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.

The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson’s Disease Pathogenesis

“…Hence, IR could promote neuroinflammation by overproducing proinflammatory cytokines inducing neuronal death and PD progression. GSK3β inhibitory molecules have been tested as PD therapeutic options [ 88 ]. However, due to GSK3β having an important physiological role in glycogen metabolism, its inhibition in neuroinflammatory processes must be fully evaluated.…”

The recent progress of peptide regulators for the Wnt/β-catenin signaling pathway

“…IAGIP can directly target the N-terminal region of GSK-3β, which includes Ser9, and can block GSK-3β activity. The inhibition of excessive GSK-3β activity provided a possible approach to controlling neuroinflammation in neurodegenerative diseases (44).…”