Activation of Dopamine D3 Receptor on Nigrostriatal Dopamine Recovery and Subventricular Zone Stem/Progenitor Cell Proliferation in Parkinson Disease Animal Model

Autor: Yen Hsi Kuo, 郭妍希
Rok vydání: 2011
Druh dokumentu: 學位論文 ; thesis
Popis: 99
In the adult mammalian brain, neurogenesis occurs primarily in two regions, the dentate gyrus (DG) of the hippocampus and subventricular zone (SVZ) nearby the lateral ventricle. Neurogenesis can be regulated by variety stimulus, such as hormones, neurotransmmiters, environmental factor, growth factor, exercise and/or ages. SVZ has three different types neural progenitor cell,of each has different biological properties in the process of the SVZ neurogenesis. Dopamine D3 receptors are abundantly expressed during early brain development and also expressed heavily in the neural progenitor/stem cells (NPCs) of SVZ in the adulthood. Considering cell-based therapy in PD represents an effective way to replace the loss of dopaminergic neurons, the development of non-invasive cell regeneration program can avoid the side effects due to treatment of traditional L-dopa-based pharmacotherapy. Hence, in this study, we assess if dopamine D3 receptor could offer protection on presynaptic dopamine neuron and stimulate neurogenesis of SVZ in MPTP-treated PD animal model. Via immunohistochemistry and immunofluorescence detection, we first observed that treatment of D3 receptor agonist 7-OH-DPAT recovered MPTP-reduced tyrosine hydroxylase immunoreactivity in both substantia nigra and striatum of wild-type, but not in D3 receptor knockout B6 mice. Secondly, by using immunofluorescence detection, it was found that after MPTP-induce lesion, the neural progenitor cells of the SVZ were increased but no apparent changes observed in the D3R KO mice. The expression of GFAP+ cells was increased in the SVZ area, but the GFAP+/BrdU+ co-localized newborn type B cells were decreased in both groups after MPTP. In addition, type A cells (Dcx+ cell) were increased after MPTP treatment in both groups. After 7-OH-DPAT post-treatment, most of the type B and type A cells remained the same, except decreased BrdU+/GFAP+ cells due to MPTP insult reversed to the control level. To evaluate if change of tyrosine hydroxylase immunoreactivity and/or SVZ neurogenesis would restore the motor defect due to MPTP treatment, behavioral test of gait analysis was adopted. The results showed that post-treatment of 7-OH-DPAT and SVZ neurosphere transplantation could recover several motor index in MPTP-lesioned PD animal model. Overall, our results suggest that activation of D3 dopamine receptor could effectively promote SVZ neurogenesis, recover the immunoreactivity of tyrosine hydroxylase in nigrostriatal pathway and restore the motor functions in MPTP-lesioned PD animal.
Databáze: Networked Digital Library of Theses & Dissertations
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