The prooxidant effect of 5-aminolevulinic acid in the brain tissue of rats: Implications in neuropsychiatric manifestations in porphyrias
The prooxidant effect of 5-aminolevulinic acid in the brain tissue of rats: Implications in neuropsychiatric manifestations in porphyrias
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DOI：
10.1016/0891-5849(95)02035-7
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发表时间：
1996-01-01
影响因子：
7.4
通讯作者：
Bechara, EJH
中科院分区：
文献类型：
--
作者：
Demasi, R;Penatti, CAA;Bechara, EJH
5-氨基乙酰丙酸 (ALA) 是一种血红素前体，在急性间歇性卟啉症、铅中毒和酪氨酸中毒的临床表现期间积累，已被假设为氧化自由基的内源性来源。我们现在报告了接受 ALA 治疗的大鼠脑组织的氧化作用。急性治疗（40 毫克/千克体重）后，观察到皮质中非血红素铁总量增加 (20%)。长期服用ALA（两周内隔天40mg/kg体重）后，发现以下氧化应激指标显着增加：全脑匀浆中的CuZnSOD活性（67％）、皮质中的总铁（68％）和铁蛋白（71％）、纹状体中的铁蛋白（44％）、大脑皮质匀浆中的蛋白质羰基（三倍）和Ca-45（2+）摄取皮质突触体（45%）。此外，用放射性配体 H-3-蝇蕈醇测定的全脑制备的突触膜显示，高亲和力 GABA 受体结合的 K-d 值增加（两倍），并形成蛋白质羰基、硫代巴比妥酸反应产物和共轭二烯。在体外，ALA 对高亲和力 H-3-蝇蕈醇结合产生类似的作用。没有观察到多巴胺能或血清素能[H-3]-配体结合的明显改变。这些结果支持 ALA 触发的大脑氧化应激，并伴有铁代谢改变和 GABA 受体损伤，这可能与上述卟啉症的神经精神表现有关。
5-Aminolevulinic acid (ALA), a heme precursor accumulated during the clinical expression of acute intermittent porphyria, lead poisoning, and tyrosinosis, has been hypothesized to act as an endogenous source of oxyradicals. We now report oxidative effects on brain tissue of rats submitted to ALA treatment. Upon acute treatment (40 mg/kg body weight) increased total nonheme iron in the cortex (20%) was observed. After prolonged ALA administration (40 mg/kg body weight on alternate days during 2 weeks), the following indicators of oxidative stress were found to be significantly increased: CuZnSOD activity (67%) in total brain homogenate, total iron (68%) and ferritin (71%) in the cortex, ferritin in striatum (44%), protein carbonyls in homogenate of cerebral cortex (threefold) and Ca-45(2+) uptake by cortical synaptosomes (45%). In addition, synaptic membranes prepared from whole brain assayed with the radioligand H-3-muscimol, revealed increased K-d values (twofold) of the high-affinity GABAergic receptor binding and formation of protein carbonyl groups, thiobarbituric acid reactive products, and conjugated dienes. In vitro, ALA produced similar effects upon the high affinity H-3-muscimol binding. No apparent alteration of either dopaminergic or serotonergic [H-3]-ligand binding was observed. These results argue in favor of ALA-triggered oxidative stress in brain accompanied by iron metabolism alterations and GABAergic receptor damage, which may be implicated in the neuropsychiatric manifestations of the aforementioned porphyrias.