Lithium regulation of aldolase A expression in the rat frontal cortex: identification by differential display (original) (raw)
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International Journal of Molecular Sciences, 2021
Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 s...
Exploring lithium’s transcriptional mechanisms of action in bipolar disorder: a multi-step study
Neuropsychopharmacology
Lithium has been the first-line treatment for bipolar disorder (BD) for more than six decades. Although the molecular effects of lithium have been studied extensively and gene expression changes are generally believed to be involved, the specific mechanisms of action that mediate mood regulation are still not known. In this study, a multi-step approach was used to explore the transcriptional changes that may underlie lithium’s therapeutic efficacy. First, we identified genes that are associated both with lithium exposure and with BD, and second, we performed differential expression analysis of these genes in brain tissue samples from BD patients (n = 42) and healthy controls (n = 42). To identify genes that are regulated by lithium exposure, we used high-sensitivity RNA-sequencing of corpus callosum (CC) tissue samples from lithium-treated (n = 8) and non-treated (n = 9) rats. We found that lithium exposure significantly affected 1108 genes (FDR
Neuroscience, 2008
The mechanisms underlying lithium's therapeutic efficacy in the chronic treatment of bipolar disorder are not clearly understood. Useful insights can be obtained by identifying genes that are differentially regulated during chronic lithium treatment. Toward this end, we have used microarray technology to identify mRNAs that are differentially expressed in a human neuronal cell line that has been continuously maintained in therapeutic levels of lithium for 33 days. Significantly, unlike other transcriptomes where predominantly rodent cells were used and a limited number of genes probed, we have used human cells probed with more extensive 44,000 gene microarrays. A total of 671 differentially regulated transcripts, after correcting for false discovery rates, were identified, of which 347 and 324, respectively, were found to be upand downregulated. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, was the most upregulated while tribbles homolog 3 (TRB3), a pro-apoptotic protein, was the most downregulated, implying a beneficial effect of lithium on neuronal cells. Several of the most highly regulated genes are novel, uncharacterized and encode proteins of unknown function. Differentially expressed genes associated with phosphoinositide metabolism include those encoding phosphatidyl inositol 4-phosphate 5-kinase type II ␣ (PIP5K2A), WD repeat domain, phosphoinositide interacting 1 protein (WIPI49), tribbles homolog 3 (TRB3) and sorting nexin 14 (SNX14). A protein interactome using some of the saliently regulated genes identified protein kinase C (PKC) as a major target for lithium action while a global analysis of all 671 differentially expressed genes identified the mitogen-activated protein kinase pathway as the most regulated. The list of highly regulated genes, besides encoding putative targets for antimanic agents, should prove useful in defining novel pathways, or to better understand the mechanisms, underlying the mood stabilization process.
Regulation of a2-adrenoceptor gene expression by chronic lithium treatment in rat brain
Methods and Findings in Experimental and Clinical Pharmacology, 2010
One of the approaches for the treatment of bipolar disorder involves the coadministration of lithium, a mood stabilizer, with α 2 -adrenoceptor antagonists possessing an antidepressant effect. Since lithium accelerates the recovery of α 2D -adrenoceptors following their irreversible inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), our aim was to examine if it could be to some changes in Adra2A gene expression which codifies these adrenoceptors. Animals were treated with lithium chloride (120 mg/kg i.p.) or saline once a day for 10 days. A group of lithium-or saline-treated rats was killed 48 h after the last injection. The remaining animals were treated with EEDQ and were killed at 0.25, 4 and 14 days following this administration. Total RNA was extracted from cerebral cortex and Adra2A gene expression was measured by RT-QPCR. The results show that chronic lithium raised the Adra2A gene expression (P < 0.05), and after EEDQ administration this expression decreased to the basal level. No change in Adra2A gene expression was detected in the saline-treated group. However, EEDQ administration produced an insignificant increase in α 2D -adrenoceptors mRNA levels followed by a progressive decrease until basal levels. Lithium produced an overexpression of the Adra2A gene after chronic treatment that made the neuron ready to produce α 2D -adrenoceptors to deal with their inactivation.
Lithium stimulates gene expression through the AP-1 transcription factor pathway
Molecular Brain Research, 1998
Ž. Lithium, a monovalent cation, is the mainstay in the treatment of manic-depressive MDI illness, but despite extensive research, its mechanism of action remains to be elucidated. Since lithium requires chronic administration for therapeutic efficacy, and because its beneficial effects last well beyond its discontinuation, it has been postulated that lithium may exert major effects at the genomic level. In the present study we found that lithium, at therapeutically relevant concentrations, increases AP-1 DNA binding activity in human SH-SY5Y cells and rat C6 glioma cells. Additionally, in both SY5Y and C6 cells transiently transfected with a reporter gene vector driven by an SV40 promoter, lithium increased the activity of the reporter gene in a time-and concentration-dependent manner. Furthermore, mutations in the AP-1 sites of the reporter gene promoter significantly attenuated lithium's effects. These data indicate that lithium stimulates gene expression through the AP-1 transcription factor pathway, effects which may play a role in its long-term mood-stabilizing effects.
