Elsevier

Brain, Behavior, and Immunity

Volume 66, November 2017, Pages 94-102
Brain, Behavior, and Immunity

Full-length Article
Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain

https://doi.org/10.1016/j.bbi.2017.07.008Get rights and content

Highlights

  • Nerve injury induces depression and upregulates kynurenine 3-monoxygenase (KMO) expression and activity.

  • KMO is upregulated in neurons in the contralateral hippocampus and not in microglia.

  • Upregulation of KMO is downstream of cerebral interleukin-1 signaling.

  • Inhibition of brain KMO reverses depression but not allodynia after nerve injury.

Abstract

Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain interleukin (IL)-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior.

SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia.

Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1 receptor antagonist after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI.

We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression.

Introduction

The lifetime prevalence of major depressive disorder in the general population is in the range of 10–20% (Demyttenaere et al., 2004, Kessler et al., 2012). However, the prevalence of depression is significantly higher in individuals presenting with chronic pain (20–80%), indicating that chronic pain is an important risk factor for developing depression (Bair et al., 2003, Gustorff et al., 2008, Leo, 2005, Poole et al., 2009). The treatment of major depression remains a major challenge. Only a small portion of patients with major depression responds to treatments targeting monoamine reuptake (Souery et al., 2011, Thase et al., 2001). Moreover, patients with chronic pain and depression are poorly responsive to current antidepressant treatments (Karp et al., 2005).

Depression is associated with activation of the innate immune system (Capuron et al., 2002, Dowlati et al., 2010, Miller and Raison, 2016). Preclinical studies have shown that peripheral inflammation induces depression-like behavior in addition to sickness in rodents (Dantzer et al., 2008). The development of inflammation-induced depression-like behavior is mediated by activation of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO1) (O'Connor et al., 2009). IDO1 initiates the metabolism of tryptophan into kynurenine (KYN). Kynurenine can be further converted to 3-hydroxy-kynurenine (3-HK) by kynurenine 3-monooxygenase (KMO), and ultimately transformed into quinolinic acid (QA) by kynureninase (KYNU) and 3-hydroxyanthralinic acid dioxygenase (HAAO) (Schwarcz and Stone, 2017). Quinolinic acid is a neurotoxic N-methyl-D-aspartate receptor (NMDAR) agonist (Guillemin, 2012, Santamaria and Rios, 1993). Elevations of QA concentrations have been reported in serum and CSF of patients with symptoms of depression (Baranyi et al., 2015, Bay-Richter et al., 2015, Raison et al., 2010, Savitz et al., 2015b, Vogelgesang et al., 1996). Interestingly, elevated QA is associated with smaller hippocampal volume in unmedicated individuals with major depression (Savitz et al., 2015a), which is important because reduced hippocampal volume is a hallmark of major depressive disorder (Arnone et al., 2016). Modulating the kynurenine pathways has been proposed to represent a potential novel strategy to treat depression (Dantzer et al., 2011, Parrott and O'Connor, 2015).

The role of inflammation in the pathophysiology of depression is usually studied in rodents injected with the potent pro-inflammatory cytokine inducer lipopolysaccharide (LPS). LPS induces a transient episode of depression-like behavior followed by a return to baseline within 48 h (Dantzer et al., 2008). In this model, the development of depression-like behavior is dependent on the activation of NMDA receptors by elevated QA (Walker et al., 2013). Kynurenine metabolism is strongly skewed toward production of neurotoxic KMO-dependent metabolites in the hippocampus following LPS challenge (Parrott et al., 2016a). Genetic deletion of Kmo or Haao, the downstream enzyme of KMO responsible for QA production, prevents depression-like behavior in response to LPS (Parrott et al., 2016b). Depression-like behavior is also observed in animal models of neuropathic pain induced by peripheral nerve injury (Kontinen et al., 1999, Norman et al., 2010, Zhou et al., 2015). In contrast to LPS, nerve injury induces a long-lasting (if not permanent) depression-like behavior together with a low grade peripheral inflammation, which closely reflects what is observed clinically.

