Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Behav Brain Res. 2011 Oct 31;224(2):336-43. doi: 10.1016/j.bbr.2011.06.011. Epub 2011 Jun 17.
In this study, the potential antidepressant-like effects of pioglitazone and the possible involvement of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide system in antidepressant effects of pioglitazone were determined using forced swimming test (FST) in mice.
After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses (5, 10, 20 and 30 mg/kg) 2 and 4h before FST. To assess the involvement of PPARγ in the possible antidepressant effect of pioglitazone, GW9662, a PPARγ antagonist (2mg/kg) was administered before pioglitazone (20mg/kg). For determination of possible role of nitric oxide pathway in this effect, a non-specific NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME, 10mg/kg, i.p.), a specific iNOS inhibitor, aminoguanidine (50mg/kg, i.p.), or a NO precursor, L-arginine (750 mg/kg, i.p.) was co-administered with pioglitazone, either 2 or 4h before FST.
The immobility time significantly decreased after pioglitazone administration (20 and 30 mg/kg). GW-9662 significantly reversed antidepressant effect of pioglitazone administered 2 and 4h prior to FST. Co-administration of non-effective doses of pioglitazone and l-NAME revealed antidepressant-like effect in FST; while, co-administration of non-effective doses of aminoguanidine and pioglitazone did not affect the immobility time. l-Arginine also reversed the antidepressant-like effect of pioglitazone.
The antidepressant-like effect of pioglitazone on mice in the FST is mediated at least in part through PPARγ receptors and nitric oxide pathway.
本研究采用小鼠强迫游泳试验（FST），观察吡格列酮的潜在抗抑郁样作用，以及过氧化物酶体增殖物激活受体γ（PPARγ）和一氧化氮系统在吡格列酮抗抑郁作用中的可能参与情况。
在旷场试验中评估运动活性后，将小鼠单独强迫游泳，评估最后 4 分钟的不动时间。吡格列酮灌胃给药，剂量分别为 5、10、20 和 30mg/kg，于 FST 前 2 和 4 小时给药。为评估 PPARγ在吡格列酮可能的抗抑郁作用中的作用，给予 PPARγ拮抗剂 GW9662（2mg/kg），于吡格列酮（20mg/kg）前给药。为确定一氧化氮通路在此作用中的可能作用，给予非特异性 NOS 抑制剂 Nω-硝基-L-精氨酸甲酯（L-NAME，10mg/kg，ip）、特异性 iNOS 抑制剂氨基胍（50mg/kg，ip）或 NO 前体 L-精氨酸（750mg/kg，ip），与吡格列酮一起，于 FST 前 2 或 4 小时给药。
吡格列酮给药后，不动时间明显减少（20 和 30mg/kg）。GW9662 显著逆转了 FST 前 2 和 4 小时给予吡格列酮的抗抑郁作用。非有效剂量的吡格列酮和 L-NAME 联合给药在 FST 中显示出抗抑郁样作用；而，非有效剂量的氨基胍和吡格列酮联合给药不影响不动时间。L-精氨酸也逆转了吡格列酮的抗抑郁样作用。
吡格列酮对 FST 中小鼠的抗抑郁样作用至少部分通过 PPARγ 受体和一氧化氮通路介导。
