A GLP-2 Analogue Protects SH-SY5Y and Neuro-2a Cells Against Mitochondrial Damage, Autophagy Impairments and Apoptosis in a Parkinson Model

Abstract

Glucagon-like peptide-2 (GLP-2) is a peptide hormone that belongs to the glucagon-derived peptide family. We have previously shown that analogues of the sister hormone Glucagon-like peptide-1 (GLP-1) showed neuroprotective effects. Here we investigated the effect of a GLP-2 agonist in a cell model of Parkinsonʼs disease (PD) created by treating SH-SY5Y or Neuro-2a cells with 1-Methyl-4-phenyl-pyridine ion (MPP+). Cell viability and cell cytotoxicity was detected by MTT and LDH assays, respectively. The protein expression levels of mitochondrial, autophagy and apoptotic biomarkers including PGC-1α, Mfn2, IRE1, ATG7, LC3B, Beclin1 and Bcl-2 were detected by western blot. Mitochondrial superoxide was detected by MitoSOX Red. In addition, mitochondrial morphology, autophagosome and apoptotic corpuscles were observed by transmission electron microscope (TEM). We found that the GLP-1 and the GLP-2 agonists both protect cells against mitochondrial damage, autophagy impairments and apoptosis induced by MPP+both in SH-SY5Y and Neuro-2a cells. Cell signaling for mitogenesis was enhanced, and oxidative stress levels much reduced by the drugs. This demonstrates for the first time the neuroprotective effects of a GLP-2 analogue in PD cellular models, in which oxidative stress, autophagy and apoptosis play crucial roles. The protective effects were comparable to those seen with the GLP-1 analogue liraglutide. The results suggest that not only GLP-1, but also GLP-2 has neuroprotective properties and may be useful as a novel treatment of PD.

The neuropeptide landscape of human prefrontal cortex

“…In fact, today nearly 50 drugs acting via GPCRs have been approved by the Food and Drug Administration for various therapeutic interventions ( 106 ), some acting via neuropeptide systems: a substance P antagonist for treatment of chemotherapy-induced nausea ( 108 ), orexin antagonists for treatment of insomnia ( 109 ), and CGRP antibodies/antagonists for treatment of migraine ( 110 ). Finally, GLPR1 agonists are not only useful for treatment of metabolic syndrome ( 111 ) but together with GIPR and GLPR2 agonists they have in animal experiments/models (e.g., AD and Parkinson’s disease) been shown to reduce chronic inflammation and mitochondrial damage, improve memory, and reduce plaque load ( 112 , 113 ). In fact, recently a clinical trial has been initiated by Novo Nordisk, the Danish pharmaceutical company, with an agonist (Rybelsus) at the peptide receptor GLP1R for treatment of AD.…”

ACTH(6–9)PGP Peptide Protects SH-SY5Y Cells from H2O2, tert-Butyl Hydroperoxide, and Cyanide Cytotoxicity via Stimulation of Proliferation and Induction of Prosurvival-Related Genes

“…Its structure (His–Phe–Arg–Trp–Pro–Gly–Pro) does not entirely preclude such activity, as phenylalanine and tryptophan residues may react with ROS [ 30 ]. In this assay, the peptide appeared to be inferior to the redoxin-mimetic peptide PSELT [ 31 ] and glucagon-like peptide-2 [ 32 ]. It could be proposed that the concentration of the peptide is not enough for this activity to manifest.…”

Gastrointestinal Dysfunction in Parkinson’s Disease: Current and Potential Therapeutics

“…In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned mice, GLP-2 analogue administration improved the bradykinesia and movement imbalance of mice, protected dopaminergic neurons and restored tyrosine hydroxylase expression in the substantia nigra and reduced markers of inflammation and mitochondrial dysfunction [162]. Similarly, in Neuro-2a cells treated with 1-Methyl-4-phenyl-pyridine ion, GLP-2 agonist administration protected cells against mitochondrial damage, autophagy impairments and apoptosis, whilst enhancing cell signalling for mitogenesis, and reducing oxidative stress levels [163]. Whilst the impact of GLP-2 administration on GI health and function is yet to be assessed in PD, these promising findings strongly suggest a beneficial role for GLP-2 in PD.…”

“…Several pre-clinical studies have highlighted the efficacy of GLP-2 in mouse and cell culture models of PD [162,163]. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned mice, GLP-2 analogue administration improved the bradykinesia and movement imbalance of mice, protected dopaminergic neurons and restored tyrosine hydroxylase expression in the substantia nigra and reduced markers of inflammation and mitochondrial dysfunction [162].…”