%0 Journal Article
%T Subthalamic hGAD65 Gene Therapy and Striatum TH Gene Transfer in a ParkinsonĄ¯s Disease Rat Model
%A Deyu Zheng
%A Xiaohua Jiang
%A Junpeng Zhao
%A Deyi Duan
%A Huanying Zhao
%A Qunyuan Xu
%J Neural Plasticity
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/263287
%X The aim of the present study is to detect a combination method to utilize gene therapy for the treatment of ParkinsonĄ¯s disease (PD). Here, a PD rat model is used for the in vivo gene therapy of a recombinant adeno-associated virus (AAV2) containing a human glutamic acid decarboxylase 65 (rAAV2-hGAD65) gene delivered to the subthalamic nucleus (STN). This is combined with the ex vivo gene delivery of tyrosine hydroxylase (TH) by fibroblasts injected into the striatum. After the treatment, the rotation behavior was improved with the greatest efficacy in the combination group. The results of immunohistochemistry showed that hGAD65 gene delivery by AAV2 successfully led to phenotypic changes of neurons in STN. And the levels of glutamic acid and GABA in the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr) were obviously lower than the control groups. However, hGAD65 gene transfer did not effectively protect surviving dopaminergic neurons in the SNc and VTA. This study suggests that subthalamic hGAD65 gene therapy and combined with TH gene therapy can alleviate symptoms of the PD model rats, independent of the protection the DA neurons from death. 1. Introduction The hallmark feature of ParkinsonĄ¯s disease (PD) is degeneration of dopamine neurons in the substantia nigra pars compacta (SNc) and a consequent striatal dopamine deficiency [1¨C3]. Current clinic treatments for PD mainly focus on alleviating the symptoms with L-3,4-dihydroxyphenylalanine, which increases the synthesis and release of dopamine (DA), particularly during early stages of the disease [4¨C7]. As the disease progresses, however, pharmacological therapies cannot arrest or reverse neurodegeneration of dopaminergic neurons, and the effectiveness of treatment progressively decreases. Gene therapy techniques may provide an interesting alternative to the treatment of PD. Previous studies have focused on dopamine restoration in the neurotransmitter-depleted and denervated striatum [8, 9] by introducing essential enzymes for dopamine production, such as tyrosine hydroxylase (TH) [10¨C14], aromatic L-amino acid decarboxylase (AADC) [15, 16], and guanosine triphosphate (GTP) cyclohydrolase I (GTPC-I) [1, 17]. This strategy could potentially increase dopamine levels in the striatum and then improve symptoms in PD rat models. Actually, the dopamine deficiency in PD leads to a cascade of functional changes in basal ganglia circuitry [2, 3]. The essential pathophysiological characteristic of the PD state is increased neuronal firing activity in the output nuclei of
%U http://www.hindawi.com/journals/np/2013/263287/