Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy

Abstract

Objective. To discuss the link between glycogen synthase kinase-3 (GSK3) and the main biological alterations demonstrated in bipolar disorder (BD), with special attention to the redox status and the evidence supporting the efficacy of lithium (a GSK3 inhibitor) in the treatment of BD. Methods. A literature research on the discussed topics, using Pubmed and Google Scholar, has been conducted. Moreover, a manual selection of interesting references from the identified articles has been performed. Results. The main biological alterations of BD, pertaining to inflammation, oxidative stress, membrane ion channels, and circadian system, seem to be intertwined. The dysfunction of the GSK3 signalling pathway is involved in all the aforementioned "biological causes" of BD. In a complex scenario, it can be seen as the common denominator linking them all. Lithium inhibition of GSK3 could, at least in part, explain its positive effect on these biological dysfunctions and its superiority in terms of clinical efficacy. Conclusions. Deepening the knowledge on the molecular bases of BD is fundamental to identifying the biochemical pathways that must be targeted in order to provide patients with increasingly effective therapeutic tools against an invalidating disorder such as BD.

Figure 1

The figure shows the main regulatory mechanisms of GSK3 activity. GSK3: glycogen synthase kinase 3.

Figure 2

The strict link between GSK3 and redox status is explained according to the evidence. GSK3: glycogen synthase kinase 3; OS: oxidative stress.

Figure 3

The biological alterations reported in bipolar disorder are shown, as well as their consequences. ER: endoplasmic reticulum.

Figure 4

The main activities exerted by lithium, largely reconducted to GSK3 inhibition are here summarized. GSK3: glycogen synthase kinase 3; ROS: reactive oxygen species; BDNF: brain-derived neurotrophic factor.