Involvement of PI3K, GSK-3β and PPARγ in the antidepressant-like effect of folic acid in the forced swimming test in mice
Involvement of PI3K, GSK-3β and PPARγ in the antidepressant-like effect of folic acid in the forced swimming test in mice
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DOI：
10.1177/0269881111424456
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发表时间：
2012-05-01
影响因子：
4.1
通讯作者：
Rodrigues, Ana Lucia S.
中科院分区：
文献类型：
--
作者：
Budni, Josiane;Lobato, Kelly R.;Rodrigues, Ana Lucia S.
临床前和临床研究表明，叶酸缺乏在抑郁症的病理生理学中起作用。考虑到调节神经可塑性和细胞存活的信号通路的改变与抑郁症有关，本研究调查了磷酸肌醇3-激酶（PI 3 K），糖原合成酶激酶-3（GSK-3 β）和过氧化物酶体增殖物激活受体-γ（PPAR γ）在强迫游泳试验（FST）中叶酸抗抑郁样作用中的参与。脑室内（i. c. v.）用LY 294002（10 nmol/位点，一种PI 3 K抑制剂）或GW-9662（1 μ g/位点，一种PPAR γ拮抗剂）预处理小鼠阻止了叶酸（50 mg/kg，p.o.）在FST。此外，给药亚有效剂量的选择性GSK-3 β抑制剂AR-A014418（3 mg/kg，i. p.），非选择性GSK-3 β抑制剂氯化锂（10 mg/kg，p.o.）或PPAR γ激动剂罗格列酮（1 μ g/部位，i. c. v.）与亚有效剂量的叶酸（10 mg/kg，p.o.）与单独使用任一种药物相比，显著减少了FST中的不动时间，而不改变运动活性。这些结果表明，叶酸在FST中的抗抑郁样作用可能依赖于GSK-3 β的抑制和PPAR γ的激活，加强了这些是抗抑郁活性的重要靶点的概念。
Preclinical and clinical studies indicate that deficiency in folic acid plays a role in the pathophysiology of depression. Considering that alterations in the signaling pathways that regulate neuroplasticity and cellular survival are implicated in depressive disorders, the present study investigated the involvement of the phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3 (GSK-3 beta), and peroxisome proliferator-activated receptor-gamma (PPAR gamma) in the antidepressant-like effect of folic acid in the forced swimming test (FST). The intracerebroventricular (i.c.v.) pre-treatment of mice with LY294002 (10 nmol/site, a PI3K inhibitor) or GW-9662 (1 A mu g/site, a PPAR gamma antagonist) prevented the antidepressant-like effect of folic acid (50 mg/kg, p.o.) in the FST. In addition, the administration of subeffective doses of the selective GSK-3 beta inhibitor, AR-A014418 (3 mg/kg, i.p.), a non-selective GSK-3 beta inhibitor, lithium chloride (10 mg/kg, p.o) or a PPAR gamma agonist, rosiglitazone (1 A mu g/site, i.c.v.) in combination with a subeffective dose of folic acid (10 mg/kg, p.o.) significantly reduced the immobility time in the FST as compared with either drug alone, without altering the locomotor activity. These results indicate that the antidepressant-like effect of folic acid in the FST might be dependent on inhibition of GSK-3 beta and activation of PPAR gamma, reinforcing the notion that these are important targets for antidepressant activity.