Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor
Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor
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DOI：
10.1016/j.pbb.2003.10.016
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发表时间：
2004-02-01
影响因子：
3.6
通讯作者：
Segura-Aguilar, J
中科院分区：
文献类型：
--
作者：
Diaz-Véliz, G;Mora, S;Segura-Aguilar, J
本研究的目的是评估DT-diaphorase抑制多巴胺（DA）氧化为相应的邻醌的体内神经退行性作用的贡献。将焦磷酸锰（Mn3+）络合物作为促氧化剂单独或与DT-diaphorase抑制剂双藻醇联合注入右侧大鼠黑质，诱导其对黑质纹状体DA神经元的神经毒性。比较了6-羟基多巴胺（6-OHDA）选择性损伤多巴胺能神经元后的行为效应。与对照动物相比，神经内注射Mn3+和Mn3+加双豆酚对运动行为有显著损害。然而，注射Mn3+双聚马罗组的效果明显比单独注射Mn3+组更严重。在运动活动和饲养行为中，同时注射Mn3+和双豆酚可产生6- ohda样损伤。在条件回避反应（CAR）的习得中也观察到类似的效果。双糖美洛尔显著损害回避条件反射，但不影响运动行为。行为效应与纹状体酪氨酸羟化酶（TH）阳性纤维损失的程度相关。与对侧未注射侧相比，单侧接受Mn3+和Mn3+ +双丘马罗注射的大鼠内侧前脑束黑质纹状体th阳性纤维密度显著降低。综上所述，本研究提供了Mn3+在体内的神经毒性通过抑制DT-diaphorase而增强的证据，表明该酶可能在黑质纹状体DA系统中发挥神经保护作用。(C) 2003 Elsevier Inc.版权所有。
The purpose of this study was to evaluate the contribution of DT-diaphorase inhibition to in vivo neurodegenerative effects of dopamine (DA) oxidation to the corresponding o-quinones. The neurotoxicity to nigrostriatal DA neurons was induced by injection of manganese pyrophosphate (Mn3+) complex as a prooxidizing agent alone or together with the DT-diaphorase inhibitor dicumarol into the right rat substantia nigra. The behavioral effects were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Intranigral injection of Mn3+ and Mn3+ plus dicumarol produced significant impairment in motor behavior compared with control animals. However, the effect seen in the Mn3+ plus dicumarol injected group was significantly more severe than that observed in the Mn3+ alone injected group. In motor activity and rearing behavior, the simultaneous injection of Mn3+ plus dicumarol produced a 6-OHDA-like impairment. Similar effects were observed in the acquisition of a conditioned avoidance response (CAR). Dicumarol significantly impaired avoidance conditioning although without affecting the motor behavior. The behavioral effects were correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving unilateral intranigral Mn3+ and Mn3+ plus dicumarol injections exhibited a significant reduction in nigrostriatal TH-positive fiber density in medial forebrain bundle compared with the contralateral noninjected side. In conclusion, this study provides evidence that the neurotoxicity of Mn3+ in vivo is potentiated by DT-diaphorase inhibition, suggesting that this enzyme could play a neuroprotective role in the nigrostriatal DA systems. (C) 2003 Elsevier Inc. All rights reserved.