ABSTRACT
Recent post-mortem and brain imaging studies suggest that decreased neuronal and glial densities may account for cell loss in vulnerable brain regions such as the hippocampus and the frontal cortex in patients with bipolar disorder. Investigations into the mechanisms of action of mood stabilizers suggest that these drugs may regulate the expression of neuroprotective genes and protect against excitotoxicity. In this study, we characterized the ultrastructural appearance of rat hippocampal neurons pretreated with mood stabilizers and then exposed to the glutamate receptor agonist N-methyl-D-aspartate. Using transmission electron microscopy we found that rat hippocampal neurons exposed to 0.5 mM N-methyl-D-aspartate for 10 min produced more cytoplasmic vacuolization than in control neurons. Chronic treatment with mood stabilizers, lithium, valproate or carbamazepine for 7 days at therapeutically relevant concentrations fully attenuated N-methyl-D-aspartate-mediated cytoplasmic vacuolization. These results suggest that inhibition of neurotoxicity may be involved in the action of mood stabilizers.
Subject(s)
Antimanic Agents/pharmacology , Bipolar Disorder/drug therapy , Cytoplasm/drug effects , Hippocampus/drug effects , N-Methylaspartate/antagonists & inhibitors , Nerve Degeneration/drug therapy , Neuroprotective Agents/pharmacology , Animals , Bipolar Disorder/pathology , Bipolar Disorder/physiopathology , Carbamazepine/pharmacology , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Cytoplasm/pathology , Cytoplasm/ultrastructure , Drug Interactions/physiology , Fetus , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/pathology , Hippocampus/ultrastructure , Lithium/pharmacology , Microscopy, Electron , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Neurons/drug effects , Neurons/pathology , Neurons/ultrastructure , Phosphopyruvate Hydratase/metabolism , Rats , Treatment Outcome , Vacuoles/drug effects , Vacuoles/pathology , Vacuoles/ultrastructure , Valproic Acid/pharmacologyABSTRACT
An increasing body of evidence demonstrates that lithium and valproate have a regulatory effect on signal transduction pathways. Alteration of signalling molecules triggers changes in gene expression which are thought to contribute to the therapeutic effects of these drugs on bipolar disorder. Differential-display PCR was used to identify genes in rat cerebral cortex that are regulated by chronic treatment with lithium and valproate. One novel lithium-regulated gene was identified and was characterized and studied further with 5'-RACE-PCR and library screening. We also found that valproate regulated the expression of the 78-kDa glucose-regulated protein (GRP78). Chronic treatment with valproate has also been found to increase gene transcription, mRNA and protein levels of GRP78. These results suggest novel targets for lithium and valproate that may be relevant to their mechanism of action. The data further our understanding of the mechanism of the action of mood stabilizers, and help identify new targets for genetic studies and therapeutic strategies in bipolar disorder.
Subject(s)
Antimanic Agents/pharmacology , Carrier Proteins/drug effects , Cerebral Cortex/drug effects , Gene Expression Profiling/methods , Gene Expression Regulation/drug effects , Heat-Shock Proteins , Molecular Chaperones/drug effects , Valproic Acid/pharmacology , Animals , Bipolar Disorder/drug therapy , Bipolar Disorder/genetics , Bipolar Disorder/metabolism , Carrier Proteins/metabolism , Cerebral Cortex/metabolism , Endoplasmic Reticulum Chaperone BiP , Gene Expression Regulation/physiology , Humans , Lithium Chloride/pharmacology , Molecular Chaperones/metabolism , Polymerase Chain Reaction/methods , RNA, Messenger/analysis , Valproic Acid/therapeutic useABSTRACT
The anticonvulsant sodium valproate has been shown to be an effective treatment for bipolar disorder, however, its precise mechanism of action has yet to be determined. It has been suggested that adaptational changes in gene expression are critical for valproate's prophylactic effects. Previous studies in our lab have shown that one gene that may be regulated by valproate is the 78-kilodalton glucose-regulated protein (GRP78). We report that treatment of rat C6 glioma cells with valproate can also increase the expression of additional endoplasmic reticulum stress proteins, GRP94 and calreticulin. All three proteins showed similar concentration-dependent increases in messenger RNA abundance. Chronic (seven days) treatment significantly increased GRP78 and GRP94 messenger RNA expression, whereas calreticulin expression increased after both acute and chronic treatment. Increases in mRNA expression corresponded to a similar increase in protein expression. The roles of GRP78, GRP94 and calreticulin as molecular chaperones and calcium binding proteins, suggest that these results might have functional relevance to the therapeutic action of valproate.
