Abstract
Cell therapy is a promising treatment for Parkinson’s disease (PD), however clinical trials to date have shown relatively low survival and significant patient-to-patient variability. Glucagon Like Peptide-1 receptor (GLP-1R) agonists have potential neuroprotective effects on endogenous dopaminergic neurons. This study explores whether these agents could similarly support the growth and survival of newly transplanted neurons. 6-OHDA lesioned Sprague Dawley rats received intra-striatal grafts of dopaminergic ventral mesencephalic cells from embryonic day 14 Wistar rat embryos. Transplanted rats then received either saline or L-dopa (12 mg/kg) administered every 48 h prior to, and following cell transplantation. Peripheral GLP-1R agonist administration (exendin-4, 0.5 μg/kg twice daily or liraglutide, 100 μg/kg once daily) commenced immediately after cell transplantation and was maintained throughout the study. Graft survival increased under administration of exendin-4, with motor function improving significantly following treatment with both exendin-4 and liraglutide. However, this effect was not observed in rats administered with L-dopa. In contrast, L-dopa treatment with liraglutide increased graft volume, with parallel increases in motor function. However, this improvement was accompanied by an increase in leukocyte infiltration around the graft. The co-administration of L-dopa and exendin-4 also led to indicators of insulin resistance not seen with liraglutide, which may underpin the differential effects observed between the two GLP1-R agonists. Overall, there may be some benefit to the supplementation of grafted patients with GLP-1R agonists but the potential interaction with other pharmacological treatments needs to be considered in more depth.
Highlights
L-dopa showed a statistically significant but small (3.5%) increase in weight not seen in the liraglutide and exendin-4 treated groups
We examined whether exendin-4 and liraglutide could impact graft function using amphetamine-induced rotation, vibrissae, stepping, and cylinder tests, 12 weeks posttransplantation both with and without concomitant L-dopa
We investigated whether the Glucagon-like peptide-1 receptor agonists (GLP-1R) agonists −/+ LD had an effect on the density of CD11b+ microglia and/or CD45+ leukocyte infiltration in the grafted area
Summary
The main pathological feature of the disease is the progressive degeneration of the nigrostriatal dopaminergic neurons resulting in depletion of striatal dopamine. There are no disease modifying treatments, with all available therapies providing symptomatic relief alone. One of the potential therapeutic approaches that can achieve long-lasting relief for the motor and non-motor symptoms is cell replacement therapy [3,4,5]. This approach is based on restoring the lost striatal dopamine by transplanting dopaminergic neurons ectopically into the striatum. E.M.; Monville, C.; Gates, M.A.; Bagga, V.; Dunnett, S.B. Improved survival of young donor age dopamine grafts in a rat model of Parkinson’s disease.
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