The kynurenine pathway: A missing piece in the puzzle of valproate action?

Maciejak, Piotr; Szyndler, Janusz; Turzyńska, Danuta; Sobolewska, Alicja; Kołosowska, Karolina; Lehner, Małgorzata; Płaźnik, Adam

doi:10.1016/j.neuroscience.2012.12.052

Cited by 27 publications

(12 citation statements)

References 48 publications

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“…Interestingly, atypical antipsychotic medications have been reported to attenuate the typical pattern of hippocampal volume loss observed over time in schizophrenic patients (Koolschijn et al, 2010). In addition, administration of valproic acid, which we previously demonstrated to be associated with larger amygdala volumes in patients with bipolar disorder (BD) (Savitz et al, 2010), reportedly increased the levels of KA in the rat brain (Maciejak et al, 2013). In mice, peripheral administration of low-dose ketamine after injection with lipopolysaccharide (LPS) abrogated the LPS-induced depressive behavior, an effect that was due to ketamine's antagonistic effect at the NMDA receptor rather than suppression of cytokine release per se (Walker et al, 2013).…”

Section: Discussionmentioning

confidence: 82%

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

208

139

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Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/ QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

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Section: Discussionmentioning

confidence: 82%

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Savitz

Drevets

Smith

et al. 2014

Neuropsychopharmacol

208

139

View full text Add to dashboard Cite

show abstract

“…In our current sample of 38 BD patients, only 2 were treated with lithium and 4 were treated with divalproex, suggesting that atypical antipsychotics, lamotrigine, and SSRIs, the most commonly prescribed medications in our current sample, may not exert the equivalent hypertrophic effects. Interestingly, administration of valproic acid, which we previously demonstrated to be associated with larger amygdala volumes in BD patients (Savitz et al, 2010), reportedly increased the levels of KynA in the rat brain (Maciejak et al, 2013). Similarly, (Kocki et al, 2012) reported that 24–48 hours of exposure to selective serotonin reuptake inhibitors or tricyclic antidepressant medications stimulated the de novo synthesis of KynA and decreased 3HK production in astroglial cultures, thus resulting in an increase in the KynA to 3HK ratio.…”

Section: Discussionmentioning

confidence: 90%

Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder

Savitz

Dantzer

Wurfel

et al. 2015

Psychoneuroendocrinology

110

101

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Inflammation-related changes in the concentrations of kynurenine-pathway metabolites occur in depression secondary to medical conditions but have not been well characterized in primary bipolar disorder (BD), with contradictory results potentially attributable to the presence or absence of psychosis and/or medication effects. In contrast, reductions in hippocampal and amygdalar volume that theoretically reflect dendritic atrophy occurring in the context of a neurotoxic process are commonly reported in unmedicated BD patients. Here we tested whether the concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid, QA) kynurenine-pathway metabolites were altered in primary BD and whether these metabolites were associated with hippocampal and amygdalar volume. Twenty-five moderately-to-severely depressed unmedicated subjects and 38 moderately-to-severely depressed medicated subjects who met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs) completed a structural MRI scan and provided a blood sample for kynurenine metabolite analysis, performed using high performance liquid chromatography with tandem mass spectrometry. Gray matter volumes were measured with the automated segmentation software, FreeSurfer. A putative neuroprotective index, KynA/QA, was significantly lower in the BD subjects relative to the HCs, a finding that was unrelated to current treatment with medication or a prior history of psychosis. Further, another putative neuroprotective index, KynA/3HK was positively associated with hippocampal volume in the BD group after controlling for age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK was significantly associated with total amygdalar volume in the BD group, but after controlling for age, sex, BMI, but not ICV, this association was reduced to a trend. In addition, Kyn/3HK was positively associated with amygdalar volume in the HCs although the association was no longer significant after accounting for the effects of age, sex, and BMI. The results raise the possibility that BD-associated abnormalities in kynurenine metabolism may impact the structure of the hippocampus and amygdala, highlighting a pathway through which inflammation may exert neuropathological effects in the context of depression.

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“…7 Finally, VPA has anti-inflammatory and antioxidant properties 2 ; exerts transcriptional effects through epigenetic modulation of gene expression, 2 including histone deacetylase inhibition; and has beneficial effects on the kynurenine pathway. 8 Currently, the data on VPA's efficacy in delirium are limited to only two case series comprising a total of eight patients. 9,10 In addition, there are limited data on VPA's usefulness in the management of agitation in patients with dementia, 11 traumatic brain injury (TBI), 12 alcohol withdrawal, and corticosteroidinduced mania.…”

mentioning

confidence: 99%

Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale

Sher¹,

Miller²,

Lolak³

et al. 2015

JNP

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The kynurenine pathway: A missing piece in the puzzle of valproate action?

Cited by 27 publications

References 48 publications

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Putative Neuroprotective and Neurotoxic Kynurenine Pathway Metabolites Are Associated with Hippocampal and Amygdalar Volumes in Subjects with Major Depressive Disorder

Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder

Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale

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