Department of Narcotics, Ergogenic Aids and Poisons, National Research Centre, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini St., Cairo, 11562, Egypt.
Inflammopharmacology. 2024 Apr;32(2):1421-1437. doi: 10.1007/s10787-023-01305-x. Epub 2023 Aug 4.
Parkinson's disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3β and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation.
帕金森病（PD）是第二常见的与年龄相关的进行性神经退行性疾病。大量证据表明，PI3K/AKT 信号通路的激活在神经退行性疾病的治疗中起着关键作用。PI3K/AKT 信号通路可通过磷酸二酯酶 4（PDE4）抑制作用激活 cAMP 依赖性途径。罗氟司特是一种众所周知的 PDE4 抑制剂，目前用于治疗慢性阻塞性肺疾病。此外，罗氟司特已被提议作为治疗神经退行性疾病的有利候选药物。本研究旨在探讨罗氟司特在大鼠 Rotenone 诱导的 PD 模型中的神经保护作用。将 90 只雄性大鼠分为 6 组：对照组、Rotenone（1.5mg/kg/48h，sc）、L-多巴（22.5mg/kg，po）和罗氟司特（0.2、0.4 或 0.8mg/kg，po）。所有治疗均在 Rotenone 注射后 1 小时开始，持续 21 天。用罗氟司特治疗的大鼠表现出运动活动和协调能力的改善，以及纹状体多巴胺能神经元的保存。此外，罗氟司特通过刺激 CREB/BDNF/TrkB 和 SIRT1/PTP1B/IGF1 信号级联增加 cAMP 水平并激活 PI3K/AKT 轴。罗氟司特还引起 mTOR 和 Nrf2 的增加，阻止 GSK-3β 和 NF-κB，并抑制 FoxO1 和 caspase-3。我们的研究表明，罗氟司特在 Rotenone 诱导的大鼠神经毒性中发挥神经保护作用。这些神经保护作用是通过 CREB/BDNF/TrkB 和 SIRT1/PTP1B/IGF1 信号通路的串扰介导的，该串扰激活了 PI3K/AKT 途径。因此，通过激活 PI3K/AKT 信号通路抑制 PDE4 可能为治疗 PD 提供可靠的途径。
