Höglinger Günter U, Féger Jean, Prigent Annick, Michel Patrick P, Parain Karine, Champy Pierre, Ruberg Merle, Oertel Wolfgang H, Hirsch Etienne C
INSERM U 289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France.
J Neurochem. 2003 Feb;84(3):491-502. doi: 10.1046/j.1471-4159.2003.01533.x.
In Parkinson's disease, nigral dopaminergic neurones degenerate, whereas post-synaptic striatal target neurones are spared. In some atypical parkinsonian syndromes, both nigral and striatal neurones degenerate. Reduced activity of complex I of the mitochondrial respiratory chain has been implicated in both conditions, but it remains unclear if this affects the whole organism or only the degenerating brain structures. We therefore investigated the differential vulnerability of various brain structures to generalized complex I inhibition. Male Lewis rats infused with rotenone, a lipophilic complex I inhibitor [2.5 mg/kg/day intraveneously (i.v.) for 28 days], were compared with vehicle-infused controls. They showed reduced locomotor activity and loss of striatal dopaminergic fibres (54%), nigral dopaminergic neurones (28.5%), striatal serotoninergic fibres (34%), striatal DARPP-32-positive projection neurones (26.5%), striatal cholinergic interneurones (22.1%), cholinergic neurones in the pedunculopontine tegmental nucleus (23.7%) and noradrenergic neurones in the locus ceruleus (26.4%). Silver impregnation revealed pronounced degeneration in basal ganglia and brain stem nuclei, whereas the hippocampus, cerebellum and cerebral cortex were less affected. These data suggest that a generalized mitochondrial failure may be implicated in atypical parkinsonian syndromes but do not support the hypothesis that a generalized complex I inhibition results in the rather selective nigral lesion observed in Parkinson's disease.
在帕金森病中，黑质多巴胺能神经元发生退化，而突触后纹状体靶神经元则未受影响。在一些非典型帕金森综合征中，黑质和纹状体神经元均发生退化。线粒体呼吸链复合体I活性降低与这两种情况均有关，但尚不清楚这是影响整个机体还是仅影响发生退化的脑结构。因此，我们研究了各种脑结构对全身性复合体I抑制的不同易损性。将注入鱼藤酮（一种亲脂性复合体I抑制剂，静脉注射2.5mg/kg/天，共28天）的雄性Lewis大鼠与注入赋形剂的对照组进行比较。它们表现出运动活性降低，纹状体多巴胺能纤维损失（54%）、黑质多巴胺能神经元损失（28.5%）、纹状体5-羟色胺能纤维损失（34%）、纹状体DARPP-32阳性投射神经元损失（26.5%）、纹状体胆碱能中间神经元损失（22.1%）、脚桥被盖核中的胆碱能神经元损失（23.7%）以及蓝斑中的去甲肾上腺素能神经元损失（26.4%）。银染显示基底神经节和脑干核有明显退化，而海马、小脑和大脑皮层受影响较小。这些数据表明，全身性线粒体功能障碍可能与非典型帕金森综合征有关，但不支持全身性复合体I抑制导致帕金森病中观察到的相当选择性的黑质病变这一假说。
