Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease
Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease
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DOI：
10.1006/exnr.2001.7825
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Shults, CW
中科院分区：
文献类型：
--
作者：
Tsuboi, K;Shults, CW
Sonic hedgehog（Shh）是hedgehog（hh）信号分子家族的一员，在中枢神经系统发育过程中，对中枢神经系统的正常轴向构型和细胞分化是必需的。Shh还促进胎儿多巴胺能神经元的存活，并保护胎儿中脑多巴胺能神经元的培养物免受N-甲基-4-苯基吡啶（MPP+）的毒性作用，MPP+是一种选择性损伤黑质多巴胺能神经元的神经毒素。Shh及其假定的受体在成年脑中的mRNA表达表明，除了在胚胎发育过程中的作用外，Shh在成熟神经系统中也具有重要作用。在这项研究中，我们研究了行为和解剖学的影响，纹状体内注射的单一肉豆蔻酰化野生型人类音速刺猬N-末端片段（Shh-M）在帕金森病（PD）的大鼠模型。在第1、3、5和S天，5组大鼠接受一系列的4次纹状体内注射Shh-M（每次注射180 ng、540 ng或4.275 μ g）、胶质细胞源性神经营养因子（GDNF）（1 μ g/注射）或溶媒。在第4天，动物接受15 μ g 6-羟基多巴胺（6-OHDA）游离碱的纹状体内注射。在单次纹状体内注射6-OHDA之前和之后两次纹状体内注射Shh（180 ng/注射）减少了阿扑吗啡和苯丙胺诱导的旋转和前肢运动不能，并部分保留了纹状体中的多巴胺能轴突。这是Shh减少纹状体内6-OHDA损伤诱导的行为缺陷的首次体内证明，并表明Shh可能用于治疗影响黑质纹状体系统的疾病，如PD。(C)2002年，Elsevier Science。
Sonic hedgehog (Shh), a member of hedgehog (hh) family of signaling molecules, is necessary for normal axial patterning and cellular differentiation in the developing central nervous system. Shh also promotes the survival of fetal dopaminergic neurons and protects cultures of fetal midbrain dopaminergic neurons from the toxic effects of N-methyl-4-phenylpyridinium (MPP+), a neurotoxin that selectively injures nigral dopaminergic neurons. The mRNA expression of Shh and its putative receptor in the adult brain indicates an important role of Shh in the mature nervous system in addition to its roles during embryogenesis. In this study we examined the behavioral and anatomical effects of intrastriatal injection of singly myristoylated wild-type human Sonic hedgehog N-terminal fragment (Shh-M) in a rat model of Parkinson's disease (PD). Five groups of rats received a series of four intrastriatal injections of Shh-M (180 ng, 540 ng, or 4.275 mug per injection), glial cell line-derived neurotrophic factor (GDNF) (1 mug/injection), or vehicle on days 1, 3, 5, and S. On day 4, the animals received an intrastriatal injection of 15 [mug 6-hydroxydopamine (6-OHDA) free base. Intrastriatal administration of Shh (180 ng/injection) twice before and after a single intrastriatal injection of 6-OHDA reduced apomorphine- and amphetamine-induced rotation and forelimb akinesia and partially preserved dopaminergic axons in the striatum. This is the first demonstration in vivo that Shh reduces behavioral deficits induced by intrastriatal 6-OHDA lesion and suggests that Shh may be useful in the treatment of disorders that affect the nigrostriatal system, such as PD. (C) 2002 Elsevier Science.