The Effect Of A Novel Dual GLP-1 And GIP Incretin Receptor Agonist DA-JCI On Dopaminergic Neurons And Neurological Inflammatory Cells In The Brain Of Parkinson’s Disease Mice

Objective:Parkinson’s disease(PD) is a common neurodegenerative disorder of aging. Its incidence is high, and increasing year by year. The clinical symptoms include resting tremor, bradykinesia, rigidity and postural instability. Treatment of PD is symptom control mainly. There is no preventive treatment for PD currently. The glucagon-like peptide 1(GLP-1) and glucose dependent insulinotropic polypeptide(GIP) are incretins for controlling blood sugar. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. Here is a a new monomeric peptide DA-JC1 by acting as an agonist at two receptors: GLP-1R and GIPR. We studied the neuroprotective properties of the novel dual GLP-1 and GIP incretin receptor agonist DA-JC1 in a mouse model of Parkinson’s disease.Methods:1. 40 healthy male C57BL/6 mice(weight 20-25g) were randomly allocated to 4groups(n=10): control group, model group,lower dosage group and higher dosage group.The control mice were given 0.1ml normal saline though intraperitoneal administration daily for 7 days. MPTP was injected to the mice abdominal cavities in model group,and0.1ml normal saline was injected in the same way after 30 minutes daily for 7 days. MPTP was injected to the mice abdominal cavities in lower dosage group, and DA-JC(25nmol/kg)was injected in the same way after 30 minutes daily for 7 days. MPTP was injected to the mice abdominal cavities in higher dosage group, and DA-JC1(50nmol/kg)was injected in the same way after 30 minutes daily for 7 days. We observed the movement ability of mice by traction test, rotarod test, open field test after the last administration.2. Mice were sacrificed in 24 h after the last administration. Immunohistochemistry was used to observe the numbers of TH positive cells, IBA-1 positive cells and GFAP positive cells in substantia nigra, and the expression of TH in striatum by analyzing optical density of TH staining region.Results:1. Mice in model group showed typical symptoms of PD after administration of MPTP.Compared with the control group, mice of model group stayed shorter on the rotating roller,scored lower in traction test, moved shorter distance and reared few times in open field test(P<0.05). Compared with the model group, mice of lower and higher dosage group stayed longer on the rotating roller, scored higher in traction test, moved longer distance and reared more times in open field test(P<0.05). Compared with the lower dosage group, mice of higher dosage group stayed longer on the rotating roller, scored higher in traction test,moved longer distance and reared more times in open field test(P<0.05)2. Compared with the control group, the number of TH positive cells in substantia nigra and optical density of TH staining region in striatum about mice in model group decreased(P<0.05). Compared with the model group, the number of TH positive cells in substantia nigra and optical density of TH staining region in striatum about mice in lower and higher dosage group increased(P<0.05), Compared with the lower dosage group, the number of TH positive cells in substantia nigra and optical density of TH staining region in striatum about mice in higher dosage group increased(P<0.05)3. Compared with the control group, both the numbers of IBA-1 and GFAP positive cells in substantia nigra about mice in model group increased(P<0.05); Compared with the model group, the numbers of IBA-1 positive cells and GFAP positive cells in substantia nigra about mice in lower and higher dosage group decreased(P<0.05). Compared with the lower dosage group, both the numbers of IBA-1 and GFAP positive cells in substantia nigra about mice in higher dosage group decreased(P<0.05).Conclusion:1. DA-JC1 improves the dyskinesia of MPTP-induced PD mice. DA-JC1 has better therapeutic effects at the dose of 50 nmol/kg than 25 nmol/kg.2. DA-JC1 protects dopaminergic neurons and its fibers from MPTP, reduces the proliferation degree of microglial cells and astrocytes in the substantia nigra of MPTP-induced PD mice, defends dopaminergic neurons against neuroinflammation.