Keber U, Klietz M, Carlsson T, Oertel W H, Weihe E, Schäfer M K-H, Höglinger G U, Depboylu C
Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany.
Experimental Neurology, Department of Neurology, Philipps University Marburg, Marburg, Germany; Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, Marburg, Germany.
Neuroscience. 2015 Jul 9;298:302-17. doi: 10.1016/j.neuroscience.2015.04.021. Epub 2015 Apr 16.
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the therapeutic gold standard in Parkinson's disease. However, long-term treatment is complicated by the induction of debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesias (LIDs). Until today the underlying mechanisms of LID pathogenesis are not fully understood. The aim of this study was to reveal new factors, which may be involved in the induction of LID. We have focused on the expression of striatal tyrosine hydroxylase-positive (TH+) neurons, which are capable of producing either L-DOPA or dopamine (DA) in target areas of ventral midbrain DAergic neurons. To address this issue, a daily L-DOPA dose was administered over the course of 15 days to mice with unilateral 6-hydroxydopamine-induced lesions of the medial forebrain bundle and LIDs were evaluated. Remarkably, the number of striatal TH+ neurons strongly correlated with both induction and severity of LID as well as ΔFosB expression as an established molecular marker for LID. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the decarboxylation of L-DOPA to DA. Axial, limb and orolingual dyskinesias were predominantly associated with TH+ neurons in the lateral striatum, whereas medially located TH+ neurons triggered locomotive rotations. In contrast, identified accumbal and cortical TH+ cells did not contribute to the generation of LID. Thus, striatal TH+ cells and serotonergic terminals may cooperatively synthesize DA and subsequently contribute to supraphysiological synaptic DA concentrations, an accepted cause in LID pathogenesis.
左旋3,4-二羟基苯丙氨酸（L-多巴）是帕金森病治疗的金标准。然而，长期治疗会因引发使人衰弱的异常不自主运动（称为L-多巴诱导的异动症，LIDs）而变得复杂。直到如今，LID发病机制的潜在原因仍未完全明了。本研究的目的是揭示可能参与LID诱导的新因素。我们聚焦于纹状体酪氨酸羟化酶阳性（TH+）神经元的表达，这些神经元能够在腹侧中脑多巴胺能神经元的靶区域产生L-多巴或多巴胺（DA）。为解决这个问题，对单侧6-羟基多巴胺诱导内侧前脑束损伤的小鼠连续15天给予每日L-多巴剂量，并评估LIDs情况。值得注意的是，纹状体TH+神经元的数量与LID的诱导和严重程度以及作为LID既定分子标志物的ΔFosB表达密切相关。此外，异动症小鼠纹状体中血清素能纤维支配显著增加，使得L-多巴脱羧转化为DA。轴向、肢体和口面部异动症主要与外侧纹状体中的TH+神经元相关，而位于内侧的TH+神经元引发运动性旋转。相比之下，已确定的伏隔核和皮质TH+细胞对LID的产生没有作用。因此，纹状体TH+细胞和血清素能终末可能协同合成DA，随后导致超生理水平的突触DA浓度，这是LID发病机制中一个公认的原因。