In a previous study, we demonstrated that depression-like behavior in mice submitted to spared nerve injury (SNI) is mediated by activation of peripheral but not brain IDO1 in association with increased circulating KYN (Zhou et al., 2015). Circulating KYN can enter the brain (Kita et al., 2002) where it can be metabolized further into neuroprotective kynurenic acid (KYNA) or neurotoxic 3-HK and QA metabolites. This last metabolic pathway is downstream of activation of KMO. We hypothesized that the development of depression-like behavior in SNI mice is dependent on brain KMO activity which is the rate limiting step for the metabolism of brain KYN into neurotoxic QA. Very little is known about the cellular basis of this metabolic step. It is commonly accepted that inflammation activates KMO in microglia (Corona et al., 2010, Gonzalez-Pena et al., 2016, Guillemin et al., 2003). However, interleukin (IL)-1β has been shown in vitro to increase the expression of Kmo mRNA in primary cultures of hippocampal neurons (Zunszain et al., 2012). As IL-1β is up-regulated in the brain of rodents subjected to SNI (del Rey et al., 2011, Norman et al., 2010) it could also up-regulate the expression of Kmo in neurons.

The goal of this study was to determine the contribution of brain IL-1β signaling and KMO to SNI-induced mechanical allodynia and depression-like behavior.

Section snippets

Animals

Male C57BL/6J mice (10–16 weeks old, The Jackson Laboratory, Bar Harbor, ME) were individually housed on a reversed light/dark cycle (lights on at 10:00 pm and off at 10:00 am). Water and food were available ad libitum. The study was conducted in accordance with NIH guidelines for the care and use of animals and under protocols approved by the Institutional Animal Care and Use Committee.

Surgery

SNI surgery was performed as described (Bourquin et al., 2006, Laumet et al., 2015). Briefly, the sural common

Depression-like behavior in SNI mice is not dependent on mechanical allodynia

SNI mice displayed mechanical allodynia and increased duration of immobility in FST (Norman et al., 2010, Zhou et al., 2015). To ensure that increased duration of immobility as a measure of depression-like behavior is not biased by increased mechanical allodynia, we examined the effect of the analgesic retigabine (10 mg/kg) on FST. First, we confirmed that 10 mg/kg retigabine reversed mechanical allodynia after SNI (Fig. S1A). Sham- and SNI-treated mice were injected with PBS or retigabine and

Discussion

Using SNI as a model of chronic pain and comorbid depression, we show that nerve injury upregulated neuronal KMO mRNA and protein levels in the contralateral hippocampus. SNI also increased expression of Kynu and Haao, and the ratio of QA-to-KYN in the contralateral hippocampus, indicating activation of the entire KMO branch of the kynurenine pathway. The SNI-induced upregulation of neuronal KMO was dependent of brain IL-1 signaling as it was abrogated by i.c.v administration of IL-1RA.

Declaration of interest

The work of Drs. Kavelaars, Heijnen, Dantzer, and O’Connor is supported by the NIH. Drs. Heijnen and Kavelaars received a grant from Acetylon Inc. for work not related to the present study. Dr. Dantzer has received an honorarium from Danone Nutricia Research, France. Drs. Lee and Budac were employed by Lundbeck Research USA at the time the analysis of kynurenine metabolites was carried out. The authors have no other potential conflicts of interest to disclose.

Acknowledgments

This work was supported by the National Institutes of Health R01 NS073939, R01 NS074999 and R01 MH090127, a STAR grant from The University of Texas Systems (A.K.), and a Cyrus Scholar Award from The University of Texas MD Anderson Cancer Center Division of Internal Medicine (G.L.).

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  • Cited by (0)

    1

    Indicates equal contribution from both authors: co-first authorship

    2

    Present address: Department of Medicine, Division of Endocrinology, Baylor College of Medicine, Houston, TX, USA.

    3

    At the time the analysis of kynurenine metabolites was carried out.

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