Transient striatal delivery of GDNF via encapsulated cells leads to sustained behavioral improvement in a bilateral model of Parkinson disease.
ABSTRACT Numerous studies have shown the neuroprotective and regenerative benefits of glial cell line-derived neurotrophic factor (GDNF) in animal models of PD. Brain delivery of GDNF can, however, be associated with limiting side-effects in both primates and PD patients, rendering the duration of delivery a critical factor. In the present study, the effects of transient vs. sustained GDNF delivery by encapsulated cells were evaluated in a bilateral animal model, closely mimicking advanced PD. One week following bilateral striatal 6-hydroxydopamine injections in rats, capsules loaded with human fibroblasts genetically engineered to release GDNF were bilaterally implanted in the striatum. GDNF delivery resulted in a significant improvement of movement initiation and swimming performance in the lesioned animals, associated with striatal reinnervation of dopaminergic fibers. To test the sustainability of the behavioral improvement, GDNF-secreting capsules were withdrawn in a subgroup of animals, 7 weeks post-implantation. Strikingly, both the behavioral and morphological improvements were maintained until the sacrifice of the animals 6 weeks post-GDNF withdrawal. The sustained cellular and behavioral benefits after GDNF washout suggest the need for temporary delivery of the trophic factor in PD. Retrievable encapsulated cells represent an attractive delivery tool to achieve this purpose.
SourceAvailable from: Salvador HarguindeyNeuropsychiatric Disease and Treatment 01/2008; DOI:10.2147/NDT.S3800 · 2.15 Impact Factor
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ABSTRACT: Using a rat model of hemiparkinsonism, we examined the time-course of D1 agonist, SKF-38393-induced changes in extracellular signaling regulated kinases 1/2 (ERK1/2) phosphorylation in the striatum and substantia nigra (SN). We unilaterally lesioned the rat median forebrain bundle with 6-hydroxydopamine. Dopaminergic lesioned rats were ad-ministered with SKF-38393 and perfused at 15, 30, 60, or 120 minutes after the drug. Immunohistochemical analysis of striatum and SN revealed, as expected, a loss of tyrosine hydroxylase and a decrease of substance P in lesioned rats. SKF-38393 induced a robust increase in phospho-ERK1/2 levels in the lesioned striatum, which peaked at 15 min and substantially declined by 120 min. We report for the first time that similar changes were observed in the SN. The time-dependent ERK 1/2 activation in the striatonigral neurons may play a role in the therapeutic and/or side effects such as dyskinesias related to the dopamine agonist treatment for Parkinson's disease.Journal of Behavioral and Brain Science 01/2012; 02(01). DOI:10.4236/jbbs.2012.21001