Abstract：
Parkinson\'s Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses, patients display disruptions in gait such as changes in posture, bradykinesia, and shortened stride. DA replacement via L-DOPA alleviates many PD symptoms, though its effects on gait are not well demonstrated. This study aimed to assess the relationship between DA lesion, gait, and deficit-induced reversal with L-DOPA. To do so, Sprague-Dawley rats (N = 25, 14 males, 11 females) received unilateral medial forebrain bundle (MFB) DA lesions with 6-hydroxydopamine (6-OHDA). An automated gait analysis system assessed spatiotemporal gait parameters pre- and post-lesion, and after various doses of L-DOPA (0, 3, or 6 mg/kg; s.c.). The forepaw adjusting steps (FAS) test was implemented to evaluate lesion efficacy while the abnormal involuntary movements (AIMs) scale monitored the emergence of L-DOPA-induced dyskinesia (LID). High performance liquid chromatography (HPLC) assessed changes in brain monoamines on account of lesion and treatment. Results revealed lesion-induced impairments in gait, inclusive of max-contact area and step-sequence alterations that were not reversible with L-DOPA. However, the emergence of AIMs were observed at higher doses. Post-mortem, 6-OHDA lesions induced a loss of striatal DA and norepinephrine (NE), while prefrontal cortex (PFC) displayed noticeable reduction in NE but not DA. Our findings indicate that hemiparkinsonian rats display measurable gait disturbances similar to PD patients that are not rescued by DA replacement. Furthermore, non-DA mechanisms such as attention-related NE in PFC may contribute to altered gait and may constitute a novel target for its treatment.
摘要：
帕金森病（PD）是一种神经退行性运动障碍，其特征是黑质致密质（SNc）中多巴胺（DA）细胞丢失。随着PD的进展,患者表现出步态中断，如姿势变化，运动迟缓,缩短了步幅。通过L-DOPA替代DA缓解了许多PD症状，尽管它对步态的影响没有得到很好的证明。本研究旨在评估DA病变之间的关系，步态,和L-DOPA的赤字诱导逆转。要做到这一点，Sprague-Dawley大鼠（N=25，雄性14，11名女性）接受了带有6-羟基多巴胺（6-OHDA）的单侧内侧前脑束（MFB）DA病变。自动步态分析系统评估了病变前和病变后的时空步态参数，以及在各种剂量的L-DOPA(0、3或6mg/kg;s.c.)之后。实施前爪调整步骤（FAS）测试以评估病变功效，而异常不自主运动（AIM）量表监测L-DOPA引起的运动障碍（LID）的出现。高效液相色谱（HPLC）评估了由于病变和治疗而引起的脑单胺的变化。结果显示病变引起的步态损伤，包括使用L-DOPA不可逆的最大接触面积和阶梯序列改变。然而,在较高剂量下观察到AIM的出现。验尸后,6-OHDA病变引起纹状体DA和去甲肾上腺素（NE）的损失，而前额叶皮质（PFC）显示NE明显减少，而不是DA。我们的发现表明，半帕金森病大鼠表现出可测量的步态障碍，与PD患者相似，无法通过DA替代来挽救。此外，PFC中注意力相关的NE等非DA机制可能导致步态改变,并可能成为其治疗的新靶点.
