Highly Potent and Specific GSK‐3β Inhibitors That Block Tau Phosphorylation and Decrease α‐Synuclein Protein Expression in a Cellular Model of Parkinson's Disease

Abstract

Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of alpha-Syn protein expression. We conclude that the GSK-3beta inhibitors described herein offer promise in defending cells against MPP+-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.

The transcription factor Nrf2 as a new therapeutic target in Parkinson's disease

“…In the MPTP animal model of PD, this neurotoxin activated GSK-3 β in DAergic neurons but pre-administration of two GSK-3 β inhibitors, indirubin-3 ′ -oxime and AR-A014418, inhibited this kinase (as determined by attenuated Tau phosphorylation) and protected DAergic neurons from MPTP-induced apoptosis [108] . Moreover, maleimides with potent GSK-3 β inhibitory capacity blocked Tau phosphorylation and decreased α -Syn expression in a cellular model of PD, resulting in lower MPP + neurotoxicity [109] .…”

Inhibition of Glycogen Synthase Kinase 3β Attenuates Neurocognitive Dysfunction Resulting from Cranial Irradiation

“…GSK-3h belongs to a family of GSK-3, a multifunctional serine/ threonine kinase (12) that has been implicated in multiple biological processes including embryonic development, cell differentiation, apoptosis, and insulin response (13,14). GSK-3h is ubiquitously expressed in eukaryotic cells and is highly enriched in the brain and has been implicated in central nervous system dysfunctions like Alzheimer's disease (15), schizophrenia (16), dopamine-associated behaviors (17), bipolar disorders (18), and Parkinson's disease (19). Several kinases including Akt can attenuate GSK-3h enzymatic activity by phosphorylating the NH 2 -terminal serine, Ser 9 (13).…”

Vitamin B12, a chlorophyll-related analog to pheophytin a from marine brown algae, promotes neurite outgrowth and stimulates differentiation in PC12 cells

“…AD neuropathology is characterized by extracellular deposition of b-amy-loid plaques and intracellular deposition of neurofibrillary tangles in the cerebral cortex; development of neurofibrillary tangles has been linked to hyperphosphorylation of tau protein (Kozikowski et al 2006;Terry 2006). In the nerve cells, b-amyloid neurotoxicity and microtubule destabilization due to tau hyperphosphorylation cause cell death (Chen et al 2005;Maezawa et al 2006).…”