UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Neuropeptides. 2012 Oct;46(5):183-93. doi: 10.1016/j.npep.2012.07.004. Epub 2012 Aug 22.
Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal pathway; however, post-mortem studies have demonstrated that other brain regions such as the locus coeruleus (LC) and raphe nuclei (RN) are significantly affected as well. Degeneration of these crucial neuronal cell bodies may be responsible for depressive behavior and cognitive decline present in the pre-motor stage of PD. We have thus set out to create a pre-motor rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were utilized concomitantly with bilateral 6-hydroxydopamine (6-OHDA) injections into the striatum to produce a pre-motor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Our model exhibited a depressive/anhedonic condition as assessed using sucrose preference testing and the forced swim test. Our model also demonstrated deficits in object memory. These behavioral impairments were accompanied by a decline in both tissue and extracellular levels of all three neurotransmitters in both the frontal cortex and striatum. Immunohistochemistry also revealed a decrease in TH+ cells in the LC and substantia nigra. Exendin-4 (EX-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, promoted recovery of both the biochemical and behavioral dysfunction exhibited by our model. EX-4 was able to preserve the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain pre-motor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD.
帕金森病（PD）的研究主要集中在黑质纹状体通路多巴胺能神经元的变性上；然而，尸检研究表明，蓝斑核（LC）和中缝核（RN）等其他脑区也受到了显著影响。这些关键神经元细胞体的退化可能是 PD 运动前期出现抑郁行为和认知能力下降的原因。因此，我们着手建立一种模拟 PD 早期阶段的运动前期啮齿动物模型。N-（2-氯乙基）-N-乙基-2-溴苯甲胺（DSP-4），一种选择性去甲肾上腺素能神经毒素，和对氯苯丙胺（pCA），一种选择性 5-羟色胺能神经毒素，与双侧 6-羟多巴胺（6-OHDA）注射到纹状体一起使用，产生多巴胺能、去甲肾上腺素能和 5-羟色胺能系统部分缺陷的运动前期 PD 啮齿动物模型。我们的模型在蔗糖偏好测试和强迫游泳测试中表现出抑郁/快感缺失状态。我们的模型也表现出物体记忆缺陷。这些行为损伤伴随着前额叶皮层和纹状体中三种神经递质的组织和细胞外水平都下降。免疫组织化学还显示 LC 和黑质中 TH+细胞减少。Exendin-4（EX-4），一种胰高血糖素样肽-1 受体（GLP-1R）激动剂，促进了我们模型表现出的生化和行为功能障碍的恢复。EX-4 能够保持多巴胺能、去甲肾上腺素能和 5-羟色胺能系统的功能完整性。总之，我们已经建立了一种新的 PD 动物模型，它再现了某些运动前期的症状。这些症状和致病生理学在 EX-4 治疗后得到改善，因此它可以作为 PD 早期非运动症状的潜在治疗方法。
