Roedter A, Winkler C, Samii M, Walter G F, Brandis A, Nikkhah G
Neurosurgical Clinic, Nordstadt Hospital, Haltenhofstrasse 41, D-30167 Hannover, Germany.
J Comp Neurol. 2001 Apr 2;432(2):217-29. doi: 10.1002/cne.1098.
Partial lesions of the nigrostriatal dopamine system can be induced reliably by the intrastriatal injection of 6-hydroxydopamine (6-OHDA) and are considered to be analogous to the early stages of human Parkinson's disease. Previous studies have established a clear correlation between different doses and placements of the 6-OHDA toxin and the degree of neurodegenerative changes and behavioral impairments. In the present study, the influence of the interdependence between the two nigrostriatal systems in both hemispheres on the effects on sensorimotor behavioral performances after terminal 6-OHDA lesions was investigated. The behavioral effects were correlated to the extent of nigral dopamine neuron cell and striatal tyrosine-hydroxylase (TH)-positive fiber loss. Sprague-Dawley rats receiving unilateral intrastriatal 6-OHDA injections (4 x 5 microg) exhibited a 30-70% reduction in striatal TH-positive fiber density along an anterior-posterior gradient, an 80% loss of nigral dopamine neurons and a mild degree of behavioral impairments as revealed by amphetamine-induced rotational asymmetry, and a reduced performance in the stepping and postural balance tests. When the same amount of toxin was injected twice into both hemispheres (2 x 4 x 5 microg), additional behavioral deficits were observed, consisting of a significant, but temporary, weight loss, a stable reduction in general locomotor activity and explorational behavior, and a long-term deficit in skilled forelimb use. This is interesting in light of the morphological findings, in which uni- and bilaterally lesioned animals did not differ significantly in the extent of TH-immunoreactive fiber and dopamine neuron loss within the nigrostriatal system in each lesioned hemisphere. These results indicate that the interdependent regulation of the two nigrostriatal systems may provide some compensatory support for the function and behavioral performance of the lesioned side via the normal unlesioned side, which is lost in animals with bilateral lesions of the nigrostriatal system. Therefore, this model of uni- and bilateral partial lesions of the nigrostriatal system, as characterized in the present study, may foster further exploration of compensatory functional mechanisms active in the early stages of Parkinson's disease and promote development of novel neuroprotective and restorative strategies.
黑质纹状体多巴胺系统的部分损伤可通过纹状体内注射6-羟基多巴胺（6-OHDA）可靠地诱导产生，并且被认为类似于人类帕金森病的早期阶段。先前的研究已经明确了6-OHDA毒素的不同剂量和注射部位与神经退行性变化程度和行为损伤之间的相关性。在本研究中，研究了两个半球的黑质纹状体系统之间的相互依存关系对终末期6-OHDA损伤后感觉运动行为表现的影响。行为效应与黑质多巴胺能神经元细胞和纹状体酪氨酸羟化酶（TH）阳性纤维损失的程度相关。接受单侧纹状体内注射6-OHDA（4×5微克）的Sprague-Dawley大鼠，纹状体内TH阳性纤维密度沿前后梯度降低30%-70%，黑质多巴胺能神经元损失80%，并且如苯丙胺诱导的旋转不对称所示，出现轻度行为损伤，在踏步和姿势平衡测试中的表现降低。当相同剂量的毒素分两次注射到两个半球（2×4×5微克）时，观察到额外的行为缺陷，包括显著但短暂的体重减轻、一般运动活动和探索行为的持续减少，以及熟练前肢使用的长期缺陷。鉴于形态学研究结果来看这很有意思，在该结果中，单侧和双侧损伤的动物在每个损伤半球的黑质纹状体系统内TH免疫反应性纤维和多巴胺能神经元损失程度上没有显著差异。这些结果表明，两个黑质纹状体系统的相互依存调节可能通过正常未损伤侧为损伤侧的功能和行为表现提供一些代偿性支持，而在黑质纹状体系统双侧损伤的动物中这种支持则丧失。因此，本研究中所描述的黑质纹状体系统单侧和双侧部分损伤模型，可能有助于进一步探索帕金森病早期阶段活跃的代偿功能机制，并促进新型神经保护和恢复策略的发展。
