Differential neuroprotective and anti-inflammatory effects of L-type voltage dependent calcium channel and ryanodine receptor antagonists in the substantia nigra and locus coeruleus.
Differential neuroprotective and anti-inflammatory effects of L-type voltage dependent calcium channel and ryanodine receptor antagonists in the substantia nigra and locus coeruleus.
复制标题
DOI：
10.1007/s11481-014-9568-7
复制
发表时间：
2015-03
影响因子：
6.2
通讯作者：
Wenk, Gary L.
中科院分区：
文献类型：
--
作者：
Hopp, Sarah C.;Royer, Sarah E.;D'Angelo, Heather M.;Kaercher, Roxanne M.;Fisher, David A.;Wenk, Gary L.
神经炎症和儿茶酚胺能脑干核变性发生在阿尔茨海默病和帕金森病等神经退行性疾病的早期。神经炎症会增加促炎细胞因子和活性氧的水平，从而通过 L 型电压依赖性钙通道 (L-VDCC) 和兰尼碱受体 (RyR) 改变神经元钙 (Ca+2) 稳态。 SN 和 LC 中 Ca+2 通道活动的改变可能会导致这些区域正常起搏活动的破坏，从而导致行为缺陷。在这里，我们利用了慢性神经炎症的体内模型：向大鼠脑室内连续注入小剂量（0.25 µg/小时）脂多糖（LPS）或人工脑脊液（aCSF）28天。用 L-VDCC 拮抗剂尼莫地平或 RyR 拮抗剂丹曲林治疗大鼠。注入LPS的大鼠在加速旋转任务中具有显着的运动缺陷，并且在强迫游泳任务和开放场地中具有异常行为激动。与这些行为缺陷相对应的是，注射 LPS 的大鼠黑质致密部 (SNpc) 和蓝斑 (LC) 中的小胶质细胞活化也显着增加，酪氨酸羟化酶 (TH) 免疫反应性丧失。尼莫地平或丹曲林治疗使 LPS 诱导的转棒和强迫游泳异常正常化，恢复了 LC 中 TH 免疫反应细胞的数量，并显着减少了 SNpc 中的小胶质细胞活化。只有尼莫地平显着降低了 LC 中的小胶质细胞活化，并且两种药物都没有增加 SNpc 中的 TH 免疫反应性。这些发现表明，慢性神经炎症会不同程度地改变 LC 和 SN 脑干核中的 Ca+2 失调。总体而言，针对 Ca+2 失调可能是改善 SNpc 和 LC 神经变性的重要目标。
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/hr) 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.
登录
查看更多内容
DOI：
10.1093/jnen/61.5.413
发表时间：
2002-05-01
影响因子：
3.2
作者：
Del Tredici, K;Rüb, U;Braak, H
通讯作者：
Braak, H
DOI：
10.1111/j.1532-5415.1996.tb02942.x
发表时间：
1996-09-01
影响因子：
6.3
作者：
Jost, BC;Grossberg, GT
通讯作者：
Grossberg, GT
影响因子：
64.8
作者：
Chavis, P;Fagni, L;Bockaert, J
通讯作者：
Bockaert, J
影响因子：
4.1
作者：
Iannaccone, S.;Cerami, C.;Perani, D.
通讯作者：
Perani, D.
影响因子：
16.6
作者：
Cebrian, Carolina;Zucca, Fabio A.;Mauri, Pierluigi;Steinbeck, Julius A.;Studer, Lorenz;Scherzer, Clemens R.;Kanter, Ellen;Budhu, Sadna;Mandelbaum, Jonathan;Vonsattel, Jean P.;Zecca, Luigi;Loike, John D.;Sulzer, David
通讯作者：
Sulzer, David