Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Life Sci. 2023 Aug 15;327:121806. doi: 10.1016/j.lfs.2023.121806. Epub 2023 May 29.
Roflumilast, a well-known phosphodiesterase-4 (PDE-4) inhibitor, possess an anti-inflammatory activity with approved indications in chronic obstructive pulmonary disease. This study aimed to evaluate the neuroprotective role of roflumilast in ovariectomy (OVX)-induced depressive-like behavior in female rats and to shed light on a potential autophagy enhancing effect.
Rats were randomly divided into four groups: sham, OVX, OVX + roflumilast (1 mg/kg, p.o), and OVX + roflumilast + chloroquine (CQ) (50 mg/kg, i.p). Drugs were administered for 4 weeks starting 2 weeks after OVX.
Roflumilast improved the depressive-like behaviors observed in OVX rats as evidenced by decreasing both forced swimming and open field immobility times while, increasing % sucrose preference and number of open field crossed squares. Histopathological analysis provides further evidence of roflumilast's beneficial effects, demonstrating that roflumilast ameliorated the neuronal damage caused by OVX. Roflumilast antidepressant potential was mediated via restoring hippocampal cAMP and BDNF levels as well as down-regulating PDE4 expression. Moreover, roflumilast revealed anti-inflammatory and anti-apoptotic effects via hindering TNF-α level and diminishing Bax/Bcl2 ratio. Roflumilast restored the autophagic function via up-regulation of p-AMPK, p-ULK1, Beclin-1 and LC3II/I expression, along with downregulation of P62 level and p-mTOR protein expression. The autophagy inhibitor CQ was used to demonstrate the suggested pathway.
The present study revealed that roflumilast showed an anti-depressant activity in OVX female rats via turning on AMPK/mTOR/ULK1-dependent autophagy pathway; and neurotrophic, anti-inflammatory, and anti-apoptotic activities. Roflumilast could offer a more secure alternative to hormone replacement therapy for postmenopausal depression treatment.
罗氟司特是一种众所周知的磷酸二酯酶-4（PDE-4）抑制剂，具有抗炎活性，已被批准用于治疗慢性阻塞性肺疾病。本研究旨在评估罗氟司特在卵巢切除（OVX）诱导的雌性大鼠抑郁样行为中的神经保护作用，并探讨其可能的自噬增强作用。
大鼠随机分为四组：假手术组、OVX 组、OVX+罗氟司特（1mg/kg，口服）组和 OVX+罗氟司特+氯喹（CQ）（50mg/kg，腹腔注射）组。药物治疗从 OVX 后 2 周开始，持续 4 周。
罗氟司特改善了 OVX 大鼠的抑郁样行为，表现为减少强迫游泳和旷场不动时间，同时增加蔗糖偏好百分比和旷场穿越方格数。组织病理学分析提供了罗氟司特有益作用的进一步证据，表明罗氟司特改善了 OVX 引起的神经元损伤。罗氟司特的抗抑郁作用是通过恢复海马 cAMP 和 BDNF 水平以及下调 PDE4 表达来介导的。此外，罗氟司特通过抑制 TNF-α 水平和降低 Bax/Bcl2 比值发挥抗炎和抗细胞凋亡作用。罗氟司特通过上调 p-AMPK、p-ULK1、Beclin-1 和 LC3II/I 表达以及下调 P62 水平和 p-mTOR 蛋白表达来恢复自噬功能。使用自噬抑制剂 CQ 来证明所提出的途径。
本研究表明，罗氟司特通过激活 AMPK/mTOR/ULK1 依赖性自噬途径以及神经营养、抗炎和抗细胞凋亡作用，在 OVX 雌性大鼠中表现出抗抑郁活性。罗氟司特可能为绝经后抑郁症的治疗提供一种更安全的激素替代疗法替代方案。
