Hypoxia and GSK3b

This post may be of interest to individuals with both OCD and tics. In my research, I am attempting to uncover the potential causes of abnormal activation of the GSK3b enzyme.

This protein is commonly regarded as a culprit in psychiatric disorders such as schizophrenia, OCD, and depression. The known reason for its negative impact is that it hinders the activation of the Nrf2 pathway.

The Nrf2 signalling is crucial for cells as it initiates the assembly of cellular defenses against stress, particularly oxidative stress. For instance, when glucose enters a cell, it begins synthesising protective enzymes to produce molecules that reduce oxidative stress during glucose combustion for energy.

Nrf2 is also activated when harmful substances enter the cells, such as toxic substances. Some viruses have “learned” to deactivate Nrf2 to suppress the cell’s defenses.

Normally, GSK3b is active, and thus it usually inhibits Nrf2. However, signals from the cell trigger the activation of Nrf2, accomplished by the Akt protein, which deactivates GSK3b and enables Nrf2 signalling to commence defense building.

It has been demonstrated that in most common psychiatric disorders, GSK3b is overactive, contributing to increased oxidative stress through its inhibition of Nrf2. Lithium plays a significant role here as it inhibits GSK3b by replacing magnesium in the protein.

The question remains, why does GSK3b become overactive in the first place? A proper answer to this could pave the way for new treatments for these disorders.

I found a study that demonstrates how prolonged cellular hypoxia can lead to the inhibition of Akt and impaired inhibition of GSK3b.

Thus, a prolonged hypoxia activates GSK3β, which results in decreased HIF-1α accumulation.

In conclusion, hypoxia induced a biphasic effect on HIF-1α stabilization with accumulation in early hypoxia, which depends on an active PI3K/Akt pathway and an inactive GSK3β, whereas prolonged hypoxia results in the inactivation of Akt and activation of GSK3β, which then down-regulates the HIF-1 activity through down-regulation of HIF-1α accumulation. (R1)