Obeso J A, Rodriguez-Oroz M, Marin C, Alonso F, Zamarbide I, Lanciego J L, Rodriguez-Diaz M
Department of Neurology and Neurosurgery, Neuroscience Center, FIMA, Clinica Universitaria and Medical School, University of Navarra, Pamplona, Spain.
Neurology. 2004 Jan 13;62(1 Suppl 1):S17-30. doi: 10.1212/wnl.62.1_suppl_1.s17.
The severity of dopamine depletion and the consequent pathophysiologic changes that occur in basal ganglia circuits determine the severity of parkinsonian signs. Restoring the dopamine deficit or the downstream physiologic abnormalities improves Parkinson's Disease (PD) main motor features and as a result, attenuates the short-duration response (SDR). Therefore, both the magnitude and duration of the motor response are a function of the degree of motor severity, which is primarily governed by the loss of tonic dopaminergic activity and disruption of basal ganglia homeostatic mechanisms among which the STN-GPe/GPi circuits play a fundamental role. As neurodegeneration advances, standard levodopa administration give rises to wider oscillations in striatal dopamine availability and "pulsatile" stimulation of striatal dopamine receptors becomes predominant. This induces molecular and physiologic changes that further accentuate and aggravate the SDR that sustains motor fluctuations. Treatments capable of providing and restoring more tonic and physiologic dopaminergic stimulation may avoid many of these abnormalities and lead to better clinical outcomes.
多巴胺耗竭的严重程度以及基底神经节回路中随之发生的病理生理变化决定了帕金森氏症体征的严重程度。恢复多巴胺缺乏或下游生理异常可改善帕金森病（PD）的主要运动特征，从而减弱短程反应（SDR）。因此，运动反应的幅度和持续时间都是运动严重程度的函数，而运动严重程度主要由紧张性多巴胺能活动的丧失以及基底神经节稳态机制的破坏所决定，其中丘脑底核-苍白球外部/苍白球内部（STN-GPe/GPi）回路起着根本性作用。随着神经退行性变的进展，标准左旋多巴给药会导致纹状体多巴胺可用性出现更大的波动，对纹状体多巴胺受体的“脉冲式”刺激变得更为突出。这会引发分子和生理变化，进一步加剧并恶化维持运动波动的短程反应。能够提供并恢复更具持续性和生理性多巴胺能刺激的治疗方法或许可以避免许多此类异常情况，并带来更好的临床结果。
