Antisense vasopressin oligonucleotides: uptake, turnover, distribution, toxicity and behavioral effects.
Antisense vasopressin oligonucleotides: uptake, turnover, distribution, toxicity and behavioral effects.
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反义加压素寡核苷酸：摄取、周转、分布、毒性和行为影响。
DOI：
10.1111/j.1365-2826.1995.tb00778.x
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发表时间：
1995
影响因子：
3.2
通讯作者：
Shih,YH
中科院分区：
文献类型：
--
作者：
Meeker,R;LeGrand,G;Ramirez,J;Smith,T;Shih,YH
研究了反义加压素寡核苷酸的摄取、周转、分布、毒性和行为效应，以确定这些化合物如何与神经组织相互作用以抑制靶mRNA的翻译。硫代修饰的寡核苷酸和未修饰的寡核苷酸都能迅速被哺乳动物神经组织吸收。未修饰的寡核苷酸的周转速度(t1/2<；1h)比硫代修饰的寡核苷酸(t1/2=12h)快。硫代加压素反义寡核苷酸抑制了加压素的合成，体外浓度低于约5μM的毒性阈值。将硫代反义寡核苷酸注射到SOIN活体区域，在前24小时内导致加压素基因表达的小幅下降和代偿性饮水反应，与加压素翻译的缺陷一致，动力学与体外观察到的相似。第二天摄入量恢复正常，表明寡核苷酸相对较快的清除和最小的副作用。虽然积累的机制和分子相互作用的细节仍不清楚，但我们观察到神经元蛋白的一个子集优先摄取和/或保留寡核苷酸，这表明了一些选择性靶向的过程。因此，低浓度的针对加压素基因5‘端的低浓度寡核苷酸可以有效地急性和可逆地控制哺乳动物中枢神经系统中加压素的合成，并具有较快的行为效应和最小的副作用。
The uptake, turnover, distribution, toxicity and behavioral effects of antisense vasopressin oligonucleotides were investigated to define how these compounds interact with neural tissue to inhibit translation of a target mRNA. Both phosphorothioate modified and unmodified oligonucleotides are rapidly taken up by mammalian neural tissue. Turnover of the unmodified oligonucleotide was found to be fast (t1/2< 1 h) relative to the phosphorothioate modified oligonucleotide (t1/2= 12 h). The phosphorothioate vasopressin antisense oligonucleotide suppressed vasopressin synthesisin vitroat concentrations below the toxic threshold of approximately 5 μM. Intracranial injections of phosphorothioate antisense oligonucleotide into the region of the SONin vivo, resulted in a small decrease in vasopressin mRNA and a compensatory drinking response within the first 24 h, consistent with a deficit in vasopressin translation with kinetics similar to those observedin vitro.Water intake returned to normal by the second day indicating relatively rapid clearance of the oligonucleotide and minimal side effects. Although the mechanisms of accumulation and details of the molecular interactions are still unknown, our observation of preferential uptake and/or retention of oligonucleotide within a subset of neuronsin vitrosuggests some process of selective targeting. Thus, low concentrations of oligonucleotides targeted to the untranslated 5′ end of vasopressin mRNA can be effective for the acute and reversible control of vasopressin synthesis in mammalian CNS with relatively rapid onset of behavioral effects and minimal side effects.