Anti-Inflammatory Effect of IKK-Activated GSK-3β Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson's Disease

• Published in: International journal of molecular sciences Vol. 23; no. 2; p. 998
• Main Authors: Lee, Seulah, Hong, Dong Geun, Yang, Seonguk, Kim, Jaehoon, Baek, Minwoo, Kim, Seoyeong, Thirumalai, Dinakaran, Chung, Hae Young, Chang, Seung-Cheol, Lee, Jaewon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.01.2022; MDPI
• Subjects: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Alzheimer's disease; Animal models; Animals; anti-inflammation; Astrocytes; Cell activation; Colitis; Disease Models, Animal; Extracellular signal-regulated kinase; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - metabolism; Glycogens; HCT116 Cells; Humans; I-kappa B Kinase - metabolism; IKK protein; Immune system; In vivo methods and tests; Inflammation; Inflammatory response; inhibitory κB kinase-activated GSK-3β inhibitory peptide; Intravenous administration; Isoforms; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; Microglial cells; MPP; MPTP; Neurodegeneration; neuroinflammation; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Peptides - administration & dosage; Peptides - pharmacology; Protein kinase; Protein-serine/threonine kinase; RAW 264.7 Cells; Tumor Necrosis Factor-alpha - pharmacology; anti-inflammation; inhibitory κB kinase-activated GSK-3β inhibitory peptide; neuroinflammation; Parkinson’s disease; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23020998

Parkinson's disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3β, and GSK-3β plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3β inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP -induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD.