Rodriguez M C, Obeso J A, Olanow C W
Department of Neurology and Neurosurgery, HOSPITEN, Medical School, Universidad de La Laguna, Tenerife, Spain.
Ann Neurol. 1998 Sep;44(3 Suppl 1):S175-88. doi: 10.1002/ana.410440726.
Dopamine deficiency causes disinhibition and overactivity of the subthalamic nucleus (STN). Output neurons from the STN are excitatory and use glutamate as a neurotransmitter. They project to the external and internal segments of the globus pallidum (GPe and GPi), the substantia nigra pars reticulata (SNr), and the pedunculopontine nucleus (PPN). In addition, STN neurons provide excitatory innervation to dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that contain glutamate receptors. Stimulation of the STN induces bursting activity in SNc dopaminergic neurons. This raises the possibility that the disinhibition of STN neurons that occurs as a result of a dopamine lesion might induce excitotoxic damage in target structures, including the SNc. In addition, the reduction in complex I activity found in the nigra in Parkinson's disease (PD) may cause mitochondrial dysfunction and make SNc dopaminergic neurons vulnerable to even physiologic concentrations of glutamate. We postulate that the dopamine loss that occurs in PD produces augmented STN activity which, in turn, causes further damage to vulnerable dopaminergic neurons, thereby creating a scenario for an increasing cycle of neuronal loss in the SNc. In addition, STN overactivity could, in theory, cause damage to the GPi, SNr, and PPN and thereby account for the development of parkinsonian features that do not respond to levodopa in patients with advanced disease. This hypothesis suggests that pharmacologic or surgical therapies that reduce STN neuronal overactivity or block glutamate receptors in the SNc and other target structures might be neuroprotective and might slow or halt the progression of neurodegeneration in PD.
多巴胺缺乏会导致丘脑底核（STN）的去抑制和过度活跃。STN的输出神经元是兴奋性的，使用谷氨酸作为神经递质。它们投射到苍白球的外部和内部节段（GPe和GPi）、黑质网状部（SNr）和脚桥核（PPN）。此外，STN神经元为黑质致密部（SNc）中含有谷氨酸受体的多巴胺能（DA）神经元提供兴奋性神经支配。刺激STN会诱导SNc多巴胺能神经元产生爆发性活动。这增加了一种可能性，即由于多巴胺损伤而发生的STN神经元去抑制可能会在包括SNc在内的靶结构中诱导兴奋性毒性损伤。此外，在帕金森病（PD）中黑质中发现的复合体I活性降低可能会导致线粒体功能障碍，并使SNc多巴胺能神经元更容易受到即使是生理浓度谷氨酸的影响。我们推测，PD中发生的多巴胺缺失会导致STN活性增强，进而对易损的多巴胺能神经元造成进一步损伤，从而在SNc中形成神经元损失不断增加的循环。此外，理论上STN过度活跃可能会对GPi、SNr和PPN造成损害，从而解释晚期疾病患者中对左旋多巴无反应的帕金森特征的发展。这一假设表明，降低STN神经元过度活跃或阻断SNc和其他靶结构中谷氨酸受体的药物或手术治疗可能具有神经保护作用，并可能减缓或阻止PD中神经退行性变的进展。
