The GLP‐1/GIP dual‐receptor agonist DA5‐CH inhibits the NF‐κB inflammatory pathway in the MPTP mouse model of Parkinson's disease more effectively than the GLP‐1 single‐receptor agonist NLY01

Abstract

The GLP-1 receptor agonist exendin-4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP-1/GIP dual receptor agonist DA5-CH and NLY01, a 40 kDa pegylated form of exendin-4, on motor impairments and reducing inflammation in the 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5-CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection.Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5-CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5-CH, while NLY01 showed weak effects. When analyzing levels of α-synuclein (α-Syn), DA5-CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll-like receptor 4 (TLR4), specific markers of microglia activation (Iba-1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), and transforming growth factor β1 (TGF-β1), DA5-CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell-derived neurotrophic factor (GDNF) and Brain-derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5-CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro-inflammatory cytokines (IL-6 and IL-Iβ) were much reduced by DA5-CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood-brain barrier. After injecting fluorescin-labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin-4 and the dual agonist DA5-CH did. The results show that DA5-CH shows promise as a therapeutic drug for PD.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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

“…Crucially, all forementioned GLP-1 analogs and GLP-1R/GIPR dual agonists cross the BBB in vivo , albeit at varying rates. In comparison, DA4-JC4 (t 1/2 = 151.94 min) and, similarly, DA5-CH showed the highest BBB penetration rates, followed by medium BBB translocation of Exendin-4, lixisenatide and DA3-CH as well as poor brain influx of the lipidated peptides liraglutide, semaglutide, DA1-JC as well as the PEGylated DA2 and NLY01, a variant of Exendin-4 with prolonged t 1/2 ( Li et al, 2020a ; Salameh et al, 2020 ; Zhang et al, 2020 ; Lv et al, 2021 ). We confirmed that GLP-1R/GIPR dual agonists demonstrated superior neuroprotective effects compared to other synthetic GLP-1 analogs in AD ( Maskery et al, 2020 ; Salles et al, 2020 ) and PD ( Yuan et al, 2017 ; Feng et al, 2018 ; Zhang and Holscher, 2020 ; Lv et al, 2021 ; Zhang L.Y.…”

“…Various studies confirm that GLP-1 analogs show potent anti-inflammatory effects. Liraglutide, lixisenatide, semaglutide, exendin-4 or NLY01 [a pegylated and rather poorly BBB-penetrant version of Exendin-4 ( Yun et al, 2018 ; Lv et al, 2021 ; Park et al, 2021 )] reduced IBA-1 or Mac-1 immunoreactivity, indicative of microgliosis, in the hippocampus ( Cai et al, 2018 ; Holubova et al, 2019 ; Salles et al, 2020 ; Paladugu et al, 2021 ; Park et al, 2021 ), cortex ( McClean et al, 2011 , 2015 ; Long-Smith et al, 2013 ; Paladugu et al, 2021 ) and global brain tissue ( McClean and Holscher, 2014a ) of aged WT, APP/PS1, 5xFAD, 3 × Tg-AD or sporadic STZ AD mice. Likewise, microgliosis was attenuated by GLP-1R agonists the SN pars compacta (SNpc) ( Kim et al, 2009 ; Feng et al, 2018 ; Zhang et al, 2018 , 2019 , 2020 ), striatum ( Kim et al, 2009 ; Yun et al, 2018 ) or cortex ( Yuan et al, 2017 ) of MPTP or α-synuclein-injected mice.…”

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

“…Numerous studies focusing on diverse brain illnesses such as Alzheimer's disease (AD) and ischemic brain injury have corroborated the localization of GLP-1R in the CNS. [32][33][34] In addition, a study reported GLP-1R expression on pericytes, which are multi-functional mural cells located at the center of the neurovascular unit (NVU). 35 Other studies have mapped the action of GLP-1RAs, demonstrating that GABA neurons in the NTS express GLP-1 receptors and mediate the anorectic effects of liraglutide in rats.…”

“…46 Several preclinical and clinical studies on ischemia-induced brain injury, Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders have established that GLP-1RAs can cross the BBB and exert a significant neuroprotective effect. [32][33][34] Furthermore, various studies have examined the anorexia-promoting properties of GLP-1RAs. The studies have demonstrated that GLP-1R is also expressed in nuclei controlling food intake, such as the arcuate nucleus (ARC) and paraventricular thalamic nucleus (PVN).…”

Neuroprotective Effects of a Cholecystokinin Analogue in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Parkinson’s Disease Mouse Model

“…Mice received 20 mg/kg/day MPTP in saline i.p. for seven consecutive days, a dose that previously showed good effects (Li et al, 2016;Lv et al, 2021). Simultaneously, starting on the first day of MPTP injections, the CCK analogue and liraglutide were administered for 14 consecutive days injection once-daily.…”