腹腔注射），可剂量依赖性地抑制心理应激诱导的大脑脂质过氧化增强。NOS的底物L - 精氨酸（300毫克/千克，腹腔注射）可拮抗L - NAME的作用。对NO代谢产物的测量显示，应激小鼠大脑中的NO生成显著增加。苯二氮䓬（BZD）受体激动剂地西泮（0.05 - 0.5毫克/千克，腹腔注射）、5 - HT(1A)受体激动剂(±)-8 - 羟基 - 二 - 丙基氨基四氢萘和丁螺环酮（0.1 - 1毫克/千克，腹腔注射），但不是5 - HT(3)受体激动剂MDL72222，可剂量依赖性地抑制心理应激诱导的大脑脂质过氧化增强。相反，给予致焦虑药物FG7142（一种反向BZD激动剂：1 - 10毫克/千克，腹腔注射）和1 - (3 - 氯苯基)哌嗪（一种混合的5 - HT(2A/2B/2C)激动剂：0.1 - 1毫克/千克，腹腔注射）可增强这种作用。地西泮和FG7142的作用可被BZD受体拮抗剂氟马西尼（10毫克/千克，腹腔注射）消除。这些结果表明，心理应激通过增强组成型NOS介导的NO生成对大脑脂质造成氧化损伤，且具有BZD或5 - HT(1A)受体激动剂特征的药物对心理应激诱导的氧化脑细胞膜损伤具有保护作用。
