title: 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.
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 (25mg/kg ip.) combination with probenecid (250mg/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.
authors.affiliation: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China; Department of human anatomy, Shaoyang Medical College, Shaoyang, Hunan, PR China.
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.
authors.forename: WeiZhen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China. Electronic address: linlilin999@163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK; Second hospital, Neurology department, Shanxi medical University, Taiyuan, Shanxi, PR China.
authors.forename: Christian
authors.initials: C
authors.lastname: Hölscher
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002452:Cell Count; D002908:Chronic Disease; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C000616901:Ala2-GIP-Glu-PAL; D019208:Brain-Derived Neurotrophic Factor; D051844:alpha-Synuclein; D005749:Gastric Inhibitory Polypeptide
keywords: Brain; Dopamine; Growth factor; Incretin; Insulin; Neurodegeneration