Hopp Sarah C, Royer Sarah E, D'Angelo Heather M, Kaercher Roxanne M, Fisher David A, Wenk Gary L
Department of Neuroscience, Ohio State University, Columbus, OH, 43210, USA.
J Neuroimmune Pharmacol. 2015 Mar;10(1):35-44. doi: 10.1007/s11481-014-9568-7. Epub 2014 Oct 16.
Neuroinflammation and degeneration of catecholaminergic brainstem nuclei occur early in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Neuroinflammation increases levels of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal calcium (Ca(+2)) homoeostasis via L-type voltage dependent calcium channels (L-VDCCs) and ryanodine receptors (RyRs). Alterations in Ca(+2) channel activity in the SN and LC can lead to disruption of normal pacemaking activity in these areas, contributing to behavioral deficits. Here, we utilized an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose (0.25 μg/h) of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days. Rats were treated with either the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene. LPS-infused rats had significant motor deficits in the accelerating rotarod task as well as abnormal behavioral agitation in the forced swim task and open field. Corresponding with these behavioral deficits, LPS-infused rats also had significant increases in microglia activation and loss of tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra pars compacta (SNpc) and locus coeruleus (LC). Treatment with nimodipine or dantrolene normalized LPS-induced abnormalities in the rotarod and forced swim, restored the number of TH-immunoreactive cells in the LC, and significantly reduced microglia activation in the SNpc. Only nimodipine significantly reduced microglia activation in the LC, and neither drug increased TH immunoreactivity in the SNpc. These findings demonstrate that the Ca(+2) dysregulation in the LC and SN brainstem nuclei is differentially altered by chronic neuroinflammation. Overall, targeting Ca + 2 dysregulation may be an important target for ameliorating neurodegeneration in the SNpc and LC.
神经炎症和儿茶酚胺能脑干核的退化在神经退行性疾病如阿尔茨海默病和帕金森病的早期就会发生。神经炎症会增加促炎细胞因子和活性氧的水平，它们可通过L型电压依赖性钙通道（L-VDCCs）和兰尼碱受体（RyRs）改变神经元钙（Ca(+2)）稳态。黑质（SN）和蓝斑（LC）中Ca(+2)通道活性的改变可导致这些区域正常起搏活动的破坏，从而导致行为缺陷。在此，我们利用了一种慢性神经炎症的体内模型：给大鼠脑室内连续小剂量（0.25μg/h）注入脂多糖（LPS）或人工脑脊液（aCSF），持续28天。给大鼠使用L-VDCC拮抗剂尼莫地平或RyR拮抗剂丹曲林进行治疗。注入LPS的大鼠在加速转棒试验中有明显的运动缺陷，在强迫游泳试验和旷场试验中有异常的行为激动。与这些行为缺陷相对应，注入LPS的大鼠在致密部黑质（SNpc）和蓝斑（LC）中，小胶质细胞激活也显著增加，酪氨酸羟化酶（TH）免疫反应性丧失。用尼莫地平或丹曲林治疗可使LPS诱导的转棒试验和强迫游泳试验中的异常恢复正常，恢复LC中TH免疫反应性细胞的数量，并显著降低SNpc中小胶质细胞的激活。只有尼莫地平显著降低了LC中小胶质细胞的激活，两种药物均未增加SNpc中TH的免疫反应性。这些发现表明，慢性神经炎症对LC和SN脑干核中Ca(+2)失调的影响存在差异。总体而言，针对Ca + 2失调可能是改善SNpc和LC中神经退行性变的一个重要靶点。
