The main pathology underlying disease symptoms in Parkinson's disease (PD) is a progressive degeneration of nigrostriatal dopamine (DA) neurons. No effective disease-modifying treatment currently exists. Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective and neuroregenerative effects and it enhances dopaminergic function in animal models of PD. These findings raise the possibility that intrastriatal administration of GDNF might be developed into a new clinical strategy for functional preservation and restoration also in PD patients. Gene therapy is a novel tool to increase local levels of GDNF. Transplantation of encapsulated, GDNF-secreting cells is one strategy for ex vivo cell-based gene delivery which has the advantage to allow for removal of the cells if untoward effects occur. Here we summarize studies with such cells in animals, and discuss the results from previous trials with GDNF in PD patients and their implications for the further development of neuroprotective/neuroregenerative therapies. Finally, we describe the different scientific and regulatory issues that need to be addressed in order to reach the clinic and start the first trial in patients.
"According to the scientific literature, and fueled by the positive results obtained in a previous study published by our group,7 we decided to continue with the application of NTFs in future works, and, in particular, with the promising combination of glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF). GDNF is a potent factor that is able to act in vitro and in vivo, promoting the survival and differentiation of dopaminergic neurons and protecting these cells from dopaminergic toxins.8–12 Several clinical trials have been conducted to analyze the potential of GDNF in PD patients; however, in all these studies, intracerebroventricularly or intraputaminally administered GDNF solution presented numerous negative side effects and no significant clinical improvements.13–15 "
[Show abstract][Hide abstract] ABSTRACT: Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson's disease.
International Journal of Nanomedicine 05/2014; 9 Suppl 1(1):2677-87. DOI:10.2147/IJN.S61940 · 4.38 Impact Factor
"As it has been recognized that the efficacy of transplanted cells is almost mediated by soluble factors, cell encapsulation should preserve the biological activity of transplanted stem cells. Also, with regard to clinical translation, cell encapsulation adds another important safety feature, i.e. the retrievability of the implant in case of adverse effects . Finally, again improving the application's clinical safety, cell encapsulation allows for the usage of highly standardized and well-characterized bankable allogeneic cell lines  . "
[Show abstract][Hide abstract] ABSTRACT: According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation.
Fluids and Barriers of the CNS 05/2014; 11(1):10. DOI:10.1186/2045-8118-11-10
"Studies on dopamine regulation have shown that PC12 cells, a rat pheochromocytoma cell line, synthesize, release, and reuptake dopamine in a manner similar to that of dopaminergic neurons , . Compared to brain neuron cultures or tissue slices, PC12 cell culture consists of a homogeneous dopamine-containing population, which had been widely used in dopaminergic cell investigations, including those on cell differentiation, neural protection, drug screening, and cell implantation therapies , , , , , , , . Conventional approaches for regulating dopamine release in PC12 cells are pharmaceutical or electrical stimulation (ES) techniques, which have critical limitation on controlling dopamine release. "
[Show abstract][Hide abstract] ABSTRACT: Dopaminergic PC12 cells can synthesize and release dopamine, providing a good cellular model for investigating dopamine regulation. Optogenetic stimulation of channelrhodopsin-2 provides high spatial and temporal precision for selective stimulation as a powerful neuromodulation tool for neuroscience studies. The aim of this study is to measure dopamine release from dopaminergic PC12 cells under optogenetic stimulation using electrochemical recording of self-assembled monolayers modified microelectrode with amperometric measurement in real time. The activation of PC12 cells under various optogenetic stimulation schemes are characterized by measuring single-cell Ca(2+) imaging. After 10 seconds of optogenetic stimulation, the evoked intracellular Ca(2+) level and dopamine current of channelrhodopsin-2-transfected PC12 cells were 1.6- and 3.5-fold higher than those of the control cells. The optogenetic stimulation effects on Ca(2+) influx and dopamine release were 81% and 63% inhibition by using a Ca(2+) channel antagonist Nifedipine. The results indicate that optogenetic stimulation can evoke voltage-gated Ca(2+) channel-dependent dopamine exocytosis from PC12 cells in a cell specific, temporally precise and dose-dependent manner. This proposed dopamine recording system can be developed to be a good cell model for dopamine regulation and drug screening in vitro, or dopaminergic cell implantation therapy in vivo using optogenetic stimulation in a precise and convenient way.
PLoS ONE 02/2014; 9(2):e89293. DOI:10.1371/journal.pone.0089293 · 3.23 Impact Factor
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