1 Nantong Maternal and Child Health Care Hospital, China.
2 Department of Pharmacology, School of Pharmacy, Nantong University, China.
J Psychopharmacol. 2018 Apr;32(4):469-481. doi: 10.1177/0269881118762072. Epub 2018 Mar 14.
Major depressive disorder has become one of the most serious neuropsychiatric disorders worldwide. However, currently available antidepressants used in clinical practice are ineffective for a substantial proportion of patients and always have side effects. Besides being a lipid-regulating agent, gemfibrozil is an agonist of peroxisome proliferator-activated receptor-α (PPAR-α). We investigated the antidepressant effects of gemfibrozil on C57BL/6J mice using the forced swim test (FST) and tail suspension test (TST), as well as the chronic unpredictable mild stress (CUMS) model of depression. The changes in brain-derived neurotrophic factor (BDNF) signaling cascade in the brain after CUMS and gemfibrozil treatment were further assessed. Pharmacological inhibitors and lentivirus-expressed short hairpin RNA (shRNA) were also used to clarify the antidepressant mechanisms of gemfibrozil. Gemfibrozil exhibited significant antidepressant actions in the FST and TST without affecting the locomotor activity of mice. Chronic gemfibrozil administration fully reversed CUMS-induced depressive-like behaviors in the FST, TST and sucrose preference test. Gemfibrozil treatment also restored CUMS-induced inhibition of the hippocampal BDNF signaling pathway. Blocking PPAR-α and BDNF but not the serotonergic system abolished the antidepressant effects of gemfibrozil on mice. Gemfibrozil produced antidepressant effects in mice by promoting the hippocampal BDNF system.
重度抑郁症已成为全球最严重的神经精神疾病之一。然而，目前临床上使用的抗抑郁药对相当一部分患者无效，而且总是有副作用。吉非贝齐除了是一种调节脂质的药物外，还是过氧化物酶体增殖物激活受体-α（PPAR-α）的激动剂。我们使用强迫游泳试验（FST）和悬尾试验（TST）以及慢性不可预测轻度应激（CUMS）抑郁模型，研究了吉非贝齐对 C57BL/6J 小鼠的抗抑郁作用。进一步评估了 CUMS 和吉非贝齐治疗后大脑中脑源性神经营养因子（BDNF）信号级联的变化。还使用药理学抑制剂和慢病毒表达短发夹 RNA（shRNA）来阐明吉非贝齐的抗抑郁机制。吉非贝齐在 FST 和 TST 中表现出明显的抗抑郁作用，而不影响小鼠的运动活性。慢性吉非贝齐给药完全逆转了 FST、TST 和蔗糖偏好测试中 CUMS 诱导的抑郁样行为。吉非贝齐治疗还恢复了 CUMS 诱导的海马 BDNF 信号通路的抑制。阻断 PPAR-α和 BDNF 但不阻断 5-羟色胺能系统可消除吉非贝齐对小鼠的抗抑郁作用。吉非贝齐通过促进海马 BDNF 系统对小鼠产生抗抑郁作用。
