Overexpression of spermidine/spermine N1-acetyltransferase elevates the threshold to pentylenetetrazol-induced seizure activity in transgenic mice
Overexpression of spermidine/spermine N1-acetyltransferase elevates the threshold to pentylenetetrazol-induced seizure activity in transgenic mice
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DOI：
10.1016/s0014-4886(03)00186-9
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发表时间：
2003-10-01
影响因子：
5.3
通讯作者：
Jänne, J
中科院分区：
文献类型：
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作者：
Kaasinen, SK;Gröhn, OHJ;Jänne, J
在转基因小鼠中，通过过表达精脒/精胺N-1-乙酰转移酶（SSAT）激活多胺催化剂，导致二胺腐胺在包括脑在内的大多数组织中大量过量积累。在转基因动物中，腐胺池在目前分析的每六个脑区中显著增加。脑桥（23倍）、小脑（37倍）、大脑（34倍）和海马（16倍）显示腐胺水平增加最多。此外，腐胺与亚精胺的摩尔比在转基因动物的不同脑区中平均增加了近40倍。在暴露的动物戊四唑（PTZ）输注，一种化合物已知诱导癫痫样发作活动，SSAT转基因小鼠表现出显着升高的癫痫发作阈值，以阵挛性和强直性惊厥相比，其同系同窝。然而，这种差异。当在PTZ输注之前用艾芬地尔处理动物时，这些变化消失。后一种化合物通过与N-甲基-D-天冬氨酸受体的多胺位点结合而作为该受体的拮抗剂。SSAT的过表达似乎也保护转基因动物免受PTZ诱导的海马神经元损失。因为腐胺是已知的作为γ-氨基丁酸（GABA）的前体。我们进行了1H-1 NMR分析，其结果显示，在所分析的所有脑区域中，同基因和转基因动物中抑制性氨基酸GABA和其兴奋性对应物谷氨酸的水平是不可区分的。目前的结果表明，经常观察到的腐胺的积累，在响应脑损伤属于神经保护措施，而不是随后的损伤的原因。(C)2003 Elsevier Science（美国）。All rights reserved.
Activation of polyamine catabolism in transgenic mice through an overexpression of spermidine/spermine N-1-acetyltransferase (SSAT) results in a massive overaccumulation of the diamine putrescine in most tissues including brain. Putrescine pool in transgenic animals was strikingly expanded in every six brain regions analyzed at present. Pons (23-fold), cerebellum (37-fold), cerebrum (34-fold), and hippocampus (16-fold) showed the greatest increases in putrescine levels. Moreover, the molar ratio of putrescine to spermidine was increased in the different brain regions of the transgenic animals on an average of nearly 40-fold. Upon an exposure of the animals to pentylenetetrazol (PTZ) infusions, a compound known to induce epilepsy-like seizure activity, the SSAT transgenic mice showed significantly elevated seizure threshold to both clonic and tonic convulsions in comparison with their syngenic littermates. This difference, however. disappeared when the animals were treated with ifenprodil prior to PTZ infusions. The latter compound acts as an antagonist of N-methyl-D-aspartate receptor by binding to the polyamine site of the receptor. Overexpression of SSAT likewise appeared to protect the transgenic animals from PTZ-induced neuron loss in the hippocampus. As putrescine is known to serve as a precursor to gamma-aminobutyric acid (GABA). we carried out H-1 NMR analyses the results of which revealed that the levels of the inhibitory amino acid GABA and its excitatory counterpart glutamate were indistinguishable in syngenic and transgenic animals in all brain regions analyzed. The present results suggest that the frequently observed enhanced accumulation of putrescine in response to brain insults belongs to neuroprotective measures rather than being a cause of the subsequent injury. (C) 2003 Elsevier Science (USA). All rights reserved.