NEUROTROPHIC AND NEUROPROTECTIVE EFFICACY OF INTRANASAL GDNF IN A RAT MODEL OF PARKINSON'S DISEASE
NEUROTROPHIC AND NEUROPROTECTIVE EFFICACY OF INTRANASAL GDNF IN A RAT MODEL OF PARKINSON'S DISEASE
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DOI：
10.1016/j.neuroscience.2014.05.019
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发表时间：
2014-08-22
期刊：
影响因子：
3.3
通讯作者：
Waszczak, B. L.
中科院分区：
文献类型：
--
作者：
Migliore, M. M.;Ortiz, R.;Waszczak, B. L.
胶质细胞源性神经营养因子（GDNF）对黑质（SN）多巴胺神经元具有神经营养和神经保护作用，对帕金森病（PD）具有巨大的治疗潜力。阻碍这种潜力的是GDNF不能穿过血脑屏障的事实。本研究的目的是评估通过鼻内途径给予GDNF在正常大鼠和单侧6-羟基多巴胺（6-OHDA）PD模型中的作用。在第一项研究中，大鼠接受单次鼻内剂量的磷酸盐缓冲盐水（PBS）或阳离子脂质体中的50 μ g GDNF，但没有6-OHDA。在第二项研究中，在注射6-OHDA前1小时，对大鼠鼻内给予10、50或150 μ g溶于PBS或阳离子脂质体中的GDNF。3-4周后处死所有组。两种鼻内GDNF治疗均诱导SN中的神经营养作用，因为酪氨酸羟化酶（TH）阳性神经元的数量显著高于给予鼻内PBS脂质体的对照组。与给予PBS脂质体的对照组相比，6-OHDA损伤大鼠的完整SN中的多巴胺细胞计数也更高。最重要的是，鼻内GDNF提供了显著的神经保护功效，这通过与给予PBS脂质体的损伤大鼠相比，给予单次50 μ g剂量的GDNF的PBS溶液或150 μ g剂量的脂质体GDNF的大鼠的损伤相对于完整SN中更大的TH免疫染色密度来指示。每日间隔（6-OHDA给药前1天、给药前1小时和给药后1天）给予3次50 μ g剂量，其保护作用甚至比单次150 μ g剂量更强。因此，短时间间隔多次给药可能比单次推注给药提供更大的神经保护作用。这些结果证明了鼻内GDNF在完整SN中的神经营养作用以及在单侧6-OHDA模型中的神经保护功效，支持追求这种方法作为PD的潜在治疗。(C)2014年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Glial cell line-derived neurotrophic factor (GDNF) exerts neurotrophic and neuroprotective effects on substantia nigra (SN) dopamine neurons and has great therapeutic potential for Parkinson's disease (PD). Hindering this potential is the fact that GDNF cannot cross the blood-brain barrier. The aim of this study was to assess the effects of GDNF administered by the intranasal route in normal rats, and in the unilateral 6-hydroxydopamine (6-OHDA) model of PD. In the first study, rats received single intranasal doses of 50-mu g GDNF in phosphate-buffered saline (PBS) or cationic liposomes, but no 6-OHDA. In the second study, rats were nasally administered 10, 50 or 150 mu g of GDNF in PBS or cationic liposomes 1 h before injection of 6-OHDA. All groups were sacrificed 3-4 weeks later. Both intranasal GDNF treatments induced a neurotrophic effect in the SN insofar as the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher than in controls given intranasal PBS liposomes. Dopamine cell counts were also higher in the intact SN of 6-OHDA-lesioned rats compared to controls given PBS liposomes. Most importantly, intranasal GDNF provided significant neuroprotective efficacy indicated by greater TH immunostaining density in the lesioned versus intact SN of rats given single 50-mu g doses of GDNF in PBS, or 150-mu g doses of liposomal GDNF, compared to lesioned rats given PBS liposomes. Three 50-mu g doses given at daily intervals (1 day before, 1 h before, and 1 day after 6-OHDA) provided even greater protection than single 150-mu g doses. Multiple doses at short intervals may therefore provide greater neuroprotection than single bolus doses. These results demonstrate both a neurotrophic effect of intranasal GDNF in the intact SN as well as neuroprotective efficacy in the unilateral 6-OHDA model, supporting pursuit of this approach as a potential treatment for PD. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.