Trophic factors therapy in Parkinson's disease

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
Progress in brain research (Impact Factor: 2.83). 02/2009; 175:201-16. DOI: 10.1016/S0079-6123(09)17514-3
Source: PubMed

ABSTRACT Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.

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    • "However, several problems have risen from the use of GDNF in the treatment of PD, namely difficulties related to the delivery of GDNF directly into the appropriate central nervous system structures (reviewed by [10] [23]). "
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    ABSTRACT: Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective molecule for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson’s disease. We have previously shown that H2O2- or L-3,4-dihydroxyphenylalanine (L-DOPA)-challenged dopaminergic neurons trigger the release of soluble factors that signal ventral midbrain astrocytes to increase GDNF expression. In the present work, we evaluated whether the factors released by ventral midbrain-challenged cells were able to alter GDNF expression in striatal cells, the targets of dopaminergic neurons projecting from the substantia nigra, and investigated the signalling pathways involved. Our data showed that soluble mediators released upon H2O2- or L-DOPA-induced dopaminergic injury up-regulated GDNF in striatal cells, with different temporal patterns depending on the oxidative agent used. Conditioned media from H2O2- or L-DOPA-challenged midbrain astrocyte cultures failed to up-regulate GDNF in striatal cultures. Likewise, there was no direct effect of H2O2 or L-DOPA on striatal GDNF levels suggesting that GDNF up-regulation was mediated by soluble factors released in the presence of failing dopaminergic neurons. Both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways were involved in striatal GDNF up-regulation triggered by H2O2-induced dopaminergic injury, while diffusible factors released in the presence of L-DOPA-challenged dopaminergic neurons induced GDNF expression in striatal cells through the activation of the MAPK pathway. These soluble mediators may constitute, in the future, important targets for the control of endogenous GDNF expression enabling the development of new and, hopefully, more efficient neuroprotective/neurorestorative strategies for the treatment of Parkinson’s disease.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 07/2014; 1842(7). DOI:10.1016/j.bbadis.2014.03.003 · 4.88 Impact Factor
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    • "In fact, most of the established biocompatible medical polymers can be processed into thin walled tubular scaffolds using the phase inversion technique, offering a wide range of options regarding the scaffold properties and functions. When a biodegradable scaffold is used in vivo, it may conveniently allow for the controlled release of trophic factors that may provide additional protection and stimulation of the implanted neural circuit's growth, as well as preventing further neural degeneration of the host brain [33–37]. It may also serve as a source for factors that stimulate the growth of the neurons in the in vitro cultivation phase. "
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    ABSTRACT: Implanting pieces of tissue or scaffolding material into the mammalian central nervous system (CNS) is wrought with difficulties surrounding the size of tools needed to conduct such implants and the ability to maintain the orientation and integrity of the constructs during and after their transplantation. Here, novel technology has been developed that allows for the implantation of neural constructs or intact pieces of neural tissue into the CNS with low trauma. By "laying out" (instead of forcibly expelling) the implantable material from a thin walled glass capillary, this technology has the potential to enhance neural transplantation procedures by reducing trauma to the host brain during implantation and allowing for the implantation of engineered/dissected tissues or constructs in such a way that their orientation and integrity are maintained in the host. Such technology may be useful for treating various CNS disorders which require the reestablishment of point-to-point contacts (e.g., Parkinson's disease) across the adult CNS, an environment which is not normally permissive to axonal growth.
    01/2014; 2014:651236. DOI:10.1155/2014/651236
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    • "Glial cell line–derived neurotrophic factor (GDNF) has been considered the most promising neurotrophic factor, showing positive effects in several animal models of PD (Hoffer et al. 1994; Kearns and Gash 1995; Tomac et al. 1995a; Gash et al. 1996; Zhang et al. 1997; Kirik et al. 2004), but not in the a-synuclein model of PD (Decressac et al. 2011). Controversial results from clinical trials with GDNF (Gill et al. 2003; Nutt et al. 2003; Slevin et al. 2005; Lang et al. 2006) have pointed out the importance of effective and reliable administration techniques (discussed by Sherer et al. 2006; Ramaswamy et al. 2009). Indeed, more emphasis should be paid on the delivery methods, as intracranial infusion has been associated with large variability in the diffusion of the protein (Sherer et al. 2006). "
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    ABSTRACT: Cerebral dopamine neurotrophic factor (CDNF) protein has been shown to protect the nigrostriatal dopaminergic pathway when given as intrastriatal infusions in rat and mouse models of Parkinson's disease (PD). In this study, we assessed the neuroprotective effect of CDNF delivered with a recombinant adeno-associated viral (AAV) serotype 2 vector in a rat 6-hydroxydopamine (6-OHDA) model of PD. AAV2 vectors encoding CDNF, glial cell line-derived neurotrophic factor (GDNF), or green fluorescent protein were injected into the rat striatum. Protein expression analysis showed that our AAV2 vector efficiently delivered the neurotrophic factor genes into the brain and gave rise to a long-lasting expression of the proteins. Two weeks after AAV2 vector injection, 6-OHDA was injected into the rat striatum, creating a progressive degeneration of the nigrostriatal dopaminergic system. Treatment with AAV2-CDNF resulted in a marked decrease in amphetamine-induced ipsilateral rotations while it provided only partial protection of tyrosine hydroxylase (TH)-immunoreactive cells in the rat substantia nigra pars compacta and TH-reactive fibers in the striatum. Results from this study provide additional evidence that CDNF can be considered a potential treatment of Parkinson's disease.
    Brain and Behavior 03/2013; 3(2):75-88. DOI:10.1002/brb3.117 · 2.24 Impact Factor
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