The Mood‐Stabilizing Agents Lithium and Valproate RobustlIncrease the Levels of the Neuroprotective Protein bcl‐2 in the CNS

Chen, Guang; Zeng, Wei‐Zhang; Yuan, Peixiong; Huang, Li-Dong; Jiang, Yiming; Zhao, Zhenying; Manji, Husseini K.

doi:10.1046/j.1471-4159.1999.720879.x

Cited by 456 publications

(283 citation statements)

References 21 publications

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“…Hence, we were unable to investigate the effect of longer chronic drug administration on gene expression. However, other groups have successfully maintained chronic administration of mood-stabilizing drugs in rats, 56,57 and as such, this may be a better therapeutic model for the future assessment of the differential expression of FAT and genes encoding its protein partners.…”

Section: Discussionmentioning

confidence: 99%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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“…This method has been used extensively to study the pharmacology of psychiatric medications. 7,40 The human prefrontal cortex, the post-mortem brain area under investigation here, has no known anatomical correlate in the rat brain. The approach here, therefore, was to examine the medication's effect in several different rat brain regions with the assumption that the changes that were found consistently in those regions would likely occur in the rat equivalent to the prefrontal cortex.…”

Section: Post-mortem Brain Tissue Analysismentioning

confidence: 97%

“…[3][4][5][6] Both medications have also been found to regulate biochemical processes involved in cellular protection. 7,8 Furthermore, in vivo magnetic resonance spectroscopy (MRS) of the brain has provided evidence for a neurotrophic/neuroprotective effect of lithium in patients. For example, lithium treatment has been shown to increase both gray matter density and levels of N-acetyl aspartate (NAA), a marker of neuronal viability, in the brain following chronic treatment.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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“…A recent report found that valproate also alters inositol metabolism by inhibiting myoinositol-1-phosphate synthase and causes inositol depletion by blocking de novo synthesis (Shaltiel et al, 2004). Manji and co-workers Chen et al, 1999b) have demonstrated in vivo that the apoptosis-inhibiting gene bcl-2 is induced both by lithium and valproate, assigning a potential neuroprotective role to these mood stabilizers. This group also reported that lithium treatment is associated with an increase in grey matter volume in patients (Moore et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila

Dokucu

Taghert

2005

Neuropsychopharmacol

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Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3b gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3b gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3b as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3b heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.

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The Mood‐Stabilizing Agents Lithium and Valproate RobustlIncrease the Levels of the Neuroprotective Protein bcl‐2 in the CNS

Cited by 456 publications

References 21 publications

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

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

Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila

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