/ In the News

Tideglusib: From Alzheimer's to Caries Lesion Natural Repair

Nowadays, it is fairly common in science to discover that a drug with an initial indication can be repurposed to target a completely different condition; this is the case with Tideglusib.

Tideglusib is an inhibitor of GSK-3, and even though this may not say much, this characteristic action is crucial for tissue repair. To give you context, GSK-3 is an enzyme that forms part of the Wnt/β-cat signaling pathway, which provides the immediate response of the body against tissue damage. So, when the body suffers an injury, the Wnt/β-cat signaling pathway will be triggered in order to try to repair the damaged tissue. As in all of the pathways in the body, there are different regulators to control any possible false alarms or malfunctions; this is the role of GSK-3. To achieve its action, GSK-3 will mark β-catenin with phosphorous, and this action will inhibit the production of proteins for tissue repair. As I said before, GSK-3 is a regulator in the tissue repair pathway and that is why it is a very attractive target for development of drugs related to tissue damage and repair.

Tideglusib was initially formulated for its use in Alzheimer's disease, in which it has reached clinical trials. Tideglusib is very appealing as it irreversibly inhibits the GSK-3 enzyme. This action permits a continuous decrease in Tau hyperphosphorylation and a decrease in brain amyloid plaque, the major features of Alzheimer's. After Tideglusib action, improvements in learning, memory and a decrease in neuronal loss have been reported.

However, while the drug development community was focused and amazed by the potential for tideglusib as a treatment for Alzheimer's disease, researchers at the King's College London Dental Institute, discovered a novel use of tideglusib in a completely different field.

As commented in their Nature paper, Dr. Sharpe and his collaborators decided to give tideglusib a try in the management of deep caries lesions. Dr. Sharpe's group decided to use tideglusib after noticing that "Axin 2 expression and hence Wnt/β-cat signaling is upregulated following tooth damage". To understand their rationale, it is important to point out that Axin 2 is a major activated gene in the Wnt/β-cat signaling pathway and that its activation is linked to the stimulation of formation of reparative dentine following tooth damage.

But why is the formation of dentine so important? To understand this, we need to know that dentine is a tooth mineral, produced by odontoblasts (dental specialized cells), that protects the soft pulp tissue from being infected. When we have caries, the currently available treatment involves the use of mineral non-degradable aggregates to fill the space created in the dentine by the injury. These aggregates do not allow the body to restore its normal mineral volume. It has been reported that if the damage is too large and the pulp is exposed, new odontoblasts will differentiate for the secretion of discrete amounts of reparative dentine. But this innate reparative dentine is not sufficient to repair the tissue and it is usually located in the pulp tissue side.

Being aware of this background, Dr. Sharpe and his collaborators decided to inhibit GSK-3 with Tideglusib, resulting in an increase of Axin 2 and thus the secretion of natural dentine. They also used a collagen-based sponge to deliver tideglusib to the target. The collagen is then degraded and replaced by the self-formed dentine, covering the damaged space. The results of Dr. Sharpe's research are very promising, showing a complete dentine repair just 6 weeks after initial treatment. This novel use for tideglusib is currently in pre-clinical trials.

This provides more insight into how drug development works, and how the basic mechanism of an Alzheimer's drug can be adapted to other fields. For now, I recommend we keep an eye out for the approval of this innovative application of Tideglusib, so that we can give a heads-up to our dentist as soon as possible.

Tideglusib: From Alzheimer's to Caries Lesion Natural Repair
Share this