Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease

Abstract

Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p. When comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD.

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease

“…Motor coordination and activity was improved by the newer GLP-1 mimetics, and the expression of TH was also rescued by both drugs. Importantly, levels of the pro-apoptotic signal BAX were reduced, the cell survival signal Bcl-2 was increased by both drugs (Liu et al, 2015a). Similar protective effects were observed with the GLP-1 analogue (Val8)GLP-1-Glu-PAL (Zhang et al, 2015).…”

“…Mimetics of GLP-1 and GIP have shown neuroprotective effects in animal models of Alzheimer's disease (Bomfim et al, 2012;Duffy and Holscher, 2013;Faivre and Holscher, 2013a, b;Li et al, 2010;McClean et al, 2011) and were found to re-sensitise insulin signaling in the brain (Long-Smith et al, 2013). GLP-1 receptor agonists also have neuroprotective effects in animal models of PD (Bertilsson et al, 2008;Harkavyi et al, 2008;Li et al, 2009;Liu et al, 2015a;Zhang et al, 2015). The GLP-1 mimetic exendin-4 showed protective effects in a pilot clinical study in PD patients (Aviles-Olmos et al, 2013a;Aviles-Olmos et al, 2014).…”

“…We previously tested GLP-1 or GIP analogues in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD, demonstrating that both incretin signaling pathways protect the brain from the MPTP induced pathology such as motor impairment, increase of -synuclein levels, chronic inflammation in the brain, loss of dopaminergic neurons, oxidative stress and growth factor expression (Ji et al, 2016a;Li et al, 2016;Liu et al, 2015a;Liu et al, 2015b;Zhang et al, 2015).…”

Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson’s disease mouse model

“…We have shown in a previous study that Val(8)GLP--1(glu--PAL) is neuroprotective and protects memory and synaptic plasticity in diabetic animals (Lennox et al, 2013). We also have previously shown that liragutide and the newer diabetes drug lixisenatide are protective in the MPTP mouse model of PD (Liu et al, 2015). Here, we demonstrate for the first time that Val(8)GLP--1(glu--PAL) is also neuroprotective in this mouse model of PD.…”

Parkinson';s Disease, Diabetes and Cognitive Impairment

“…Furthermore, there has been evidence that GIP enhances cell survival in both β-cells of the pancreas and in neurons [53]. Glucagonlike peptide-1 (GLP-1) is also an incretin hormone and analogues such as Lixisenatide, Liraglutide and Exenatide have shown neuroprotective effects in animals and humans [54][55][56][57]. Li et al provided evidence for the role of GIP in neuronal survival in animal models of PD [58].…”