Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Department of Neurology, Scania University Hospital, 22185 Lund, Sweden.
Neurobiol Dis. 2016 Oct;94:95-105. doi: 10.1016/j.nbd.2016.06.002. Epub 2016 Jun 7.
Parkinson's disease (PD) is a neurodegenerative disease where the degeneration of the nigrostriatal pathway leads to specific motor deficits. There is an unmet medical need for regenerative treatments that stop or reverse disease progression. Several growth factors have been investigated in clinical trials to restore the dopaminergic nigrostriatal pathway damaged in PD. Platelet-derived growth factor-BB (PDGF-BB), a molecule that recruits pericytes to stabilize microvessels, was recently investigated in a phase-1 clinical trial, showing a dose-dependent increase in dopamine transporter binding in the putamen of PD patients. Interestingly, evidence is accumulating that PD is paralleled by microvascular changes, however, whether PDGF-BB modifies pericytes in PD is not known. Using a pericyte reporter mouse strain, we investigate the functional and restorative effect of PDGF-BB in a partial 6-hydroxydopamine medial forebrain bundle lesion mouse model of PD, and whether this restorative effect is accompanied by changes in pericyte features. We demonstrate that a 2-week treatment with PDGF-BB leads to behavioural recovery using several behavioural tests, and partially restores the nigrostriatal pathway. Interestingly, we find that pericytes are activated in the striatum of PD lesioned mice and that these changes are reversed by PDGF-BB treatment. The modulation of brain pericytes may contribute to the PDGF-BB-induced neurorestorative effects, PDGF-BB allowing for vascular stabilization in PD. Pericytes might be a new cell target of interest for future regenerative therapies.
帕金森病（PD）是一种神经退行性疾病，黑质纹状体通路的退化导致特定的运动缺陷。目前，人们迫切需要开发再生疗法来阻止或逆转疾病进展。已经有几种生长因子在临床试验中被用于恢复 PD 中受损的多巴胺能黑质纹状体通路。血小板衍生生长因子-BB（PDGF-BB）是一种募集周细胞以稳定微血管的分子，最近在一项 1 期临床试验中进行了研究，结果显示 PD 患者壳核中的多巴胺转运体结合呈剂量依赖性增加。有趣的是，越来越多的证据表明 PD 伴随着微血管变化，然而，PDGF-BB 是否会改变 PD 中的周细胞尚不清楚。使用周细胞报告小鼠品系，我们在 PD 的部分 6-羟多巴胺内侧前脑束损伤小鼠模型中研究了 PDGF-BB 的功能和恢复作用，以及这种恢复作用是否伴随着周细胞特征的变化。我们证明，PDGF-BB 治疗 2 周可通过多种行为测试导致行为恢复，并部分恢复黑质纹状体通路。有趣的是，我们发现 PD 损伤小鼠的纹状体中周细胞被激活，而 PDGF-BB 治疗可逆转这些变化。脑周细胞的调节可能有助于 PDGF-BB 诱导的神经修复作用，PDGF-BB 允许 PD 中的血管稳定。周细胞可能成为未来再生疗法的新的细胞靶点。
