Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, Av Do Café S/n, 14040-903, Ribeirão Preto, SP, Brazil.
Departamento de Morfologia, Estomatologia e Fisiologia, Faculdade de Odontologia de Ribeirão Preto - USP, 14040-904, Ribeirão Preto, SP, Brazil.
Chem Biol Interact. 2021 May 25;341:109454. doi: 10.1016/j.cbi.2021.109454. Epub 2021 Mar 30.
Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.
多西环素自 20 世纪 60 年代以来一直被用作抗生素。最近的研究表明，多西环素在神经退行性疾病和脑损伤的模型中具有神经保护作用，主要是由于其抗炎和抗细胞凋亡作用。然而，目前尚不清楚多西环素是否具有神经营养潜力，因为考虑到阿尔茨海默病、肌萎缩侧索硬化症和帕金森病以及正常衰老过程中轴突退化在神经退行性病变早期的作用，这一点很重要。轴突是由神经突起形成的，神经突起是神经生长因子等神经营养因子诱导的神经元分化的标志。因此，调节神经营养因子受体以形成和再生轴突已被提议作为一种延迟神经退行性变进展的策略，并随着早期诊断新技术的出现而变得相关。基于这些前提，我们研究了多西环素模拟神经生长因子（NGF）作用的潜力，重点关注神经元突起起始、生长和分支的信号通路和神经元调节剂。我们使用 PC12 细胞，这是一种广泛用于研究 NGF 诱导的神经营养途径和机制的神经元模型。结果表明，多西环素通过激活 trkA 受体及其下游信号通路 PI3K/Akt 和 MAPK/ERK 诱导神经突生长，而不诱导 NGF 的表达。多西环素还增加了 GAP-43、突触素 I 和 NF200 的表达，这些蛋白参与轴突和突触可塑性。总之，这些数据首次证明了多西环素的神经营养潜力，这可能有助于恢复神经退行性病变早期失去的神经元连接。
