Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

Abstract

Bipolar disorder is a major medical, social and economic burden worldwide. However, the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review studies using a neuropharmacological approach in unanesthetized rats, combined with kinetic, biochemical and molecular biology techniques, showing that chronic administration of three Food and Drug Administration-approved mood stabilizers (lithium, valproate and carbamazepine) at therapeutically relevant doses, selectively target the brain arachidonic acid (AA) cascade. Whereas chronic lithium and carbamazepine decrease the binding activity of activator protein-2 and in turn the transcription, translation and activity of its AA-selective calcium-dependent phospholipase A 2 gene product, valproate appears to be a non-competitive inhibitor of long-chain acyl-CoA synthetase. The net overlapping effects of the three drugs are decreased turnover of AA but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E 2 . Although these observations support the hypothesis proposed by Rapoport and colleagues that the AA cascade is a common target of mood stabilizers, this hypothesis is not necessarily exclusive of other targets. Targeting the AA cascade with drugs or diet may be a useful therapeutic approach in bipolar disorder, and examining the AA cascade in patients might help in better understanding the disease.

Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids

“…These effects are approximately opposite of what was observed with the low versus high n-3 PUFA diets in previous studies where low n-3 PUFA leads to conservation of DHA but not ARA ( 10,11 ). Recently, the Nurses' Health Study reported that an elevated intake of LA was associated with an increased risk of developing major depression ( 50 ), and preclinical studies suggest that drugs used to manage bipolar disorder decrease brain arachidonic acid metabolism ( 51,52 ). While much interest in dietary LA levels have focused around coronary heart disease risk, understanding how dietary n-6 PUFAs regulate the metabolism of ARA and DHA in the brain may also be important for determining dietary requirements.…”

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

“…[14][15][16][17][18][19] Moreover, a large body of data implies that inhibition of inflammation may contribute to the therapeutic effects of psychotropic drugs. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] However, it is important to emphasize that many studies reported opposite findings; namely, that psychotropic drugs also exhibit pro-inflammatory effects. 10,31,[38][39][40][41] Furthermore, the mechanism underlying the anti-inflammatory properties of psychotropic drugs is not fully understood and it is not known whether their influence on inflammation contributes to their therapeutic and toxic effects.…”

“…[56][57][58][59] Another inflammatory pathway that is frequently linked to the pathophysiology of neurological disorders is the cyclo-oxygenase (COX)-PGs cascade. 20,21 PGs such as PGE 2 not only have many important physiological functions, but also contribute to a number of pathological processes. [60][61][62][63] The biosynthesis of PGs involves the release of arachidonic acid (AA) from membrane phospholipids by phospholipase A 2 and its conversion to PGs by COX.…”

Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet

“…such as bipolar disorder, in which evidence points to a pathological upregulation of brain AA signaling ( 14 ).…”