Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan, China.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan.
Eur Neuropsychopharmacol. 2021 Sep;50:55-63. doi: 10.1016/j.euroneuro.2021.04.010. Epub 2021 May 7.
(R,S)-ketamine causes rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression although the precise molecular mechanisms underlying its antidepressant action remain unclear. We recently reported that transforming growth factor (TGF)-β1 might contribute to the antidepressant-like effects of (R)-ketamine that is a more potent enantiomer in rodents. Although TrkB signaling plays a role in the antidepressant-like actions of (R,S)-ketamine and its enantiomers, the role of TrkB signaling in the antidepressant effects of TGF-β1 remains unclear. Using behavioral tests such as tail-suspension test (TST), forced swimming test (FST), and 1% sucrose preference test (SPT), we investigated whether a single intranasal administration of the recombinant TGF-β1 (1.5 and 3.0 μg/kg) causes rapid and sustained antidepressant-like effects in a chronic social defeat stress (CSDS) model. Both doses of TGF-β1 significantly attenuated the increased immobility time of TST and FST in the CSDS susceptible mice. High dose of TGF-β1, but not low dose, significantly ameliorated the decreased sucrose preference of SPT in the CSDS susceptible mice. Pretreatment with a TrkB antagonist ANA-12 (0.5 mg/kg) blocked the antidepressant-like effects of TGF-β1 in CSDS susceptible mice. The data suggest that intranasal administration of TGF-β1 could elicit rapid-acting antidepressant-like effects via TrkB stimulation in a CSDS model. Therefore, it is likely that intranasal administration of TGF-β1 would be a novel therapeutic approach for depression.
（R，S）-氯胺酮在治疗抵抗性抑郁症患者中引起快速起效和持续的抗抑郁作用，尽管其抗抑郁作用的确切分子机制仍不清楚。我们最近报道，转化生长因子（TGF）-β1 可能有助于（R）-氯胺酮的抗抑郁作用，而（R，S）-氯胺酮的（R）-对映体在啮齿动物中更有效。尽管 TrkB 信号在（R，S）-氯胺酮及其对映体的抗抑郁作用中起作用，但 TrkB 信号在 TGF-β1 的抗抑郁作用中的作用仍不清楚。我们使用行为测试，如悬尾测试（TST）、强迫游泳测试（FST）和 1%蔗糖偏好测试（SPT），研究了单次鼻腔给予重组 TGF-β1（1.5 和 3.0μg/kg）是否在慢性社交挫败应激（CSDS）模型中引起快速和持续的抗抑郁样作用。两种剂量的 TGF-β1 均显著减轻了 CSDS 易感小鼠 TST 和 FST 中不动时间的增加。高剂量的 TGF-β1，但不是低剂量，显著改善了 CSDS 易感小鼠 SPT 中蔗糖偏好的降低。TrkB 拮抗剂 ANA-12（0.5mg/kg）预处理阻断了 TGF-β1 在 CSDS 易感小鼠中的抗抑郁样作用。数据表明，鼻腔给予 TGF-β1 通过刺激 TrkB 在 CSDS 模型中可引起快速起效的抗抑郁样作用。因此，鼻腔给予 TGF-β1 可能是治疗抑郁症的一种新方法。
