Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico.
Mol Neurobiol. 2023 Dec;60(12):7253-7273. doi: 10.1007/s12035-023-03530-5. Epub 2023 Aug 5.
Since the number of aged people will increase in the next years, neurodegenerative diseases, including Parkinson's Disease (PD), will also rise. Recently, we demonstrated that autophagy stimulation with rapamycin decreases dopaminergic neuronal death mediated by oxidative stress in the paraquat (PQ)-induced PD model. Assessing the neurotherapeutic efficacy of autophagy-inducing molecules is critical for preventing or delaying neurodegeneration. Therefore, we evaluated the autophagy inducers metformin and trehalose effect in a PD model. Autophagy induced by both molecules was confirmed in the SH-SY5Y dopaminergic cells by detecting increased LC3-II marker and autophagosome number compared to the control by western blot and transmission electron microscopy. Both autophagy inducers showed an antioxidant effect, improved mitochondrial activity, and decreased dopaminergic cell death induced by PQ. Next, we evaluated the effect of both inducers in vivo. C57BL6 mice were pretreated with metformin or trehalose before PQ administration. Cognitive and motor deteriorated functions in the PD model were evaluated through the nest building and the gait tests and were prevented by metformin and trehalose. Both autophagy inducers significantly reduced the dopaminergic neuronal loss, astrocytosis, and microgliosis induced by PQ. Also, cell death mediated by PQ was prevented by metformin and trehalose, assessed by TUNEL assay. Metformin and trehalose induced autophagy through AMPK phosphorylation and decreased α-synuclein accumulation. Therefore, metformin and trehalose are promising neurotherapeutic autophagy inducers with great potential for treating neurodegenerative diseases such as PD.
随着未来几年老年人数量的增加，包括帕金森病（PD）在内的神经退行性疾病也将上升。最近，我们证明，雷帕霉素诱导的自噬刺激可减少百草枯（PQ）诱导的 PD 模型中氧化应激介导的多巴胺能神经元死亡。评估自噬诱导分子的神经治疗效果对于预防或延迟神经退行性变至关重要。因此，我们评估了自噬诱导剂二甲双胍和海藻糖在 PD 模型中的作用。通过 Western blot 和透射电子显微镜检测到与对照组相比 LC3-II 标志物和自噬体数量增加，证实了这两种分子在 SH-SY5Y 多巴胺能细胞中的自噬诱导作用。两种自噬诱导剂均表现出抗氧化作用，改善了线粒体活性，并降低了 PQ 诱导的多巴胺能细胞死亡。接下来，我们在体内评估了这两种诱导剂的作用。C57BL6 小鼠在用 PQ 给药之前用二甲双胍或海藻糖预处理。通过巢筑和步态测试评估 PD 模型中的认知和运动功能恶化，并通过二甲双胍和海藻糖得到预防。两种自噬诱导剂均显著减少了 PQ 诱导的多巴胺能神经元丢失、星形胶质细胞增生和小胶质细胞增生。此外，通过 TUNEL 检测，二甲双胍和海藻糖还可防止 PQ 介导的细胞死亡。二甲双胍和海藻糖通过 AMPK 磷酸化诱导自噬，并减少α-突触核蛋白积累。因此，二甲双胍和海藻糖是有前途的神经治疗自噬诱导剂，具有治疗 PD 等神经退行性疾病的巨大潜力。
