Bonuccelli Ubaldo, Del Dotto Paolo
Department of Neuroscience, University of Pisa, Italy.
Neurology. 2006 Oct 10;67(7 Suppl 2):S30-8. doi: 10.1212/wnl.67.7_suppl_2.s30.
Many of the motoric features that define Parkinson's disease (PD) result primarily from the loss of dopaminergic neurons of the substantia nigra. l-dopa remains at present the most powerful symptomatic drug for the treatment of this condition. However, motor complications of chronic l-dopa treatment have emerged as a major limitation of this therapy. Slowing or delaying the progression of the disease with neuroprotective therapies may delay the need for l-dopa. In the past few years, novel insight into the pathogenetic mechanisms of neurodegeneration in PD has been provided. Mitochondrial function deficiency, increased oxidative stress, apoptosis, excitotoxicity, and inflammation are part of the processes that ultimately result in neurodegeneration. Drugs that are now under clinical scrutiny as neuroprotectant include molecules that combine one or more of the following properties: (1) monoamine oxidase inhibition (rasagiline, safinamide); (2) mitochondrial enhancement (coenzyme Q10, creatine); (3) antiapoptotic activity; (4) anti-inflammatory activity; (5) protein aggregation inhibition; (6) neurotrophic activity. In advanced Parkinson's disease, the combination of disease progression and l-dopa therapy leads to the development of motor response complications, particularly wearing off, on off, dyskinesias and dystonias. The nonphysiologic pulsatile stimulation of striatal dopamine receptors, produced by the currently available dopaminergic drugs, may trigger a dysregulation of many neurotransmitter systems within the basal ganglia, mainly localized on medium spiny striatal neurons. These include alterations of glutamatergic, serotonergic, adrenergic and adenosine A(2A) receptors. Novel strategies for pharmacological intervention with nondopaminergic treatments hold the promise of providing effective control or reversal of motor response complications. Of particular interest are NMDA and AMPA antagonists or drugs acting on 5-HT subtype 2A, alpha2-adrenergic, and adenosine A(2) receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern of basal ganglia neurons, such as synaptic vesicle proteins, nonsynaptic gap junction communication mechanisms, or signal transduction systems that modulate the phosphorylation state of glutamatergic receptors.
许多定义帕金森病（PD）的运动特征主要源于黑质多巴胺能神经元的丧失。左旋多巴目前仍是治疗该疾病最有效的对症药物。然而，慢性左旋多巴治疗的运动并发症已成为该疗法的主要限制。用神经保护疗法减缓或延迟疾病进展可能会推迟对左旋多巴的需求。在过去几年中，人们对帕金森病神经退行性变的发病机制有了新的认识。线粒体功能缺陷、氧化应激增加、细胞凋亡、兴奋性毒性和炎症是最终导致神经退行性变的部分过程。目前作为神经保护剂正在临床研究的药物包括具有以下一种或多种特性的分子：（1）单胺氧化酶抑制作用（雷沙吉兰、沙芬酰胺）；（2）线粒体增强作用（辅酶Q10、肌酸）；（3）抗凋亡活性；（4）抗炎活性；（5）抑制蛋白质聚集；（6）神经营养活性。在晚期帕金森病中，疾病进展和左旋多巴治疗的结合会导致运动反应并发症的出现，尤其是疗效减退、开关现象、异动症和肌张力障碍。目前可用的多巴胺能药物产生的纹状体多巴胺受体非生理性脉冲刺激，可能会引发基底神经节内许多神经递质系统的失调，主要发生在中等棘状纹状体神经元上。这些包括谷氨酸能、5-羟色胺能、肾上腺素能和腺苷A(2A)受体的改变。用非多巴胺能治疗进行药理学干预的新策略有望有效控制或逆转运动反应并发症。特别值得关注的是NMDA和AMPA拮抗剂或作用于5-HT 2A亚型、α2-肾上腺素能和腺苷A(2)受体的药物。未来的策略也可能针对调节基底神经节神经元放电模式的突触前和突触后成分，如突触小泡蛋白、非突触间隙连接通讯机制或调节谷氨酸能受体磷酸化状态的信号转导系统。
