Do Impaired Akt and overactive GSK3b lead to OCD?

Proper function of PI3K/Akt is required for Nrf2 activation in response to oxidative stress

Study (R5) demonstrates that PI3K activity is necessary for Nrf2 to be activated in response to oxidative stress. When PI3K was inhibited by the selective inhibitor, expression of Nrf2-target enzymes was also inhibited.

This shows the importance of inhibition of GSK3b and activation of PI3K/Akt pathway to lower oxidative stress.

Pretreatment with LY 294002 (a selective PI3-kinase inhibitor), however, inhibited both hNQO1-ARE-luciferase expression and endogenous NQO1 protein induction. In support of a role for PI3-kinase in ARE activation we show that:

1. transfection of IMR-32 cells with constitutively active PI3-kinase selectively activated the ARE in a dose-dependent manner that was completely inhibited by treatment with LY 294002;

2. pretreatment of cells with the PI3-kinase inhibitors, LY 294002 and wortmannin, significantly decreased NF-E2-related factor 2 (Nrf2) nuclear translocation induced by tBHQ; and

3. ARE activation by constitutively active PI3-kinase was blocked completely by dominant negative Nrf2.

Taken together, these data clearly show that ARE activation by tBHQ depends on PI3-kinase, which lies upstream of Nrf2. (R5)

Chronic oxidative stress downregulates Akt

The first response to increased H2O2 is activation of Akt protein, which will down-regulate GSK3b by phosphorylation of Ser9.

However, when the exposure to oxidative stress lasts too long, the level of Akt protein is decreased. Similar effect is observed in hypoxia:

The PI3K/Akt pathway was necessary for HIF-1α stabilization early during hypoxia. Indeed, its inhibition was sufficient to decrease HIF-1α protein level after 5-h incubation in hypoxia.

However, longer exposure (16 h) in hypoxia resulted in a decreased HIF-1α protein level compared with early exposure (5 h). At that time, Akt was no longer present or active, which resulted in a decrease in the inhibiting phosphorylation of GSK3β on Ser-9 and hence in an increased GSK3β activity. GSK3 inhibition reverted the effect of prolonged hypoxia on HIF-1α protein level (R4)

It’s suggested that ROS and Ceramide may play a role in this (R1).

Reduced concentration of Akt protein leads to decreased sensitivity to insulin and reduced activation of Nrf2 in preparation to glucose oxidation, at the same time inhibition of GSK3b is also reduced because Akt is a potent inhibitor of GSK3b.

Increased activity of GSK3b leads to increased oxidative stress, impaired formation of GABA receptors and so on.

Role of Akt in neurotransmission

TBD

Factors improving Akt activity

Calcium and Calmodulin

In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs.

We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). 

Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. (R2)

Note: strontium may have the opposite effect, because it replaces calcium. Personal experience with strontium shows increased OCD (Just Right OCD, but not contamination OCD).

Chromodulin

Chromodulin - a low weight protein that carries up to 4 atoms of Chromium was shown to amplify and rescue activities of both PI3K and Akt:

In a nutritional model of insulin resistance in which the mice were fed a high-sucrose diet or a high-fat diet, chromium treatment reconciled the blunted Akt phosphorylation and the attenuated PI3-kinase activity, consistent with the studies by Cefalu and coworkers.

To understand whether this was a direct effect of chromium on insulin signaling, cultured adipocytes were rendered insulin resistant by chronic treatment with insulin and glucose (hyperinsulinemic, hyperglycemic conditions) resulted in a blunting of insulin-stimulated Akt phosphorylation and cellular glucose uptake. Both these effects were inhibited by pretreating the cells with the chromium complex, results consistent with a direct action of chromium on insulin signalling. (R3)