Metabolic disturbances such as diabetes and obesity, are a potential risk factors for progressive neurodegenerative disease such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and multiple sclerosis (MS). There is evidence that an antidiabetic or obesity drug of the glucagon-likepeptide-1(GLP-1) family has direct neuroprotective effects in an experimental models of neurodegenerative disease. Recently, we have developed HM15211, a novel long-acting GLP-1/GIP/Glucagon triple agonist. Previous studies have shown that HM15211 with a unique activity profile exerted neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced subchronic PD mice model. In the present study, we evaluated 1) the neuroprotective effects of HM15211 in chronic MPTP/probenecid PD model, 2) the protection of AD progression in diabetic model, and 3) neuroprotective effect in the relapsing-remitting experimental autoimmune encephalomyelitis (EAE) model of MS. In chronic PD mice model, HM15211 administration protected dopaminergic neuronal death and decreased alpha synuclein in striatum. HM15211 also significantly improved the MPTP/probenecid induced motor impairments in behavior tests. In addition, HM15211 increased phosphorylated tau, and reversed inflammatory cytokines and oxidative stress marker in aged db/db mice, which have a pathological characters of AD. These results suggest that HM15211 have a protective effect in progression from diabetes to AD. In another experiment, HM15211 have shown the anti-inflammatory and neuroprotective effects in the EAE mouse model. HM15211 significantly reduced the EAE clinical score and resulted in the reversal of histopathological sequelae compared to vehicle. Furthermore, HM15211 decreased pro-inflammatory cytokines, while it upregulated anti-inflammatory cytokines. Based on these observations, HM15211 might be a potential therapeutic option for the neurodegenerative diseases.
K. Wonki: Employee; Self; Hanmi Pharm. Co., Ltd. J.A. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: None. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. Y. Kim: None.