Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice
Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice
复制标题
DOI：
10.1124/jpet.108.137208
复制
发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
O'Donnell, James M.
中科院分区：
文献类型：
--
作者：
Masood, Anbrin;Nadeem, Ahmed;O'Donnell, James M.
包括焦虑和抑郁在内的几种神经精神疾病的发病机制与氧化应激有关，部分是通过环核苷酸信号传导的改变而导致的。磷酸二酯酶-2 (PDE2) 调节 cGMP 和 cAMP 信号传导，可能通过减少氧化应激来影响焦虑相关行为。本研究评估了氧化应激对行为的影响，并评估了 PDE2 抑制剂 Bay 60-7550 [(2-(3,4-dimethoxybenzyl)7-{(1R)-1-[(1R)-1-羟乙基]-4-苯基丁基}-5-甲基咪唑并[5,1-f][1,2,4]三嗪-4(3H)-one)]的抗焦虑作用。用氧化应激诱导剂 L-丁硫氨酸 (S,R)-亚磺酰亚胺 (300 mg/kg) 治疗小鼠，通过 NADPH 氧化酶途径在高架十字迷宫、开放场和洞板测试中引起焦虑样行为效应；这些作用可被 Bay 607550 (3 mg/kg) 和 NADPH 氧化酶抑制剂罗布麻素 (3 mg/kg) 拮抗。 Bay 60-7550介导的氧化应激（即培养的神经元中超氧阴离子和活性氧的产生以及杏仁核和下丘脑中的总抗氧化能力和脂质过氧化物）和NADPH氧化酶亚基表达（即杏仁核、下丘脑和培养的神经元中的p47 phox和gp91 phox表达）的减少与cGMP和磷酸化的增加有关Ser239 处的血管舒张剂刺激的磷蛋白，表明 cGMP-蛋白激酶 G 信号传导在减轻焦虑方面发挥着重要作用。总体而言，目前的结果表明，氧化应激会诱发小鼠的焦虑样行为，而 PDE2 抑制可通过增加 cGMP 信号传导来逆转这种行为。因此，PDE2 可能是治疗涉及氧化应激的神经精神和神经退行性疾病中焦虑的新药理学靶点。
The pathogenesis of several neuropsychiatric disorders, including anxiety and depression, has been linked to oxidative stress, in part via alterations in cyclic nucleotide signaling. Phosphodiesterase-2 (PDE2), which regulates cGMP and cAMP signaling, may affect anxiety-related behavior through reduction of oxidative stress. The present study evaluated the effects of oxidative stress on behavior and assessed the anxiolytic effects of the PDE2 inhibitor Bay 60-7550 [(2-(3,4-dimethoxybenzyl)7-{(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl}-5-methyl imidazo[5,1-f][1,2,4] triazin-4(3H)-one)]. Treatment of mice with L-buthionine(S,R)- sulfoximine (300 mg/kg), an inducer of oxidative stress, caused anxiety-like behavioral effects in elevated plus-maze, open-field, and hole-board tests through the NADPH oxidase pathway; these effects were antagonized by Bay 607550 (3 mg/kg) and apocynin (3 mg/kg), an inhibitor of NADPH oxidase. The Bay 60-7550-mediated decrease in oxidative stress (i.e., superoxide anion and reactive oxygen species generation in cultured neurons and total antioxidant capacity and lipid peroxides in amygdala and hypothalamus) and expression of NADPH oxidase subunits (i.e., p47 phox and gp91 phox expression in amygdala, hypothalamus, and cultured neurons) was associated with increased cGMP and phosphorylation of vasodilator-stimulated phosphoprotein at Ser239, suggesting an important role of cGMP-protein kinase G signaling in reduction of anxiety. Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling. Thus, PDE2 may be a novel pharmacological target for treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress.