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.

A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model

“…Furthermore, another GLP-1 receptor agonist, exendin-4, has shown good protective effects in a pilot study in patients with Parkinson's disease [64]. It is therefore of interest to develop more efficient drugs that can activate not just GLP-1 but also the sister incretin signaling pathway GIP, which has shown neuroprotective effects on its own in preclinical studies of AD (Duffy and Holscher, 2013;Faivre and Holscher, 2013) and PD [65,66]. Novel dual agonists therefore may be superior in the clinic for treating chronic neurodegenerative disorders such as AD or PD.…”

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease

“…Moreover, MPTP treatment increased the levels of alpha-synuclein in the brain, and D-Ala2-GIP-glu-PAL reduced these levels to almost normal values. D-Ala2-GIP-glu-PAL also reduced the chronic inflammation response in the brain, reduced oxidative stress and lipid peroxidation, and increased the expression of Brain Derived Neurotrophic Factor (BDNF) (Li et al, 2017).…”

“…GLP-1 and GIP are members of the growth factor family (Holscher, 2014). We have previously shown that GLP-1 or GIP analogues enhance the expression of Brain-Derived Neurotrophic Factor (BDNF) (Ji et al, 2016b;Li et al, 2017), a growth factor that protects synaptic activity from stressors (Nagahara et al, 2009). GLP-1 and GIP can cross the BBB (Dogrukol-Ak et al, 2004;Hunter and Holscher, 2012;Kastin et al, 2002) and enhance the expression of key growth factors such as BDNF or GDNF.…”

The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD

“…Glucose‐dependent insulinotropic polypeptide (GIP) is a sister hormone of GLP‐1 with similar properties as GLP‐1 (Lund, Vilsboll, Bagger, Holst, & Knop, ). GIP analogues have also shown neuroprotective effects in animal models of AD and Parkinson's disease (Duffy & Hoelscher, ; Faivre & Hoelscher, ; Li, Liu, Li, & Hoelscher, ; Li, Liu, Li, & Holscher, ).…”

“…GIP analogues have also shown neuroprotective effects in animal models of AD and Parkinson's disease (Duffy & Hoelscher, 2013;Faivre & Hoelscher, 2013;Li, Liu, Li, & Hoelscher, 2016;Li, Liu, Li, & Holscher, 2017).…”