Glial cell line-derived neurotrophic factor: Distribution and pharmacology in the rat following a bolus intraventricular injection
Glial cell line-derived neurotrophic factor: Distribution and pharmacology in the rat following a bolus intraventricular injection
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DOI：
10.1016/s0006-8993(96)01265-6
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发表时间：
1997-01-30
期刊：
影响因子：
2.9
通讯作者：
Miller, PJ
中科院分区：
文献类型：
--
作者：
Lapchak, PA;Jiao, SS;Miller, PJ
神经胶质细胞系来源的神经营养因子（GDNF）已被证明在体外和体内增加多巴胺能参数，并可以减少帕金森病动物模型中的帕金森行为。本研究通过检查单次脑室内注射的分布和神经化学后果，确定了侧脑室作为GDNF给药途径的潜力。放射自显像分析显示，在注射后1和24小时，脑室内给予的[I-125]GDNF分布在整个心室系统。大脑皮层、中隔、对角带、皮层、纹状体、海马、下丘脑、黑质/腹侧被盖区和小脑也被标记。第7天，脑室系统、下丘脑、黑质和小脑仍有标记。在胃内注射[I-125]GDNF 24小时后，在黑质/腹侧被盖区观察到标签，显示逆行运输。同时观察了GDNF （0.1 ~ 100 μ g）在注射后7天的神经化学作用。GDNF显著增加纹状体多巴胺（约28%）和黑质多巴胺（高达40%），并调节多巴胺代谢物同质香草酸和二羟基苯乙酸。额叶皮层的多巴胺水平没有变化。下丘脑多巴胺含量显著增加（高达35%），这一增加可能有助于抑制GDNF给药后的体重增加。此外，在分析的大脑区域中，多巴胺周转量减少或保持不变，这可能表明在未受损的大鼠中，脑室内给予GDNF刺激多巴胺的合成和储存。本研究表明，脑室内注射GDNF可以进入基底神经节结构，尤其是中脑多巴胺细胞体区域，并且在单次给药后至少7天内仍存在于该区域。GDNF在包括黑质纹状体通路在内的多种脑结构中以不同的方式增加多巴胺能张力。这些数据支持脑室内给药GDNF治疗帕金森病的潜在有效性。
Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase dopaminergic parameters in vitro and in vivo and can reduce parkinsonian behaviors in animal models of the disease. This study determined the potential of the lateral ventricle as an administration route for GDNF by examining the distribution and neurochemical consequences of a single intraventricular injection. Autoradiographic analysis showed that intraventricularly administered [I-125]GDNF was distributed throughout the ventricular system at 1 and 24 h following injection. The cerebral cortex, septum, diagonal band, fimbria, striatum, hippocampus, hypothalamus, substantia nigra/ventral tegmental area, and cerebellum were also labeled. At 7 days, there was still labeling throughout the ventricular system, hypothalamus, substantia nigra, and cerebellum. Twenty-four hours following an intrastriatal injection of [I-125]GDNF, label was observed in the substantia nigra/ventral tegmental area, demonstrating retrograde transport. The neurochemical effects of intraventricularly administered GDNF (0.1-100 mu g) at 7 days post injection were also examined. GDNF significantly increased striatal (approximately 28%) and nigral (up to 40%) dopamine, as well as regulated the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid. Dopamine levels were unchanged in the frontal cortex. Dopamine content was significantly increased in the hypothalamus (up to 35%), an increase which may contribute to the inhibition of weight gain seen after administration of GDNF. Additionally, dopamine turnover was decreased or unchanged across the brain regions analyzed, which may indicate that in unlesioned rats, intraventricularly administered GDNF stimulates the synthesis and storage of dopamine. This study shows that intraventricularly injected GDNF can access basal ganglia structures, most notably the midbrain dopamine cell body region, and remains present in this area for at least 7 days following a single administration. GDNF differentially increases dopaminergic tone within a variety of brain structures, including the nigrostriatal pathway. These data support the potential effectiveness of intraventricular administered GDNF as a treatment for Parkinson's disease.