CDNF in an experimental model of Parkinson's disease: studies on gene therapy and protein infusion
Year: 2014
Type: dissertation
Abstract: Neurodegenerative diseases are characterized by progressive loss of distinct neuronal populations. In Parkinson s disease (PD) the most prominent cell loss is seen in the dopamine (DA) neuron population in the substantia nigra pars compacta (SNpc). The resulting decrease in striatal DA levels causes dysregulation of neuronal circuits controlling movement and leads to motor symptoms typical to the disease. As for other neurodegenerative diseases, there are no available treatments that would interfere with the degenerative process in PD. The purpose of this work was therefore to test the therapeutic potential of long-term delivery of the neurotrophic factor (NTF) cerebral dopamine neurotrophic factor (CDNF) in the rat partial 6-hydroxydopamine (6-OHDA) lesion model of PD. When injected unilaterally in the striatum, 6-OHDA causes progressive dose-dependent loss of DA neurons in the SNpc accompanied by asymmetrical motor impairment. The 6-OHDA model used in our NTF studies (2x10 µg 6-OHDA) showed a stable lesion progression with a cell loss at two weeks post-lesion corresponding to that seen in PD at symptom onset. In the 6-OHDA model, the DAergic system is traditionally evaluated using immunodetection methods or measurements of tissue neurotransmitter levels. Imaging methods, such as single-photon emission computed tomography (SPECT), allows in vivo detection of neuronal circuits, and together with the DA transporter (DAT) radioligand 2β-carbomethoxy-3β-(4-[123I]iodophenyl)tropane ([123I]β-CIT), SPECT/CT provided reliable estimations of the DA cell degeneration showing high correlation to immunohistochemical findings. The method is sensitive and selective and provides substantial benefits in pre-clinical research allowing longitudinal studies in living animals. The neuroprotective effect of CDNF was studied by applying the NTF intrastriatally as two-week protein infusion with osmotic pumps, or as gene therapy with a recombinant adeno-associated viral vector in 6-OHDA-lesioned rats. Both CDNF delivery methods normalized the amphetamine-induced rotational asymmetry and provided partial protection of the tyrosine hydroxylase (TH) reactive DAergic cells in the SNpc and DA fibers in the striatum. As for GDNF, there were indications of retrograde transport of CDNF, but contrary to what has been reported for GDNF, CDNF did not affect the intact rat DAergic system. In addition, there were differences between the treatments in the capacity to induce sprouting of TH-reactive fibers. Our results confirm that CDNF can be considered as a potential therapy in PD, and that the neuroprotective mechanism of CDNF differs from that of GDNF.
Source: Työväentutkimus Vuosikirja
Author: Susanne Bäck
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1579380910