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

Abstract

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.

• Authors: Seulah Lee, Dong Geun Hong, Seonguk Yang, Jaehoon Kim, Minwoo Baek, Seoyeong Kim, Dinakaran Thirumalai, Hae Young Chung, Seung-Cheol Chang, Jaewon Lee
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 2 (Jan 17 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35055183 (Publication Type: Journal Article)

Chemical References

• Lipopolysaccharides
• Peptides
• Tumor Necrosis Factor-alpha
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• I-kappa B Kinase

Topics

• Animals
• Disease Models, Animal
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, metabolism)
• HCT116 Cells
• Humans
• I-kappa B Kinase (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Parkinson Disease (drug therapy, metabolism, pathology)
• Peptides (administration & dosage, pharmacology)
• RAW 264.7 Cells
• Tumor Necrosis Factor-alpha (pharmacology)