Inhibition of the High Affinity Myo-Inositol Transport System A Common Mechanism of Action of Antibipolar Drugs?

Abstract

Manic-depressive disorder is an at least in part genetically transmitted illness that affects one to two percent of the population and is characterized by episodic mood swings in the form of depressive, and manic episodes (Goodwin and Jamison 1990). It can be effectively treated acutely and prophylactically by antibipolar drugs like lithium salts, carbamazepine and valproate. Recent evidence indicates that lithium's beneficial effects might be related to a modulation of cellular signal transducing mechanisms (for review see Berridge et al. 1989;Jope and Williams 1994). In particular, the "inositol depletion" hypothesis (Berridge et al. 1989) conjectures that lithium might act via depletion of susceptible brain areas of myo-inositol, which is necessary to form inositolphospholipids, an integral part of the cell membrane. The breakdown of these lipids by receptor-triggered activation of phospholipase C leads to the formation of the two second messenger molecules, inositol-1,4,5-trisphosphate and diacylglycerol (DAG), which regulate many cellular activities. The lithium induced decrease of the cellular inositol content is postulated to selectively impair pathological overactivation of this system via insufficient supply of inositol for the resynthesis of inositolphospholipid or perhaps other mechanisms secondary to inositol depletion such as activation of protein kinase C (PKC) by accumulated DAG (Jope and Williams 1994). The reason for lithium's inositol depleting effect and for its selectivity for overactivated neural circuits is believed to be the inhibition of inositolmonophosphatase (IMPase), which is of the uncompetitive type and therefore the more pronounced the more substrate (inositolmonophosphate, IMP) is formed by breakdown of inositolphospholipids. The inositol depletion hypothesis rests

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

“…This includes inositol monophosphatase (Shamir et al 1998), diphosphoinositol polyphosphate phosphohydrolase II (Hua et al 2001), sodium/myo-inositol cotransporter (Lubrich and van Calker 1999), aldolase A (Hua et al 2000) and C isozymes (Hua and Li, unpublished), prolyl oligopeptidase (Williams et al 1999), and CD151 (present study). Such a cluster of changes is unlikely a chance event.…”

Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder

“…These data are somewhat unexpected in light of the demonstration that the mood-stabilizers lithium, valproate and carbamazepine decrease the cellular content of myo-inositol in neuronal cell lines, [40][41][42] and inositol depletion has been implicated as part of a common mechanism of action for these drugs. This apparent discrepancy might be explained by recent results showing that these mood stabilizers increase inositol uptake at low cellular inositol levels and, on the other hand, reduce the inositol uptake at high cellular inositol levels.…”

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

“…Both valproate and lithium have been shown to interact with the intracellular transport and biosynthesis of myo-inositol in the cell, [45][46][47] possibly explaining the observed decrease. Both also downregulate the inositol triphosphate second messenger system.…”