Oxindole, a sedative tryptophan metabolite, accumulates in blood and brain of rats with acute hepatic failure
Oxindole, a sedative tryptophan metabolite, accumulates in blood and brain of rats with acute hepatic failure
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DOI：
10.1046/j.1471-4159.1998.70051998.x
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发表时间：
1998-05-01
影响因子：
4.7
通讯作者：
Moroni, F
中科院分区：
文献类型：
--
作者：
Carpenedo, R;Mannaioni, G;Moroni, F
用羟吲哚（10-100 mg/kg i. p.）处理的大鼠，一种假定的色氨酸代谢物，表现出自发活动减少、翻正反射丧失、低血压和可逆性昏迷。对照组的脑羟吲哚水平为0.05 +/- 0.01 nmol/g，以10或100 mg/kg的剂量腹膜内给药后增加至8.1 +/- 1.7或103 +/- 15 nmol/g，分别为了研究羟吲哚在急性肝功能衰竭相关神经症状中的作用，我们测量了严重肝损伤后脑中羟吲哚浓度的变化，并研究了导致其合成的可能代谢途径。用硫代乙酰胺（0.2和0.4g/kg i. p.，两次）或半乳糖胺（1和2 g/kg i. p.）显示急性肝衰竭和血液或脑羟吲哚浓度的大幅增加（从对照组脑中的0.05 +/- 0.01 nmol/g到硫代乙酰胺处理动物脑中的1.8 +/- 0.3 nmol/g）。给予色氨酸（300- 1，000 mg/kg p.o.）引起两倍增加，而施用吲哚（10-100 mg/kg p.o.）导致200倍的增加，在肝脏，血液和大脑中的羟吲哚含量，从而表明，吲哚形成色氨酸是一个限制步骤羟吲哚合成。新霉素是一种广谱、局部作用的抗生素，能够减少肠道植物群，口服新霉素可显著降低脑羟吲哚含量。总之，我们的数据表明，羟吲哚是一种神经递质色氨酸代谢产物，并表明它可能在与急性肝损伤相关的神经系统症状中发挥重要作用。
Rats treated with oxindole (10-100 mg/kg i.p.), a putative tryptophan metabolite, showed decreased spontaneous locomotor activity, loss of the righting reflex, hypotension, and reversible coma. Brain oxindole levels were 0.05 +/- 0.01 nmol/g in controls and increased to 8.1 +/- 1.7 or 103 +/- 15 nmol/g after its administration at doses of 10 or 100 mg/kg i.p., respectively. To study the role that oxindole plays in the neurological symptoms associated with acute liver failure, we measured the changes of its concentration in the brain after massive liver damage, and we investigated the possible metabolic pathways leading to its synthesis. Rats treated with either thioacetamide (0.2 and 0.4 g/kg i.p., twice) or galactosamine (1 and 2 g/kg i.p.) showed acute liver failure and a large increase in blood or brain oxindole concentrations (from 0.05 +/- 0.01 nmol/g in brains of controls to 1.8 +/- 0.3 nmol/g in brains of thioacetamide-treated animals). Administration of tryptophan (300-1,000 mg/kg p.o.) caused a twofold increase, whereas administration of indole (10-100 mg/kg p.o.) caused a 200-fold increase, of oxindole content in liver, blood, and brain, thus suggesting that indole formation from tryptophan is a limiting step in oxindole synthesis. Oral administration of neomycin, a broad-spectrum, locally acting antibiotic agent able to reduce intestinal flora, significantly decreased brain oxindole content. Taken together, our data show that oxindole is a neurodepressant tryptophan metabolite and suggest that it may play a significant role in the neurological symptoms associated with acute liver impairment.