Yatin S M, Yatin M, Varadarajan S, Ain K B, Butterfield D A
Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, 40506-0055, USA.
J Neurosci Res. 2001 Mar 1;63(5):395-401. doi: 10.1002/1097-4547(20010301)63:5<395::AID-JNR1034>3.0.CO;2-Q.
The polyamines, relatively low-molecular-weight aliphatic compounds, are the main inducers of eukaryotic cell growth and proliferation. Although polyamine requirements for cell growth are well defined, their role is still enigmatic. We have previously reported that amyloid beta-peptide (A beta), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is toxic to neurons through a free radical-dependent oxidative stress mechanism and that A beta(1--42), the principal form of A beta in AD brain, causes an increase in polyamine metabolism manifested by up-regulated polyamine uptake and increased ornithine decarboxylase (ODC) activity. Both effects were prevented by the free radical scavenger vitamin E. Spermine has been reported to function directly as a free radical scavenger. In the current study, we aimed to address whether up-regulation of polyamine metabolism is a defense against, or a result of, A beta-induced oxidative stress by investigating the capability of spermine to quench A beta-associated free radicals in solution and to assert a protective function of spermine in neuronal culture against A beta. Pretreatment of cultured neurons with spermine prior to A beta exposure failed to prevent A beta-induced cell death. Indeed, A beta plus spermine added to cultured neurons was even more neurotoxic than either agent alone. Additionally, inhibition of the polyamine synthesis by difluoromethylornithine (DFMO) did not protect cells from A beta-induced free radical toxicity, and stimulation of the synthesis of putrescine and spermine by the aminopropyltransferase inhibitor S-adenosyl-1,8-diamino-thiooctane (AdoDATO), rather, further enhanced A beta-induced toxicity. Although spermine is capable of scavenging free radicals generated by A beta in solution as measured by electron paramagnetic resonance (EPR) spectroscopy, the up-regulated transport of exogenously added spermine together with A beta may lead to overaccumulation of a cellular spermine pool, with resulting enhanced neurotoxicity.
多胺是相对低分子量的脂肪族化合物，是真核细胞生长和增殖的主要诱导剂。尽管细胞生长对多胺的需求已明确，但它们的作用仍不明确。我们之前报道过，淀粉样β肽（Aβ）是阿尔茨海默病（AD）脑中老年斑的主要成分，通过自由基依赖性氧化应激机制对神经元有毒性作用，且AD脑中Aβ的主要形式Aβ（1-42）会导致多胺代谢增加，表现为多胺摄取上调和鸟氨酸脱羧酶（ODC）活性增加。这两种效应都可被自由基清除剂维生素E阻止。据报道，精胺可直接作为自由基清除剂发挥作用。在本研究中，我们旨在通过研究精胺淬灭溶液中与Aβ相关自由基的能力以及确定精胺在神经元培养中对Aβ的保护作用，来探讨多胺代谢上调是对Aβ诱导的氧化应激的防御反应还是其结果。在Aβ暴露前用精胺预处理培养的神经元并不能预防Aβ诱导的细胞死亡。实际上，添加到培养神经元中的Aβ加精胺比单独使用任何一种试剂的神经毒性都更强。此外，二氟甲基鸟氨酸（DFMO）抑制多胺合成并不能保护细胞免受Aβ诱导的自由基毒性，而氨丙基转移酶抑制剂S-腺苷-1,8-二氨基硫辛烷（AdoDATO）刺激腐胺和精胺的合成反而进一步增强了Aβ诱导的毒性。尽管通过电子顺磁共振（EPR）光谱测量发现精胺能够清除溶液中由Aβ产生的自由基，但外源性添加的精胺与Aβ一起上调的转运可能导致细胞内精胺池过度积累，从而增强神经毒性。
