Zuch C L, Nordstroem V K, Briedrick L A, Hoernig G R, Granholm A C, Bickford P C
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
J Comp Neurol. 2000 Nov 20;427(3):440-54. doi: 10.1002/1096-9861(20001120)427:3<440::aid-cne10>3.0.co;2-7.
The neurotoxin 6-hydroxydopamine (6-OHDA) has been used extensively in animal models of Parkinson's disease. Typically, rodents develop severe unilateral movement deficiencies coupled with apomorphine-induced rotation behavior at least 1 week after an ipsilateral 6-OHDA lesion of the nigrostriatal dopamine (DA) system. The short-term morphological effects of 6-OHDA have not been determined in detail, however, and the exact process by which neurons die has not been elucidated. Thus, novel degenerative markers were used to determine the temporal pattern of acute phenotypic and degenerative alterations following a unilateral 6-OHDA injection into the medial forebrain bundle of adult rats. 6-Hydroxydopamine administration resulted in an increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining as early as 6 hours postlesion. Staining for FluoroJade, a marker of neuronal degeneration, was evident at all time points examined but was maximal at 48 hours. Loss of tyrosine hydroxylase (TH) immunoreactivity began in axons at 6 hours, and progressed to cell bodies at later time points postlesion. Morphological examination of these neurons supported the conclusion of their death via apoptosis. Thus, whereas behavioral manifestations typically become evident 1 week or more following a 6-OHDA lesion, it is evident that nigral cell degeneration begins much earlier. This suggests multiple therapeutic possibilities, including the prevention of apoptosis, in affected neurons.
神经毒素6-羟基多巴胺（6-OHDA）已广泛应用于帕金森病的动物模型。通常，在黑质纹状体多巴胺（DA）系统同侧进行6-OHDA损伤后至少1周，啮齿动物会出现严重的单侧运动缺陷以及阿扑吗啡诱导的旋转行为。然而，6-OHDA的短期形态学效应尚未得到详细确定，并且神经元死亡的确切过程也尚未阐明。因此，使用新型退行性标记物来确定成年大鼠单侧注射6-OHDA到内侧前脑束后急性表型和退行性改变的时间模式。给予6-羟基多巴胺后，早在损伤后6小时，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色就增加。FluoroJade是一种神经元变性标记物，在所检查的所有时间点都有明显染色，但在48小时时达到最大值。酪氨酸羟化酶（TH）免疫反应性在损伤后6小时开始在轴突中丧失，并在后期进展到细胞体。对这些神经元的形态学检查支持它们通过凋亡死亡的结论。因此，虽然行为表现通常在6-OHDA损伤后1周或更长时间变得明显，但很明显黑质细胞变性在更早的时候就开始了。这提示了多种治疗可能性，包括预防受影响神经元中的细胞凋亡。
