Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Egypt.
Int Immunopharmacol. 2023 Dec;125(Pt B):111207. doi: 10.1016/j.intimp.2023.111207. Epub 2023 Nov 11.
β2-adrenoreceptors (β2AR have been identified recently as regulators of the α-synuclein gene (SNCA), one of the key milieus endorsed in injury of dopamine neurons in Parkinson's disease (PD). Accumulation of α-synuclein leads to mitochondrial dysfunction via downregulation of mitophagy proteins (PINK-1 and PARKIN) and inhibition of mitochondria biogenesis (PGC-1α) along with an increase in the master inflammatory regulator NF-κB p65 production that provokes neurodegeneration and diminishes neuroprotective signaling pathway (PI3k/Akt/CREB/BDNF). Recently, formoterol exhibited a promising neuroprotective effect against neurodegenerative conditions associated with brain inflammation. Therefore, the present investigation aims to unveil the possible neuroprotective activity of formoterol, β2AR agonist, against rotenone-induced PD in rats. Rats received rotenone (1.5 mg/kg; s.c.) every other day for 3 weeks and cured with formoterol (25 μg/kg/day; i.p.) 1 hr. after rotenone administration, starting from day 11. Formoterol treatment succeeded in upregulating β2-adrenoreceptor expression in PD rats and preserving the function and integrity of dopaminergic neurons as witnessed by enhancement of muscular performance in tests, open field, grip strength-meter, and Rotarod, besides the increment in substantia nigra and striatal tyrosine hydroxylase immunoexpression. In parallel, formoterol boosted mitophagy by activation of PINK1 and PARKIN and preserved mitochondrial membrane potential. Additionally, formoterol stimulated the neuro-survival signaling axis via stimulation of PI3k/pS473-Akt/pS133-CREB/BDNF cascade to attenuate neuronal loss. Noteworthy formoterol reduces neuro-inflammatory status by decreasing NFκBp65 immunoexpression and TNF-α content. Finally, formoterol's potential as a stimulant therapy of mitophagy via the PINK1/PARKIN axis and regulation of mitochondrial biogenesis by increasing PGC-1α to maintain mitochondrial homeostasis along with stimulation of PI3k/Akt/CREB/BDNF axis.
β2-肾上腺素受体（β2AR）最近被确定为调节α-突触核蛋白基因（SNCA）的调控因子之一，该基因是帕金森病（PD）中多巴胺神经元损伤的关键环境之一。α-突触核蛋白的积累通过下调线粒体自噬蛋白（PINK-1 和 PARKIN）和抑制线粒体生物发生（PGC-1α）以及增加主要炎症调节因子 NF-κB p65 的产生，导致线粒体功能障碍，从而引发神经退行性变并减少神经保护信号通路（PI3k/Akt/CREB/BDNF）。最近，福莫特罗（formoterol）对与大脑炎症相关的神经退行性疾病表现出有希望的神经保护作用。因此，本研究旨在揭示β2AR 激动剂福莫特罗（formoterol）对大鼠 Rotenone 诱导的 PD 的可能神经保护活性。大鼠每隔一天接受 Rotenone（1.5mg/kg；sc），共 3 周，从第 11 天开始，在 Rotenone 给药后 1 小时用福莫特罗（25μg/kg/天；ip）治疗。福莫特罗治疗成功地上调了 PD 大鼠中的β2-肾上腺素受体表达，并通过增强肌肉性能测试、旷场、握力计和旋转棒，以及增加黑质和纹状体酪氨酸羟化酶免疫表达，维持多巴胺能神经元的功能和完整性。同时，福莫特罗通过激活 PINK1 和 PARKIN 来促进线粒体自噬并维持线粒体膜电位。此外，福莫特罗通过刺激 PI3k/pS473-Akt/pS133-CREB/BDNF 级联反应来刺激神经存活信号轴，从而减轻神经元丢失。值得注意的是，福莫特罗通过降低 NFκBp65 免疫表达和 TNF-α 含量来减轻神经炎症状态。最后，福莫特罗通过 PINK1/PARKIN 轴作为线粒体自噬刺激治疗剂，通过增加 PGC-1α 来调节线粒体生物发生以维持线粒体稳态，并通过刺激 PI3k/Akt/CREB/BDNF 轴发挥作用。
