Neuroprotective and restorative properties of the GLP-1/GIP dual agonist DA-JC1 compared with a GLP-1 single agonist in Alzheimer's disease

Autor(es)

Salles, Geisa Nogueira ^{[1, 2]} ; Caho, Michele Longoni ^[1] ; Holscher, Christian ^[3] ; Pacheco-Soares, Cristina ^[2] ; Porcionatto, Marimelia ^[1] ; Lobo, Anderson Oliveira ^[4]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Biochem, Lab Neurobiol, Rua Pedro de Toledo 669, BR-04039032 Sao Paulo, SP - Brazil

^[2] Univ Vale Paraiba, IP&D, Lab Dynam Cellular Compartments, Ave Shishima Hifumi 2911, BR-12244000 Sao Jose Dos Campos, SP - Brazil

^[3] Henan Univ Chinese Med, Res & Expt Ctr, Zhengzhou 450000, Henan - Peoples R China

^[4] UFPI Fed Univ Piaui, LIMAV Interdisciplinary Lab Adv Mat Mat Sci & Eng, Grad Program, BR-64049550 Teresina, PI - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Neuropharmacology; v. 162, JAN 1 2020.
• Citações Web of Science: 0

Resumo

The sister incretins glucagon-like peptide-1 (GLP-1) and glucagon dependent insulinotropic polypeptide (GIP) are growth factors responsible for re-sensitizing insulin signalling. Interestingly, their analogues, originally developed to treat type 2 diabetes (T2D), have demonstrated a range of neuroprotective and neurorestorative properties. Novel peptide GLP-1/GIP dual agonist (DA) shows good effects in diabetic patients, superior to the effects demonstrated by single GIP or GLP-1 mimetics. Furthermore, novel DAs have shown considerable neuroprotection in neurodegenerative models. Here, we investigated the neuroprotective and restorative involvement of the DA DA-JC1 and liraglutide (Lg), a single GLP-1 receptor analogue, in vitro using human neuroblastoma (SH-SY5Y) against oxidative stress induced by oxygen peroxide (H2O2), and in vivo, in a mouse model of Alzheimer's disease (AD), APP/PS1. First, we determined the ideal concentration of the peptides and demonstrated that DA-JC1 protects cells against oxidative stress more than Lg, improving cell viability, normalizing reactive oxygen species (ROS) and attenuating DNA damage generated by H2O2. Moreover, in 10-to-12-months-old APP/PS1 animals treated for 4 weeks, both Lg and DA-JC1 were very efficient in stimulating neurogenesis and reducing some important hallmarks of AD, but DA-JC1 was better than Lg in attenuating crucial neuroinflammatory markers, especially reactive astrocyte, in both wild-type (WT) and APP/PS1 hippocampal regions. Altogether, this study suggests an interactive role of GLP-1 and GIP receptors, enhancing the efficiency of single GLP-1 analogues, especially in attenuating oxidative stress and neuroinflammation. We confirm that combining GLP-1 and GIP results in a variety of beneficial effects, providing key evidences for the development of a promising therapeutic strategy for AD. (AU)

• Processo FAPESP: 14/20561-0 - Nanodispositivos poliméricos biorreabsorvíveis como sistema de liberação controlada de peptídeos para a terapia da doença de Alzheimer
• Beneficiário: Geisa Rodrigues Salles
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto