A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson′s disease by increasing expression of BNDF

Abstract

The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. 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 and are tested in diabetic patients. Here we demonstrate 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 i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD.

Parkinson';s Disease, Diabetes and Cognitive Impairment

“…Reduced oxidative stress, more TH-positive dopaminergic neurons and an increase in BDNF were also demonstrated and this was similar to the effect shown using the incretin analogue DA-JC1 [60,82]. This suggests a possible overlap in the pathway by which metformin and incretins exert a neuroprotective effect.…”

“…Ji and colleagues [60] have also demonstrated the protective effects of incretins using a protease resistant GLP-1/GIP analogue (DA-JC1) on MPTP models [60]. They found that TH levels were increased following treatment with DA-JC1…”

“…in MPTP mice and DA-JC1 was able to increase growth factor signalling molecules such as B-cell lymphoma 2 (Bcl-2) and brain derived neurotrophic factor (BDNF), and decrease apoptosis signalling molecules [60]. The pathway through which DA-JC1 conveys neuroprotection may be partially due to the activation of Akt, a growth factor signalling kinase [60].…”

“…The pathway through which DA-JC1 conveys neuroprotection may be partially due to the activation of Akt, a growth factor signalling kinase [60]. Variability in Akt has been shown to be associated with the development of PD [61].…”

“…Furthermore, Akt is a downstream target of the insulin signalling pathway, and has been shown to have anti-apoptotic effects [61]. However, other pathways are also likely to be involved as inhibition of Akt did not fully attenuate the benefits of DA-JC1 [60]. It is likely that GLP-1 agonists also exert a neuroprotective effect by reducing vascular risk factors.…”