Possible role for interactions between 5-lipoxygenase (5-LOX) and AMPA GluR1 receptors in depression and in antidepressant therapy.

Emerging evidence suggests that 5-lipoxygenase (5-LOX) plays a role in central nervous system functioning. It has been shown that 5-LOX metabolic products can decrease the phosphorylation of the glutamate receptor subunit GluR1, and that this effect can be antagonized by 5-LOX inhibitors. Recent concepts about the pathobiological mechanisms of depression and the molecular mechanisms of antidepressant activity postulate a significant role for glutamatergic neurotransmission and the GluR1 receptor. Regulation of GluR1 phosphorylation, i.e., enhancement of this phosphorylation, may be a part of antidepressant activity. On the other hand, reduced GluR1 phosphorylation may be a pathobiological mechanism contributing to depression. Since 5-LOX inhibitors, along with antidepressants share the capacity to increase GluR1 phosphorylation, we hypothesize that they may also have antidepressant properties. Furthermore, we postulate that increased brain 5-LOX expression may lead to decreased GluR1 phosphorylation and favor the development of depression. For example, brain 5-LOX expression is stimulated by stress hormone glucocorticoids, and stress is a known contributing factor in depression.