Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
Oxid Med Cell Longev. 2018 Oct 16;2018:9101740. doi: 10.1155/2018/9101740. eCollection 2018.
Peroxynitrite-mediated nitrosative stress in the brain has been associated with various neurodegenerative disorders. Recent evidence highlights peroxisome proliferator-activated receptor (PPAR) as a critical neuroprotective factor in neurodegenerative diseases. Here, we observed the effect of the herb hydroxysafflor yellow A (HSYA) during nitrosative stress in neurons and investigated the mechanism based on PPAR protection. We found that a single exposure of primary neurons to peroxynitrite donor SIN-1 caused neuronal injury, which was accompanied by the increase of PPAR nitration status and lack of activation of the receptor, as measured by PPAR DNA-binding activity, by agonist (15d-PGJ2 or rosiglitazone) stimulation. The crucial role of PPAR in neuronal defense against nitrosative stress was verified by showing that pretreatment with 15d-PGJ2 or rosiglitazone attenuated SIN-1-induced neuronal injury but pretreatment with GW9662, a PPAR antagonist, aggravated SIN-1-induced neuronal injury. The addition of HSYA not only inhibited SIN-1-induced neuronal damage but prevented PPAR nitrative modification and resumed PPAR activity stimulated by either 15d-PGJ2 or rosiglitazone. Furthermore, HSYA also showed the ability to rescue the neuroprotective effect of 15d-PGJ2 or rosiglitazone when the agonists were coincubated with SIN-1. Finally, in vivo experiments demonstrated that the administration of HSYA also efficiently blocked PPAR nitration and loss of activity in the SIN-1-injected hippocampus and reversed the increased neuronal susceptibility which was supported by the inhibition of Bcl-2 protein downregulation induced by SIN-1. The results suggest that HSYA protects neurons from nitrosative stress through keeping PPAR as a functional receptor, allowing a more effective activation of this neuroprotective factor by the endogenous or exogenous agonist. Our findings provide new clues in understanding the role of the neuroprotective potential of the herbal HSYA.
过氧亚硝酸盐介导的脑内硝化应激与各种神经退行性疾病有关。最近的证据强调过氧化物酶体增殖物激活受体 (PPAR) 是神经退行性疾病中关键的神经保护因子。在这里，我们观察了在神经元硝化应激过程中羟基红花黄色素 A (HSYA) 的作用，并基于 PPAR 保护研究了其机制。我们发现，一次性暴露于过氧亚硝酸盐供体 SIN-1 会导致神经元损伤，这伴随着 PPAR 硝化状态的增加和受体的缺乏激活，如通过 PPAR DNA 结合活性、激动剂 (15d-PGJ2 或罗格列酮) 刺激来测量。通过显示用 15d-PGJ2 或罗格列酮预处理可减轻 SIN-1 诱导的神经元损伤，但用 PPAR 拮抗剂 GW9662 预处理会加重 SIN-1 诱导的神经元损伤，证明了 PPAR 在神经元防御硝化应激中的关键作用。HSYA 的添加不仅抑制了 SIN-1 诱导的神经元损伤，而且防止了 15d-PGJ2 或罗格列酮刺激的 PPAR 硝化修饰和恢复了其活性。此外，HSYA 还显示了在激动剂与 SIN-1 共孵育时能够挽救 15d-PGJ2 或罗格列酮的神经保护作用的能力。最后，体内实验表明，HSYA 的给药还能有效地阻断 SIN-1 注射的海马中 PPAR 的硝化和活性丧失，并逆转由 SIN-1 诱导的 Bcl-2 蛋白下调引起的神经元易感性增加。结果表明，HSYA 通过保持 PPAR 作为功能性受体来保护神经元免受硝化应激，从而使内源性或外源性激动剂更有效地激活这种神经保护因子。我们的发现为理解草药 HSYA 的神经保护潜力提供了新的线索。
