A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease.

The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors that have shown neuroprotective effects 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. GLP-1 analogues are currently on the market as treatments for type II diabetes. We previously showed that the novel dual agonist (DA-JC1) was effective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here we demonstrate that DA-JC1 is neuroprotective in the 6-OHDA brain lesion rat model of PD. When treating rats for 6 weeks with DA-JC1 at 25 nmol/kg ip once-daily, motor activity as tested in the Rotarod and in the open field was much improved. In the amphetamine and apomorphine circling behaviour tests, the 6-OHDA induced impairments were much reduced by the DA-JC1 treatment. The number of TH positive dopaminergic neurons in the substantia nigra was decreased by 6-OHDA lesion and was increased by DA-JC1 treatment. Dopamine levels in the basal ganglia were reduced by 6-OHDA lesion and increased by DA-JC1. In western blot analysis, levels of the growth factor GDNF and pAkt/CREB cell signaling was enhanced by DA-JC1. The autophagy marker Beclin1 was also activated by the drug. The results demonstrate that dual GLP-1/GIP receptor agonists show promise as a novel treatment for PD.

Jalewa J ，Sharma MK ，Gengler S ，Hölscher C ... -  《-》

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.

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.

Ji C ，Xue GF ，Lijun C ，Feng P ，Li D ，Li L ，Li G ，Hölscher C ... -  《-》

Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease.

Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25 nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4 × 25 mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients.

Feng P ，Zhang X ，Li D ，Ji C ，Yuan Z ，Wang R ，Xue G ，Li G ，Hölscher C ... -  《-》

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.

Cao L ，Li D ，Feng P ，Li L ，Xue GF ，Li G ，Hölscher C ... -  《-》

Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.

Hansen HH ，Fabricius K ，Barkholt P ，Mikkelsen JD ，Jelsing J ，Pyke C ，Knudsen LB ，Vrang N ... -  《-》