Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China.
Department of Orthodontics, School of Stomatology, Jilin University, 1500 Qinghua Road, Changchun 130021, PR China.
Free Radic Biol Med. 2018 May 20;120:228-238. doi: 10.1016/j.freeradbiomed.2018.03.014. Epub 2018 Mar 17.
Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage. Therefore, we established two rat models of diabetes in vivo induced by MGO and streptozocin (STZ) respectively, while utilized differentiated PC-12 cells in vitro. Treatment of PC-12 cells with PCr markedly attenuated MGO-induced change of viability, apoptosis, accompanied by decreased levels of caspase-3, casapse-9 and Bcl-2/Bax protein ratio. Determination of cellular respiratory function was performed with intact PC-12 cells and homogenized hippocampal neuron tissue of rat. Reactive oxygen species (ROS) generation was assessed by membrane permeable fluorescent probe DCFH-DA. The expressions of Akt, Nrf2 and HO-1 were examined by Western blot. PCr pretreatment significantly reduced oxidative stress-induced high LDH, MDA level, and ROS production of PC-12 cells. PCr pretreatment also significantly decreased mitochondrial dysfunction in vitro and in vivo. In addition, PCr pretreatment increased the expression of p-Akt, Nrf2 and HO-1, and reduced the apoptosis. Moreover, the expression of Cleaved caspase3 was partially increased and the p-Akt, Nrf2 and HO-1 was partially reduced by a PI3K inhibitor (LY294002). While, compared with LY294002 groups, pre-treatment with PCr at the concentrations of 20 mM significantly reduced the expression of Cleaved caspase3 and increased the expression of p-Akt, Nrf2 and HO-1. Molecular docking assay showed that PCr possessed powerful affinity towards to Akt with lower binding energy. In conclusion, the neuroprotective effects of PCr in vitro and in vivo rely on normalizing mitochondrial function and reducing oxidative stress via Akt mediated Nrf2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the treatment of diabetes-associated neurodegenerative diseases.
甲基乙二醛 (MGO) 是葡萄糖的一种活性代谢物，在糖尿病患者的组织和血液中含量很高。磷酸肌酸 (PCr) 是一种高能磷酸化合物，具有多种药理学作用，但对其神经保护作用知之甚少。本研究旨在探讨 PCr 的神经保护作用及其可能的机制。糖尿病与神经退行性疾病密切相关，不仅导致周围神经系统 (PNS) 受损，还导致中枢神经系统 (CNS) 受损。因此，我们分别建立了体内 MGO 和链脲佐菌素 (STZ) 诱导的两种糖尿病大鼠模型，同时利用体外分化的 PC-12 细胞进行研究。用 PCr 处理 PC-12 细胞可显著减轻 MGO 诱导的细胞活力和凋亡变化，同时降低 caspase-3、caspase-9 和 Bcl-2/Bax 蛋白比值。用完整的 PC-12 细胞和大鼠海马神经元组织匀浆测定细胞呼吸功能。用膜通透性荧光探针 DCFH-DA 测定活性氧 (ROS) 的产生。用 Western blot 检测 Akt、Nrf2 和 HO-1 的表达。PCr 预处理可显著降低氧化应激诱导的 PC-12 细胞内高 LDH、MDA 水平和 ROS 生成。PCr 预处理还可显著减轻体外和体内的线粒体功能障碍。此外，PCr 预处理可增加 p-Akt、Nrf2 和 HO-1 的表达，减少细胞凋亡。此外，Cleaved caspase3 的表达部分增加，而 p-Akt、Nrf2 和 HO-1 的表达部分减少，使用 PI3K 抑制剂 (LY294002)。与 LY294002 组相比，浓度为 20mM 的 PCr 预处理可显著降低 Cleaved caspase3 的表达，并增加 p-Akt、Nrf2 和 HO-1 的表达。分子对接试验表明，PCr 与 Akt 具有很强的亲和力，结合能较低。综上所述，PCr 在体外和体内的神经保护作用依赖于通过 Akt 介导的 Nrf2/HO-1 通路使线粒体功能正常化和减少氧化应激，这表明 PCr 可能是治疗与糖尿病相关的神经退行性疾病的一种新型治疗候选药物。
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