A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson’s disease by reducing chronic inflammation in the brain

Lijun, Cao and Li, Dongfang and Feng, Peng and Li, Lin and Xue, Guofang and Li, Guanglai and Holscher, Christian (2016) A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson’s disease by reducing chronic inflammation in the brain. NeuroReport, 27 (6). pp. 384-391. ISSN 0959-4965

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Abstract

The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson’s disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.

Item Type:
Journal Article
Journal or Publication Title:
NeuroReport
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2800
Subjects:
ID Code:
80982
Deposited By:
Deposited On:
08 Oct 2016 04:19
Refereed?:
Yes
Published?:
Published
Last Modified:
09 Aug 2020 04:33