Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease

• Published in: Neural regeneration research Vol. 18; no. 8; pp. 1818 - 1826
• Main Authors: Yu, Hai-Yang, Sun, Tong, Wang, Zhen, Li, Hong, Xu, Duo, An, Jing, Wen, Lu-Lu, Li, Jia-Yi, Li, Wen, Feng, Juan
• Format: Journal Article
• Language: English
• Published: India Department of Neurology,Shengjing Hospital of China Medical University,Shenyang,Liaoning Province,China%Department of Pediatrics,Shengjing Hospital of China MedicalUniversity,Shenyang,Liaoning Province,China%Laboratory of Research in Parkinson's Disease and Related Disorders,Health Sciences Institute,China Medical University,Shenyang,Liaoning Province,China%Laboratory of Research in Parkinson's Disease and Related Disorders,Health Sciences Institute,China Medical University,Shenyang,Liaoning Province,China 01.08.2023; Neural Plasticity and Repair Unit,Department of Experimental Medical Science,Lund University,Lund,Sweden; Wolters Kluwer - Medknow
• Subjects: diabetes mellitus; dipeptidyl peptidase 4 inhibitor; exendin-4; glucagon-like peptide-1 receptor agonist; 1-methyl-4-phenyl-1;2;3;6-tetrahydropyridine; linagliptin; microglia; neuroinflammation; NLRP3 inflammasome; Parkinson’s disease; pyroptosis; pyroptosis; linagliptin; Parkinson's disease; glucagon-like peptide-1 receptor agonist; neuroinflammation; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; dipeptidyl peptidase 4 inhibitor; diabetes mellitus; NLRP3 inflammasome; exendin-4; microglia
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.360242

Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus. Therefore, using these two treatments may help treat Parkinson's disease. To further investigate the mechanisms of action of these two compounds, we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin. We found that both exendin-4 and linagliptin reversed motor dysfunction, glial activation, and dopaminergic neuronal death in this model. In addition, both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion. Moreover, in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1β pathway and subsequent pyroptosis by decreasing the production of reactive oxygen species. These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1β pathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore, these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.