L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease

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.

Defining the unknowns for cell therapies in Parkinson's disease

“…2 ), regular medication will raise striatal dopamine levels in a patient with PD. Early in vivo studies were conflicting, suggesting that L-DOPA administration may or may not be toxic to foetal cell transplants ( Steece-Collier et al, 1990 , 1995 ; Yurek et al, 1991 ), but more recent animal model data have allayed concerns, demonstrating that L-DOPA might actually be of benefit, supporting graft function and driving differentiation to the preferred GIRK2 + (also known as KCNJ6 + ) dopaminergic neuronal phenotype ( Breger et al, 2017 ; Elabi et al, 2021 ), consistent with the previous in vitro findings ( Belinsky et al, 2013 ). However, more studies are required to establish whether other commonly used PD medications and neuroactive drugs affect graft survival or innervation patterns and, thus, graft function.…”

The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review

“…In contrast to the NTS-localized production and distribution of GLP-1, the GLP-1R is widely distributed in the CNS. In vivo , the enriched immunoreactivity or transcription of the GLP-1R was detected in neurons of the DVC, paraventricular and posterior thalamic nuclei, various hypothalamic regions, ventral, posterodorsal and interpeduncular tegmental areas, the periaqueductal gray and superior colliculus, while medium to low levels of GLP-1Rs were found in the posterior/caudal hippocampus, the hippocampal CA1, temporal/cerebral cortex, striatum, substantia nigra (SN) [which included tyrosine hydroxylase (SN)-expressing dopaminergic neurons ( Elabi et al, 2021 )], locus coeruleus, preoptic area, parabrachial nuclei, lateral septum, lateral habenula; zona incerta; substantia innominate, subfornical organ, interpenduncular nucleus, superior colliculus, ventral pallium; nucleus basalis of Meynert, central gray (especially medial), amygdala, spinal cord, the bed nuclei of the stria terminalis, the shell of the nucleus accumbens and the dorsal raphe nuclei. Besides neurons, astrocytes and microglia express GLP-1Rs (see Vrang and Larsen, 2010 for a general overview) ( Merchenthaler et al, 1999 ; Iwai et al, 2006 ; Lee et al, 2011a ; Darsalia et al, 2013 ; Trapp and Richards, 2013 ; Trapp and Cork, 2015 ).…”