Chang F W, Wang S D, Lu K T, Lee E H
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
Brain Res Bull. 1993;31(3-4):253-66. doi: 10.1016/0361-9230(93)90215-w.
We have previously demonstrated that chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion to the substantia nigra (SN) and the locus coeruleus (LC) both produce a long-lasting neurotoxicity on dopamine (DA) and norepinephrine (NE) neurons in these two areas, respectively. In the present study, we further examined the toxicity of MPTP in these two areas by using the immunohistochemical method. We have also assessed the role of glia cells in the SN and LC in mediating the toxicity of MPTP. Immunohistochemical results have confirmed the direct toxicity of MPTP in the SN, as revealed by significant decreases of tyrosine hydroxylase (TH)-positive cells in the SN and TH-positive fibers in the striatum. The specific gliotoxin alpha-aminoadipic acid (alpha-AA), when administered to the SN at 48 h interval, partially antagonized DA depletions and behavioral deficits produced by chronic MPTP treatment. When alpha-AA was administered to the SN every 24 h, it completely abolished the toxicity of MPTP. On the other hand, chronic MPTP infusions to the LC significantly decreased DA-beta-hydroxylase-positive cells in this area. When alpha-AA was injected into the LC at 48 h intervals, it did not prevent depletions of NE in the LC and the hippocampus caused by chronic MPTP infusions. It did not protect against the behavioral deficits produced by MPTP, either. When alpha-AA was injected into the LC every 24 h, it only partially prevented the toxicity of MPTP on NE in the LC. It also partially prevented the motor-impairing effect of MPTP; however, it barely protected against MPTP's toxicity on NE in the hippocampus and it did not antagonize the stereotypy deficit produced by chronic MPTP, either. Phasic tremor and rigidity were observed following MPTP infusions to the SN and the LC every day, but these symptoms were less frequently observed during the later experimental stage. Serotonin measures were not significantly altered by these treatments throughout these experiments. Immunoblotting results of glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, have confirmed proper lesions of astrocytes by alpha-AA. These results together suggest that chronic MPTP treatment exerts a direct and long-lasting toxicity on DA neurons along the nigrostriatal pathway and NE neurons along the coeruleus-hippocampal pathway. The neurotoxicity of MPTP is probably mediated through astrocytes in the SN, and may be partly mediated through astrocytes in the LC also. These results imply a role for dendritic uptake of DA and NE in these cell body regions. However, these findings also suggest the possibility of differential mechanisms of MPTP's toxicity in these two areas.
我们之前已经证明，向黑质（SN）和蓝斑（LC）慢性输注1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）分别会对这两个区域的多巴胺（DA）和去甲肾上腺素（NE）神经元产生持久的神经毒性。在本研究中，我们通过免疫组织化学方法进一步研究了MPTP在这两个区域的毒性。我们还评估了SN和LC中的胶质细胞在介导MPTP毒性中的作用。免疫组织化学结果证实了MPTP对SN的直接毒性，表现为SN中酪氨酸羟化酶（TH）阳性细胞和纹状体中TH阳性纤维显著减少。特异性胶质毒素α-氨基己二酸（α-AA）以48小时的间隔注入SN时，可部分拮抗慢性MPTP处理所致的DA耗竭和行为缺陷。当每24小时向SN注入α-AA时，它完全消除了MPTP的毒性。另一方面，向LC慢性输注MPTP可显著减少该区域中多巴胺-β-羟化酶阳性细胞。当以48小时的间隔将α-AA注入LC时，它不能预防慢性MPTP输注所致的LC和海马中NE的耗竭。它也不能预防MPTP所致的行为缺陷。当每24小时向LC注入α-AA时，它仅部分预防了MPTP对LC中NE的毒性。它也部分预防了MPTP的运动损害作用；然而，它几乎不能保护海马中的NE免受MPTP的毒性影响，也不能拮抗慢性MPTP所致的刻板行为缺陷。每天向SN和LC输注MPTP后观察到了阶段性震颤和强直，但在实验后期这些症状较少出现。在整个这些实验中，这些处理并未显著改变血清素水平。星形胶质细胞的标志物蛋白胶质纤维酸性蛋白（GFAP）的免疫印迹结果证实了α-AA对星形胶质细胞的适当损伤。这些结果共同表明，慢性MPTP处理对黑质纹状体通路中的DA神经元和蓝斑-海马通路中的NE神经元具有直接且持久的毒性。MPTP的神经毒性可能通过SN中的星形胶质细胞介导，也可能部分通过LC中的星形胶质细胞介导。这些结果暗示了在这些细胞体区域中DA和NE的树突摄取的作用。然而，这些发现也提示了MPTP在这两个区域中毒性的不同机制的可能性。
