D-Ala2-GIP-glu-PAL is neuroprotective in a chronic Parkinson's disease mouse model and increases BNDF expression while reducing neuroinflammation and lipid peroxidation

Li, Yanwei and Liu, WeiZhen and Li, Lin and Holscher, Christian (2017) D-Ala2-GIP-glu-PAL is neuroprotective in a chronic Parkinson's disease mouse model and increases BNDF expression while reducing neuroinflammation and lipid peroxidation. European Journal of Pharmacology, 797. pp. 162-172. ISSN 0014-2999

[thumbnail of 1-s2.0-S0014299916307622-main]
Preview
PDF (1-s2.0-S0014299916307622-main)
1_s2.0_S0014299916307622_main.pdf - Accepted Version
Available under License Creative Commons Attribution-NonCommercial-NoDerivs.

Download (1MB)
[thumbnail of GIP_EJP_manuscript]
Preview
PDF (GIP_EJP_manuscript)
GIP_EJP_manuscript.pdf - Accepted Version
Available under License Creative Commons Attribution-NonCommercial-NoDerivs.

Download (1MB)

Abstract

Type 2 diabetes mellitus (T2DM) is a risk factor for Parkinson's disease (PD). Therefore, treatment to improve insulin resistance in T2DM may be useful for PD patients. Glucose dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family that can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. We had shown previously that D-Ala2-GIP-glu-PAL, a novel long-acting GIP analogue, can play a neuroprotective role in the PD mouse model induced by acute MPTP injection. The drug reduced damage to the dopaminergic neurons and increased CREB-mediated Bcl-2 expression to prevent apoptosis and reduced chronic inflammation in the brain. In the present study, we further tested the effects of chronic treatment by D-Ala2-GIP-glu-PAL in a chronic PD mouse model induced by MPTP (25 mg/kg ip.) combination with probenecid (250 mg/kg ip.) injection for 5 weeks. The results demonstrated that chronic treatment with D-Ala2-GIP-glu-PAL inhibits MPTP -induced Parkinsonism-like motor disorders in mice, and that the drug prevents dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc). Moreover, D-Ala2-GIP-glu-PAL also inhibited the increased levels of expression of α-synuclein in the SNpc and striatum induced by MPTP. Furthermore, drug treatment reduced chronic neuroinflammation, oxidative stress and lipid peroxidation, and increased the expression of BDNF. These findings show that GIP signaling is neuroprotective and holds promise as a novel treatment of PD.

Item Type:
Journal Article
Journal or Publication Title:
European Journal of Pharmacology
Additional Information:
This is the author’s version of a work that was accepted for publication in European Journal of Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in European Journal of Pharmacology, 797, 2017 DOI: 10.1016/j.ejphar.2016.11.050
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/3000/3004
Subjects:
?? NEURODEGENERATIONINSULINBRAININCRETINGROWTH FACTORDOPAMINEPHARMACOLOGY ??
ID Code:
83297
Deposited By:
Deposited On:
30 Nov 2016 10:10
Refereed?:
Yes
Published?:
Published
Last Modified:
17 Sep 2023 01:59