Mood-stabilizers target the brain arachidonic acid cascade

Abstract

Bipolar disorder (BD) is a severe psychiatric illness characterized by recurrent manic and depressive episodes, without a characteristic neuropathology or clear etiology. Drugs effective in BD target many key signaling pathways in animal and cell studies. However, their mode of action in the BD brain remains elusive. In the rat brain, some of the mood stabilizers effective in treating mania (lithium, carbamazepine, valproate) or depression (lamotrigine) in BD are reported to decrease transcription of cytosolic phospholipase A(2) and cyclooxygenase-2 and to reduce levels of AP-2 and NF-kappaB, transcription factors of the two enzymes. The anti-manic drugs also decrease arachidonic acid (AA) turnover in brain phospholipids when given chronically to rats. Thus, drugs effective in BD commonly target AA cascade kinetics as well as AA cascade enzymes and their transcription factors in the rat brain. These studies suggest that of BD is associated with increased AA signaling in the brain. Developing therapeutic agents that suppress brain AA signaling could lead to additional treatments for BD. In this review, we discuss the mechanisms of action of mood stabilizers and the effects of docosahexaenoic acid on AA cascade enzymes in relation to BD.

Figure-1

Arachidonic acid (AA) is released from membrane phospholipids at the sn-2 position by the catalytic action of Ca⁺⁺-dependent cytosolic phospholipase A_2. Released AA directly mediates various cellular actions or is converted into many bioactive metabolites by cyclooxygenases and other enzymes.

Figure-2

Chemical structures of mood stabilizers approved for treating bipolar disorder.

Figure-3

Chronic mood stabilizer administration to rats reduces AA turnover in membrane phospholipids by either inhibiting acyl-CoA synthethase or transcription of cPLA₂. Conversion of AA into eicosanoids is reduced by reduced cyclooxygenase-2 activity.