Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats.
Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats.
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DOI：
10.3233/jpd-140410
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Tansey MG
中科院分区：
文献类型：
--
作者：
Barnum CJ;Chen X;Chung J;Chang J;Williams M;Grigoryan N;Tesi RJ;Tansey MG
帕金森病（PD）是一种复杂的多系统年龄相关性神经退行性疾病。针对PD患者中正在进行的神经炎症是一种减缓或停止疾病进展的策略。我们小组的概念验证研究表明，在黑质变性的内毒素和神经毒素大鼠模型中，通过黑质内递送显性负性TNF（DN-TNF）抑制剂选择性抑制可溶性肿瘤坏死因子（solTNF）减少神经炎症和黑质多巴胺（DA）神经元损失。作为人类临床试验的下一步，我们的目的是确定外周施用DN-TNF抑制剂XPro®1595可以在多大程度上：i）以治疗相关浓度穿过血脑屏障，ii）减弱神经炎症（小胶质细胞和星形胶质细胞），以及iii）减轻接受单侧6-羟基多巴胺（6-OHDA）纹状体损伤的大鼠中黑质DA神经元的损失。大鼠接受单侧6-OHDA（20 μg进入右侧纹状体）。损伤后3或14天，每三天给大鼠施用XPro®1595（10 mg/kg，在盐水中，皮下），持续35天。前肢不对称用于评估损伤后的运动缺陷;在损伤后35天收获脑用于分析XPro®1595水平、神经胶质活化和黑质DA神经元数目。XPro®1595的外周皮下给药实现了1-8 μg/mL的血浆水平和1-6 ng/mL的CSF水平，这取决于在最终XPro®1595注射后处死大鼠的时间。无论开始日期如何，XPro®1595显著减少了SNpc中的小胶质细胞和星形胶质细胞数量，而当在6-OHDA损伤后3天而不是14天开始给药时，黑质DA神经元的损失减弱。我们的数据表明，全身给药XPro®1595可能在炎症是其病理学一部分的PD患者中具有疾病改善潜力。
Parkinson's disease (PD) is a complex multi-system age-related neurodegenerative disorder. Targeting the ongoing neuroinflammation in PD patients is one strategy postulated to slow down or halt disease progression. Proof-of-concept studies from our group demonstrated that selective inhibition of soluble Tumor Necrosis Factor (solTNF) by intranigral delivery of dominant negative TNF (DN-TNF) inhibitors reduced neuroinflammation and nigral dopamine (DA) neuron loss in endotoxin and neurotoxin rat models of nigral degeneration. As a next step toward human clinical trials, we aimed to determine the extent to which peripherally administered DN-TNF inhibitor XPro®1595 could: i) cross the blood-brain-barrier in therapeutically relevant concentrations, ii) attenuate neuroinflammation (microglia and astrocyte), and iii) mitigate loss of nigral DA neurons in rats receiving a unilateral 6-hydroxydopamine (6-OHDA) striatal lesion. Rats received unilateral 6-OHDA (20 μg into the right striatum). Three or 14 days after lesion, rats were dosed with XPro®1595 (10 mg/kg in saline, subcutaneous) every third day for 35 days. Forelimb asymmetry was used to assess motor deficits after the lesion; brains were harvested 35 days after the lesion for analysis of XPro®1595 levels, glial activation, and nigral DA neuron number. Peripheral subcutaneous dosing of XPro®1595 achieved plasma levels of 1–8 μg/mL and CSF levels of 1–6 ng/mL depending on the time the rats were killed after final XPro®1595 injection. Irrespective of start date, XPro®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion. Our data suggest that systemically administered XPro®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology.