RRC ID 6687
Author Williams RS, Cheng L, Mudge AW, Harwood AJ.
Title A common mechanism of action for three mood-stabilizing drugs.
Journal Nature
Abstract 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.
Volume 417(6886)
Pages 292-5
Published 2002-5-16
DOI 10.1038/417292a
PII 417292a
PMID 12015604
MeSH Animals Animals, Newborn Antimanic Agents / pharmacology* Bipolar Disorder / drug therapy Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors Calcium-Calmodulin-Dependent Protein Kinases / metabolism Carbamazepine / pharmacology* Cell Aggregation / drug effects Chemotaxis / drug effects Dictyostelium / cytology Dictyostelium / drug effects* Dictyostelium / genetics Ganglia, Spinal / cytology Genes, Protozoan / genetics Glycogen Synthase Kinases Growth Cones / drug effects* Growth Cones / enzymology Histone Deacetylase Inhibitors Histone Deacetylases / metabolism Hydroxamic Acids / pharmacology Inositol 1,4,5-Trisphosphate / metabolism Lithium / pharmacology* Mice Mutation / genetics Neurons, Afferent / cytology Neurons, Afferent / drug effects* Neurons, Afferent / enzymology Rats Signal Transduction / drug effects Valproic Acid / pharmacology*
IF 41.577
Times Cited 423
Cellular slime molds G00047