Wood Paul L, Khan M Amin, Kulow Sarah R, Mahmood Siddique A, Moskal Joseph R
Department of Biomedical Engineering, The Falk Center for Molecular Therapeutics, McCormick School of Engineering and Applied Sciences, Northwestern University, 1801 Maple Avenue, Suite 4306, Evanston, IL 60201, USA.
Brain Res. 2006 Jun 20;1095(1):190-9. doi: 10.1016/j.brainres.2006.04.038. Epub 2006 May 30.
The concept of "oxidative stress" has become a mainstay in the field of neurodegeneration but has failed to differentiate critical events from epiphenomena and sequalae. Furthermore, the translation of current concepts of neurodegenerative mechanisms into effective therapeutics for neurodegenerative diseases has been meager and disappointing. A corollary of current concepts of "oxidative stress" is that of "aldehyde load". This relates to the production of reactive aldehydes that covalently modify proteins, nucleic acids, lipids and carbohydrates and activate apoptotic pathways. However, reactive aldehydes can also be generated by mechanisms other than "oxidative stress". We therefore hypothesized that agents that can chemically neutralize reactive aldehydes should demonstrate superior neuroprotective actions to those of free radical scavengers. To this end, we evaluated hydroxylamines as aldehyde-trapping agents in an in vitro model of neurodegeneration induced by the reactive aldehyde, 3-aminopropanal (3-AP), a product of polyamine oxidase metabolism of spermine and spermidine. In this model, the hydroxylamines N-benzylhydroxylamine, cyclohexylhydroxylamine and t-butylhydroxylamine were shown to protect, in a concentration-dependent manner, against 3-AP neurotoxicity. Additionally, a therapeutic window of 3 h was demonstrated for delayed administration of the hydroxylamines. In contrast, the free radical scavengers TEMPO and TEMPONE and the anti-oxidant ascorbic acid were ineffective in this model. Extending these tissue culture findings in vivo, we examined the actions of N-benzylhydroxylamine in the trimethyltin (TMT) rat model of hippocampal CA3 neurodegeneration. This model involves augmented polyamine metabolism resulting in the generation of reactive aldehydes that compromise mitochondrial integrity. In the rat TMT model, NBHA (50 mg/kg, sc, daily) provided 100% protection against neurodegeneration, as reflected by measurements of KCl-evoked glutamate release from hippocampal brain slices and septal high affinity glutamate uptake. In contrast, ascorbic acid (100 mg/kg, sc, daily) failed to protect CA3 neurons from TMT toxicity. In summary, our data support further evaluation of the concept of "aldehyde load" in neurodegeneration and the potential clinical investigation of agents that are effective traps for reactive aldehydes.
“氧化应激”的概念已成为神经退行性疾病领域的一个支柱，但未能区分关键事件与附带现象及后遗症。此外，将当前神经退行性机制的概念转化为针对神经退行性疾病的有效治疗方法的进展甚微且令人失望。当前“氧化应激”概念的一个必然结果是“醛负荷”的概念。这与活性醛的产生有关，活性醛会共价修饰蛋白质、核酸、脂质和碳水化合物并激活凋亡途径。然而，活性醛也可通过“氧化应激”以外的机制产生。因此，我们推测能够化学中和活性醛的试剂应表现出比自由基清除剂更强的神经保护作用。为此，我们在由活性醛3 - 氨基丙醛（3 - AP）诱导的神经退行性变的体外模型中评估了羟胺作为醛捕获剂的作用，3 - AP是精胺和亚精胺的多胺氧化酶代谢产物。在该模型中，羟胺N - 苄基羟胺、环己基羟胺和叔丁基羟胺呈浓度依赖性地保护细胞免受3 - AP神经毒性的影响。此外，还证明了羟胺延迟给药有3小时的治疗窗。相比之下，自由基清除剂TEMPO和TEMPONE以及抗氧化剂抗坏血酸在该模型中无效。将这些组织培养结果扩展到体内，我们研究了N - 苄基羟胺在海马CA3神经退行性变的三甲基锡（TMT）大鼠模型中的作用。该模型涉及多胺代谢增强，导致活性醛生成，从而损害线粒体完整性。在大鼠TMT模型中，NBHA（50 mg/kg，皮下注射，每日一次）对神经退行性变提供了100%的保护，这通过测量海马脑片KCl诱导的谷氨酸释放和隔区高亲和力谷氨酸摄取得以体现。相比之下，抗坏血酸（100 mg/kg，皮下注射，每日一次）未能保护CA3神经元免受TMT毒性的影响。总之，我们的数据支持进一步评估神经退行性疾病中“醛负荷”的概念以及对作为活性醛有效捕获剂的药物进行潜在的临床研究。
