Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Abstract

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a wellestablished cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC 50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood−brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

“…A GSK3β polymorphism was found to be associated with Parkinson’s disease that alters GSK3β transcription and splicing (Kwok et a., 2005). Subsequent studies have further strengthened the potential therapeutic benefits of GSK3 inhibitors in several models of Parkinson’s disease (Duka et al, 2009; Lin et al, 2010b; Morales-Garcia et al, 2013). Growing evidence has been reviewed previously demonstrating that GSK3 inhibitors are effective in mouse models of Huntington’s disease (Scheuing et al, 2014), stroke (Chuang et al, 2011), traumatic brain injury (King et al, 2014; Leeds et al, 2014), and spinocerebellar ataxia type 1 (Watase et al, 2007).…”

Why do anti-inflammatory signals of bone marrow-derived stromal cells improve neurodegenerative conditions where anti-inflammatory drugs fail?

“…The upregulation of GSK-3β expression in T cells is seen as pathogenic in autoimmune diseases (Beurel et al 2013). Blocking GSK-3 may bring down disease progression in neurodegenerative diseases by decreasing inflammation and apoptosis, and providing a cell-protective environment (Morales-Garcia et al 2013). Figure 1 presents an overview of the time axis of these three studies in which we compared the histological effects of bm-SC with the effects reached after matched interventions with placebo (vehicle), methyl prednisolone, riluzole and/or Celecoxib in SCI-lesioned and ALS-like experimental animals, at different time points after intrathecal applica- tion (1, 2, and 3).…”

Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease

“…However, the exact mechanisms of this anti-inflammatory effect of GSK-3␤ inhibitions remained to be elucidated, but it is well documented the GSK-3␤ inhibitors (SB216763 or lithium chloride) repress production of the pro-inflammatory factors such as TNF-␣ and IL-12 and stimulate the production of the anti-inflammatory cytokines such as IL-10 [156]. Furthermore, a study on in vitro and in vivo models of PD have depicted that by blocking microglial activation, GSK-3␤ inhibitor (SC001) effectively protect against 6-OHDA induced neurotoxicity [157]. Furthermore, a study on cardiomyocytes has revealed that inhibition of GSK-3␤ by SB216763 is able to block formation of mitochondrial permeability transition pore (mPTP) [158].…”