Zarate Sara M, Garcia Roger C, Pandey Gauri, Srinivasan Rahul
Department of Neuroscience & Experimental Therapeutics, Texas A&M University College of Medicine, 8447 John Sharp Pkwy, Bryan, TX, 77807-3260, USA.
Texas A&M Institute for Neuroscience (TAMIN), Interdisciplinary Life Sciences Building (ILSB), 3474 TAMU, College Station, TX, 77843-3474, USA.
NPJ Parkinsons Dis. 2025 Jan 3;11(1):6. doi: 10.1038/s41531-024-00855-3.
The smoking cessation drug cytisine exerts neuroprotection in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons of female but not male 6-hydroxydopamine (6-OHDA) lesioned parkinsonian mice. To address the important question of whether circulating 17β-estradiol mediates this effect, we employ two mouse models aimed at depleting systemically circulating 17β-estradiol: (i) bilateral ovariectomy (OVX), and (ii) aromatase inhibition with systemically administered letrozole. In both models, depleting systemically circulating 17β-estradiol in female 6-OHDA lesioned parkinsonian mice results in the loss of cytisine-mediated neuroprotection as measured using apomorphine-induced contralateral rotations and SNc DA neurodegeneration. Our experiments also reveal that OVX alone exerts neuroprotection in SNc DA neurons due to compensatory changes not observed in the letrozole model, which underscores the importance of using independent models of 17β-estradiol depletion to study neuroprotection. Taken together, our findings suggest that the smoking cessation drug cytisine is a viable neuroprotective drug for pre-menopausal women with Parkinson's disease.
戒烟药物金雀花碱对雌性而非雄性6-羟基多巴胺（6-OHDA）损伤的帕金森病小鼠黑质致密部（SNc）多巴胺能（DA）神经元具有神经保护作用。为了解决循环中的17β-雌二醇是否介导这种作用这一重要问题，我们采用了两种旨在耗尽全身循环17β-雌二醇的小鼠模型：（i）双侧卵巢切除术（OVX），以及（ii）全身给予来曲唑抑制芳香化酶。在这两种模型中，耗尽雌性6-OHDA损伤的帕金森病小鼠的全身循环17β-雌二醇，会导致使用阿扑吗啡诱导的对侧旋转和SNc DA神经变性所测量的金雀花碱介导的神经保护作用丧失。我们的实验还表明，单独的OVX由于在来曲唑模型中未观察到的代偿性变化，对SNc DA神经元具有神经保护作用，这突出了使用独立的17β-雌二醇耗竭模型来研究神经保护作用的重要性。综上所述，我们的研究结果表明，戒烟药物金雀花碱对患有帕金森病的绝经前女性是一种可行的神经保护药物。
