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

Zijuan Zhang,Zhenqiang Zhang,Ye Yuan,Hai Li,Yunfang Su,Ziyang Yu,Jinlian Ma,Christian Hölscher,Ming Shi,Simai Shao

doi:10.3389/fnins.2022.814430

Abstract

Parkinson’s disease (PD) is a chronic neurodegenerative disease. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for PD. Drugs originally developed for T2DM treatment such as liraglutide have shown neuroprotective effects in mouse models of PD. Cholecystokinin (CCK) is a peptide hormone with growth factor properties. Here, we demonstrate the neuroprotective effects of the (pGLu)-(Gln)-CCK8 analogue in an acute PD mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of CCK analogue (50 nmol/kg ip.) for 14 days treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. The CCK analogue administration also restored tyrosine hydroxylase (TH) positive dopaminergic neurons number and synapse number (synaptophysin levels) in the substantia nigra pars compacta (SNpc). The CCK analogue decreased glia activation and neuroinflammation in the SNpc, and regulated autophagy dysfunction induced by MPTP. CCK analogue protected against mitochondrial damage and ER stress, and also decreased the ratio of apoptosis signaling molecules Bax/Bcl-2. Importantly, the CCK analogue improved the decrease of p-CREBS133 growth factor signaling in the SNpc. Therefore, the CCK analogue promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB pathway that also inhibits apoptosis and regulates autophagy impairment. The present results indicate that CCK analogue shows a promising potential for the treatment of PD.

Highlights

Parkinson’s disease (PD) is a chronic degenerative disease of the central nervous system with a prevalence rate of 1.7% in people over 65 years and as high as 4–5% in people over 85 years (Kowal et al, 2013)
In this study we demonstrate for the first time that CCK receptor activation has neuroprotective effects in an animal model of PD
As animals do not naturally develop PD, several animal models of PD are used in experimental studies, such as 6-hydroxydopamine (6-OHDA) rat model, MPTP mouse model or the A53T transgenic mouse model

Summary

Introduction

Parkinson’s disease (PD) is a chronic degenerative disease of the central nervous system with a prevalence rate of 1.7% in people over 65 years and as high as 4–5% in people over 85 years (Kowal et al, 2013). The GLP-1 receptor agonist exendin-4 showed good protective effects in a pilot clinical trial and a phase II clinical trial in PD patients (viles-Olmos et al, 2013, 2014; Athauda et al, 2017, 2019) These results inspired us to examine the potential neuroprotective effects of cholecystokinin (CCK) (Irwin et al, 2012) and chose the GLP-1 analogue liraglutide as a positive control. GLP-1, GIP and CCK activate G-protein linked membrane standing receptors that enhance cAMP levels (Irwin et al, 2013; Rehfeld, 2017) and activate the PLC-PKC cell signaling pathway (Estall and Drucker, 2003; Lee et al, 2011) This pathway can modulate intracellular calcium levels and modulate the release of neurotransmitters and gene expression (Lee et al, 2011)

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Results

Conclusion