Gene-expression studies in understanding the mechanism of action of lithium
Expert Review of Neurotherapeutics, 2012
Lithium salts are among the drugs of choice for the treatment of bipolar disorder. Despite six decades of intensive research and an accumulating number of known cellular targets, lithium's mechanism of action still needs to be unraveled. The evolution of large-scale gene-expression analysis methodologies has provided a promising tool to understand the cellular events underlying the mood-stabilizing effect of the drug. However, despite great improvement achieved in transcriptome studies, findings of genes differentially expressed by lithium treatment exhibit, so far, a low reproducibility rate. This review discusses the different design and data analysis strategies applied in the studies and summarizes the possible reasons for the discrepancies among the reports.
The Pharmacogenomics Journal, 2013
This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n ¼ 28) or without (n ¼ 32) Li. Peripheral blood gene-expression was measured before and 1month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n ¼ 9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.
Neuropsychopharmacology, 2005
Lithium chloride (LiCl), when fed to rats for 6 weeks, has been reported to decrease brain mRNA, protein, and activity levels of arachidonic acid (AA)-selective cytosolic phospholipase A 2 (cPLA 2 ), without affecting secretory sPLA 2 or Ca 2 þ -independent iPLA 2 . We investigated whether transcription factors known to regulate cPLA 2 gene expression are modulated by chronic lithium treatment. Male Fischer-344 rats were fed a LiCl-containing diet for 6 weeks to produce a therapeutically relevant brain lithium concentration. Control animals were fed a LiCl-free diet. Using a gelshift assay, we found that LiCl significantly decreased activating protein 2 (AP-2)-binding activity, and protein levels of the AP-2 a and AP-2 b but not of the AP-2 g subunits in the frontal cortex. Activating protein 1 (AP-1)binding activity was increased, whereas glucocorticoid response element, polyoma enhancer activator 3, and nuclear factor kappa B DNA-binding activities were not changed significantly. Since both cPLA 2 and AP-2 can be activated by protein kinase C (PKC), we examined the frontal cortex protein levels of PKC a and PKC e, as well as AA-dependent PKC activity. The protein levels of PKC a and PKC e were decreased significantly, as was AA-dependent PKC activity, in the lithium-treated compared to control rats. Our results suggest that the reported decrease in brain gene expression of cPLA 2 by chronic lithium may be mediated by reduced AP-2 transcriptional activity, and that decreased expression of PKC a and PKC e contributes to lowering the AP-2 activity.
Neuropsychopharmacology, 2007
The molecular mechanism of action of the mood stabilizer lithium is assumed to involve changes in gene expression leading to neuronal adaptation. The transcription factor CREB (cAMP-responsive element binding protein) regulates the expression of many genes and has been implicated in important brain functions and the action of psychogenic agents. We here investigated the effect of lithium on cAMPresponsive element (CRE)/CREB-mediated gene transcription in the brain, using transgenic reporter mice that express the luciferase reporter gene under the control of four copies of the rat somatostatin gene promoter CRE. Chronic (21 days) but not acute (24 h) treatment with lithium (7.5 mmol/kg) significantly decreased CRE/CREB-directed gene expression in hippocampus, cortex, hypothalamus, and striatum to 60-70%, and likewise reduced CREB phosphorylation. As bipolar disorder is also considered as a stress-related disorder, the effect of lithium was determined in mice submitted to a paradigm for chronic psychosocial stress. As shown before, stress for 25 days significantly increased CRE/CREB-directed gene expression in several brain regions by 100-150%. Treatment of stressed mice with lithium decreased stress-induced CRE/CREB-directed gene expression to control levels in nearly all brain regions and likewise reduced CREB phosphorylation. Chronic lithium treatment induced b-catenin accumulation and decreased cAMP levels, indicating an inhibitory effect of lithium on glycogen synthase kinase 3 and the adenylate cyclase/protein kinase A signalling cascade, which are known to modulate CREB activity. We here for the first time show that lithium regulates CRE/CREB-directed gene transcription in vivo and suggest CREB as a putative mediator of the neuronal adaptation after chronic lithium treatment.
Acta Neurobiologiae Experimentalis
Lithium is a mood stabilizer widely used in the pharmacotherapy of bipolar disorder and treatment‑resistant depression. Taking into account dysregulated inflammatory activity in depression and the immunomodulatory role of lithium, we hypothesized that genes associated with inflammatory responses may be potential biomarkers of lithium action. We aimed to compare gene expression changes between the brain and the periphery after chronic lithium administration in an animal model of depression. Depressive behavior was induced by chronic mild stress protocol for 4 weeks. After 2 weeks, rats started to receive lithium (study group) or water (reference group). The control group were rats not exposed to stress. Amygdala, hippocampus, frontal cortex and peripheral blood were analyzed using whole transcriptome expression microarrays. Changes were confirmed with qPCR and ELISA assay. After 2 weeks of lithium administration, we observed significant changes in gene expression between amygdala and...