The Impact of Ghrelin on the Survival and Efficacy of Dopaminergic Fetal Grafts in the 6-OHDA-Lesioned Rat

Abstract

Ghrelin is a peptide produced in the gut with a wide range of physiological functions. Recent studies have suggested it may have potential as a neuroprotective agent in models of Parkinson’s disease, reducing the impact of toxic challenges on the survival of nigral dopaminergic neurons. The presence of the ghrelin receptor (GHSR1a) on the dopaminergic neurons of the substantia nigra raises the possibility that a potential application for this property of ghrelin may be as an adjunctive neuroprotective agent to enhance and support the survival and integration of dopaminergic cells transplanted into the striatum. Thus far, inconsistent outcomes in clinical trials for fetal cell transplantation have been linked to low rates of cell survival which we hypothesize could be ameliorated by the presence of ghrelin. To explore this, we confirmed the expression of the GHSR1a and related enzymes on e14 ventral mesencephalon. To determine a functional effect, five groups of female Sprague–Dawley rats received a unilateral 6-OHDA lesion to the medial forebrain bundle and four received an intrastriatal graft of e14 ventral mesencephalic cells. Grafted rats received saline; acyl-ghrelin (10 µg/kg); acyl-ghrelin (50 µg/kg) or the ghrelin agonist JMV-2894 (160 µg/kg) i.p. for 8 weeks. An effect of ghrelin at low dose on hippocampal neurogenesis indicated blood–brain barrier penetrance and attainment of biologically relevant levels but neither acyl-ghrelin nor JMV-2894 improved graft survival or efficacy.