Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo

Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic drugs in neuroregenerative medicine.

The Role of Wnt/β-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

“…Lange et al tested several GSK-3 inhibitors for their ability to inhibit GSK-3 in human neural progenitor cells and found kenpaullone and SB 216763 enhanced neurogenesis by stimulating the Wnt/b-catenin signaling without changing cell cycle exit or cell survival [100]. NP03112, also called tideglusib, was demonstrated by Morales-Garcia et al [101] to induce neurogenesis in the DG of adult rats. In addition, Palomo et al [102] reported substituted 5-imino-1,2,4-thiadiazoles was able to inhibit GSK-3 in a substrate competitive manner and selectively differentiate NSCs in vitro.…”

Alzheimer’s Disease: Dawn of a New Era?

“…It acts as an irreversible GSK-3β inhibitor that has been shown to reverse amyloid in brain and prevent cell loss and reduce spatial memory deficits in preclinical studies (106,107). Phase IIa studies in 30 patients reported good tolerability except for a transient increase in serum transaminase levels (108).…”

Inibidores Da GSK-3: Uma Nova Estratégia Para a Regeneração Dental

“…Em ensaios pré-clínicos, foi observado que tideglusibe reduziu uma série de alterações da doença de Alzheimer, incluindo fosforilação de tau, deposição de amiloide, perda de neurônio e gliose no córtex entorrinal e hipocampo, para reverter um déficit de memória espacial em camundongos transgênicos (SERENÓ et al, 2009;MORALES-GARCIA et al, 2012).…”