Tseng J L, Baetge E E, Zurn A D, Aebischer P
Gene Therapy Center and Division of Surgical Research, Centre Hospitalier Universitaire Vaudois, Lausanne University Medical School, 1011 Lausanne, Switzerland.
J Neurosci. 1997 Jan 1;17(1):325-33. doi: 10.1523/JNEUROSCI.17-01-00325.1997.
Parkinson's disease (PD) is characterized by the progressive loss of the substantia nigra (SN) dopaminergic neurons projecting to the striatum. Neurotrophic factors may have the potential to prevent or slow down the degenerative process occurring in PD. To that end, we examined whether low amounts of glial cell line-derived neurotrophic factor (GDNF) continuously released from polymer-encapsulated genetically engineered cells are able to prevent the loss of tyrosine hydroxylase immunoreactivity (TH-IR) in SN neurons and ameliorate the amphetamine-induced rotational asymmetry in rats that have been subjected to a unilateral medial forebrain bundle (MFB) axotomy. Baby hamster kidney (BHK) cells transfected with the cDNA for GDNF were encapsulated in a polymer fiber and implanted unilaterally at a location lateral to the MFB and rostral to the SN. ELISA assays before implantation show that the capsules release approximately 5 ng of GDNF/capsule per day. One week later, the MFB was axotomized unilaterally ipsilateral to the capsule placement. Seven days later, the animals were tested for amphetamine-induced rotational asymmetry and killed. The striatum was excised and analyzed either for catecholamine content or TH-IR, while the SN was immunostained for the presence of TH-IR. GDNF did not prevent the loss of dopamine in the striatum. However, GDNF significantly rescued TH-IR neurons in the SN pars compacta. Furthermore, GDNF also significantly reduced the number of turns per minute ipsilateral to the lesion under the influence of amphetamine. Improvement of rotational behavior in the absence of dopaminergic striatal reinnervation may reflect neuronal plasticity in the SN, as suggested by the dendritic sprouting observed in animals receiving GDNF. These results illustrate that the continuous release of low levels of GDNF close to the SN is capable of protecting the nigral dopaminergic neurons from an axotomy-induced lesion and significantly improving pharmacological rotational behavior by a mechanism other than dopaminergic striatal reinnervation.
帕金森病（PD）的特征是投射到纹状体的黑质（SN）多巴胺能神经元进行性丧失。神经营养因子可能具有预防或减缓PD中发生的退行性过程的潜力。为此，我们研究了从聚合物包裹的基因工程细胞中持续释放的少量胶质细胞源性神经营养因子（GDNF）是否能够预防SN神经元中酪氨酸羟化酶免疫反应性（TH-IR）的丧失，并改善单侧内侧前脑束（MFB）切断的大鼠中苯丙胺诱导的旋转不对称。用GDNF的cDNA转染的幼仓鼠肾（BHK）细胞被包裹在聚合物纤维中，并单侧植入到MFB外侧和SN头端的位置。植入前的ELISA分析表明，胶囊每天释放约5 ng GDNF/胶囊。一周后，在与胶囊放置同侧的一侧进行MFB切断。七天后，对动物进行苯丙胺诱导的旋转不对称测试并处死。切除纹状体并分析其儿茶酚胺含量或TH-IR，同时对SN进行TH-IR免疫染色。GDNF未能预防纹状体中多巴胺的丧失。然而，GDNF显著挽救了SN致密部中的TH-IR神经元。此外，在苯丙胺的影响下，GDNF还显著减少了损伤同侧每分钟的旋转次数。在没有多巴胺能纹状体再支配的情况下旋转行为的改善可能反映了SN中的神经元可塑性，如在接受GDNF的动物中观察到的树突发芽所表明的那样。这些结果表明，在SN附近持续释放低水平的GDNF能够保护黑质多巴胺能神经元免受切断诱导的损伤，并通过多巴胺能纹状体再支配以外的机制显著改善药理学旋转行为。
