Neuroprotective Effects of HM15211, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist in the Neurodegenerative Disease Models
| Autor: | Sung Youb Jung, Sang Hyun Lee, In Young Choi, Jeong A. Kim, Young Hoon Kim, Sun Jin Kim, Sang Don Lee |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class business.industry Endocrinology Diabetes and Metabolism MPTP Dopaminergic Hyperphosphorylation Pharmacology Neuroprotection Glucagon Proinflammatory cytokine Probenecid 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Internal Medicine medicine business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Diabetes. 67 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | HM15211 is a novel long-acting GLP-1/GIP/Glucagon triple agonist that is being developed for the treatment of obesity and nonalcoholic fatty liver disease (NASH). Accumulating evidences have shown that obesity, type 2 diabetes, and NASH increase the risk of developing progressive neurodegenerative disease such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to peripheral contributions, each of incretins consisting HM15211 have neuroprotective effects in several brain diseases like AD, PD, and ischemia. Previously, we demonstrated that HM15211 exerted neuroprotective effects in MPTP induced subacute PD mice model. Here, we evaluated 1) the neuroprotective effects of HM15211 in chronic MPTP/probenecid PD model, and 2) the protection of AD progression in db/db mice. Chronic PD mice model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in combination with probenecid injection, twice a week for 5 weeks and HM15211 was administered once a week for 6 weeks. Dopaminergic neuronal death by MPTP/probenecid was protected by HM15211, which was derived from anti-inflammatory and anti-oxidative stress effect by HM15211. Also HM15211 decreased alpha synuclein in striatum of chronic mice PD model. Together with these efficacies, HM15211 significantly improved the MPTP/probenecid induced motor impairments in behavior. A db/db mice are well-established diabetic model and reported that db/db mice develop hyperphosphorylation of tau as they grew older. Thus we chose db/db mice to elucidate the prophylactic effect of HM15211 on AD. After once every 2 days subcutaneous administration for 12 weeks, HM15211 reversed inflammatory cytokines and oxidative stress marker, which were increased in db/db mice. Also, increased phosphorylated tau in db/db mice was decreased by HM15211. Based on these observations, HM15211 might be a potential therapeutic option for the neurodegenerative disease. Disclosure J.A. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. S. Jung: None. Y. Kim: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. |
| Databáze: | OpenAIRE |
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