Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations
Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations
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DOI：
10.1073/pnas.0600554103
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发表时间：
2006-06-20
影响因子：
11.1
通讯作者：
Swanson, Raymond A.
中科院分区：
文献类型：
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作者：
Alano, Conrad C.;Kauppinen, Tiina M.;Swanson, Raymond A.
聚（ADP-核糖）聚合酶-1（PARP-1），当被DNA损伤激活时，促进细胞死亡和炎症。在这里，我们报告说，PARP-1酶活性直接抑制米诺环素和其他四环素衍生物，以前已被证明有神经保护和抗炎作用。这些代理商进行了评价，通过使用皮质。神经元培养物，其中PARP-1活化由遗传毒性剂N-甲基-N ′-硝基-N-亚硝基胍（MNNG）或3-吗啉代壬亚胺（SIN-1）诱导。在这两种情况下，神经元死亡被10 μ M 3，4-二氢-5-[4-（1-哌啶基）丁氧基]-1（2H）-异喹啉酮（一种已确定的PARP抑制剂）或100 nM米诺环素降低> 80%。神经元NAD+耗竭和聚（ADP-核糖）形成，这是PARP-1激活的生化标志物，也被100 nM米诺环素阻断。通过在无细胞试验中使用重组PARP-1证实米诺环素对PARP-1的直接竞争性抑制（Ki = 13.8 +/-1.5 nM）。几种四环素衍生物的比较显示，在MNNG孵育期间，作为PARP-1抑制剂的效力与作为神经保护剂的效力之间存在强相关性（r（2）= 0.87），效力的排序为米诺环素>多西环素>地美环素>金霉素。已知这些化合物具有其他可能有助于其神经保护作用的作用，但其浓度远高于此处显示的抑制PARP-1的浓度。在某些情况下，米诺环素和其他四环素衍生物的神经保护和抗炎作用可能归因于PARP-1抑制。
Poly(ADP-ribose) polymerase-1 (PARP-1), when activated by DNA damage, promotes both cell death and inflammation. Here we report that PARP-1 enzymatic activity is directly inhibited by minocycline and other tetracycline derivatives that have previously been shown to have neuroprotective and anti-inflammatory actions. These agents were evaluated by using cortical. neuron cultures in which PARP-1 activation was induced by the genotoxic agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or 3-morpholinosydnonimine (SIN-1). In both conditions, neuronal death was reduced by > 80% either by 10 mu M 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, an established PARP inhibitor, or by 100 nM minocycline. Neuronal NAD+ depletion and poly(ADP-ribose) formation, which are biochemical markers of PARP-1 activation, were also blocked by 100 nM minocycline. A direct, competitive inhibition of PARP-1 by minocycline (K-i = 13.8 +/- 1.5 nM) was confirmed by using recombinant PARP-1 in a cell-free assay. Comparison of several tetracycline derivatives showed a strong correlation (r(2) = 0.87) between potency as a PARP-1 inhibitor and potency as a neuroprotective agent during MNNG incubations, with the rank order of potency being minocycline > doxycycline > demeclocycline > chlortetracycline. These compounds are known to have other actions that could contribute their neuroprotective effects, but at far higher concentrations than shown here to inhibit PARP-1. The neuroprotective and anti-inflammatory effects of minocycline and other tetracycline derivatives may be attributable to PARP-1 inhibition in some settings.