inositol-1-4-5-trisphosphate and Bipolar-Disorder

Topics: Animals; Bipolar Disorder; Cerebral Cortex; Guinea Pigs; History, 20th Century; Humans; Inositol 1,4,5-Trisphosphate; Lithium; Macaca mulatta; Mice; Neurophysiology; Phosphatidylinositols; Rats; Second Messenger Systems

Medicinal drugs do not always have clearly understood mechanisms of action, especially as regards psychiatric treatment. Identification of genes involved in drug resistance is an important step toward elucidating the genetic basis of disease and the molecular mechanism of drug action. However, this approach is impractical in higher animals, as ablation and screening of every gene in an animal is not currently possible. Dictyostelium has proven a good model system for molecular pharmacological research as a result of its genetic tractability, ease of gene knockout, and creation of isogenic lines. In this system, we have identified genes that confer resistance to bipolar disorder drugs. This work has implicated inositol (1,4,5) trisphosphate (InsP3) signaling as a common mechanism of action for these drugs in patients.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Dictyostelium; Disease Models, Animal; DNA Transposable Elements; Drug Evaluation, Preclinical; Drug Resistance; Gene Deletion; Gene Targeting; Humans; Inositol 1,4,5-Trisphosphate; Pharmacogenetics; Restriction Mapping

Inositol-1,4,5-trisphosphate (InsP3) depletion has been implicated in the therapeutic action of bipolar disorder drugs, including valproic acid (VPA). It is not currently known whether the effect of VPA on InsP3 depletion is related to the deleterious effects of teratogenicity or elevated viral replication, or if it occurs via putative inhibitory effects on glycogen synthase kinase-3beta (GSK-3beta). In addition, the structural requirements of VPA-related compounds to cause InsP3 depletion are unknown. In the current study, we selected a set of 10 VPA congeners to examine their effects on InsP3 depletion, in vivo teratogenic potency, HIV replication, and GSK-3beta activity in vitro. We found four compounds that function to deplete InsP3 in the model eukaryote Dictyostelium discoideum, and these drugs all cause growth-cone enlargement in mammalian primary neurons, consistent with the effect of InsP3 depletion. No relationship was found between InsP3 depletion and teratogenic or elevated viral replication effects, and none of the VPA congeners were found to affect GSK-3beta activity. Structural requirements of VPA congers to maintain InsP3 depletion efficacy greater than that of lithium are a carboxylic-acid function without dependence on side-chain length, branching, or saturation. Noteworthy is the enantiomeric differentiation if a chiral center exists, suggesting that InsP3 depletion is mediated by a stereoselective mode of action. Thus, the effect of InsP3 depletion can be separated from that of teratogenic potency and elevated viral replication effect. We have used this to identify two VPA derivatives that share the common InsP3-depleting action of VPA, lithium and carbamazepine, but do not show the side effects of VPA, thus providing promising novel candidates for bipolar disorder treatment.

Topics: Animals; Bipolar Disorder; Cell Line; Drug Evaluation, Preclinical; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; HIV-1; Humans; Inositol 1,4,5-Trisphosphate; Rats; Teratogens; Valproic Acid; Virus Replication

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.

Topics: Animals; Animals, Newborn; Antimanic Agents; Bipolar Disorder; Calcium-Calmodulin-Dependent Protein Kinases; Carbamazepine; Cell Aggregation; Chemotaxis; Dictyostelium; Ganglia, Spinal; Genes, Protozoan; Glycogen Synthase Kinases; Growth Cones; Histone Deacetylase Inhibitors; Histone Deacetylases; Hydroxamic Acids; Inositol 1,4,5-Trisphosphate; Lithium; Mice; Mutation; Neurons, Afferent; Rats; Signal Transduction; Valproic Acid

Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder.

Topics: Adult; Base Sequence; Bipolar Disorder; Calcium Channels; DNA Mutational Analysis; Female; Humans; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Male; Middle Aged; Molecular Sequence Data; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Tacrolimus Binding Protein 1A

Valproic acid and lithium are effective antibipolar drugs. We recently showed that lithium stimulated the release of glutamate in monkey and mouse cerebral cortex slices, which, through activation of the N-methyl-D-aspartate receptor, increased accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. We show here that valproate behaves similarly to lithium in that at therapeutic concentrations it stimulates glutamate release and Ins(1,4,5)P3 accumulation in mouse cerebral cortex slices. The fact that these two effects are a common denominator for two structurally unrelated antibipolar drugs suggests that these effects are important in their antibipolar action. The effects of maximal concentrations of lithium and valproate on glutamate release are additive, suggesting different mechanisms for release, which are discussed. The additivity of the two drugs on glutamate release is consistent with the clinical benefit of combining the two drugs in the treatment of subsets of bipolar patients, e.g., in rapid cycling manic-depression. Unlike lithium, valproate does not increase accumulation of inositol monophosphates, inositol bisphosphates, or inositol 1,3,4-trisphosphate. This is additional evidence against the "inositol depletion" hypothesis, which states that, by trapping inositol in the form of inositol monophosphates and certain inositol polyphosphates, lithium exerts its antimanic action by inhibiting resynthesis of phosphoinositides with resultant blunting of Ins(1,4,5)P3 signaling.

Topics: Animals; Antidepressive Agents; Antimanic Agents; Bipolar Disorder; Cerebral Cortex; Drug Interactions; Glutamic Acid; Inositol 1,4,5-Trisphosphate; Inositol Phosphates; Lithium; Male; Mice; Mice, Inbred ICR; Molecular Mimicry; Receptors, N-Methyl-D-Aspartate; Valproic Acid