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Inflammation, immunology, stress and depression: a role for kynurenine metabolism in physical exercise and skeletal muscle

Published online by Cambridge University Press:  02 February 2016

Florian Daniel Zepf
Affiliation:
Department of Child and Adolescent Psychiatry School of Psychiatry and Clinical Neurosciences & School of Paediatrics and Child Health, The University of Western Australia, Perth WA, Australia Specialised Child and Adolescent Mental Health Services (CAMHS), Department of Health in Western Australia, Perth, WAAustralia E-mail: florian.zepf@uwa.edu.au
R.M. Stewart
Affiliation:
Department of Child and Adolescent Psychiatry School of Psychiatry and Clinical Neurosciences & School of Paediatrics and Child Health, The University of Western Australia, Perth WA, Australia
G. Guillemin
Affiliation:
Neuropharmacology Group, Motor Neurone Disease and Neurodegenerative Diseases Research Centre Macquarie University, Sydney, NSW, Australia
J.L. Ruas
Affiliation:
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Stockholm, Sweden
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Abstract

Type
Letters to the Editor
Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

Dear editor,

Recent research has highlighted the importance of inflammatory properties in the underlying neurobiology of depression (Reference Kiecolt-Glaser, Derry and Fagundes1). However, in complement of the research mentioned above, we would like to highlight a few points, which in turn may have treatment implications for patients with depressive symptoms and in view of inflammatory processes, immunological factors and stress.

In particular, recent research findings relating to the tryptophan and kynurenine pathway, which stands in close relationship to inflammatory processes and associated mood changes, need to be considered. Research has shown that physical exercise can be considered as a potential further strategy for intervention in patients with depressive symptoms with somewhat moderate effect sizes, as well as regards anxiolytic properties with smaller effects (Reference Wegner, Helmich, Machado, Nardi, Arias-Carrion and Budde2).

However, the complete mechanism of action of this approach is not entirely understood. Tryptophan and thus kynurenine metabolism can be impacted via exercise-induced skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1-alpha-1 (PGC-1α1) (Reference Agudelo, Femenía and Orhan3). This mechanism, which builds on activation of a specific pathway involving PGC-1α1 and peroxisome proliferator-activated receptors alpha/delta (PPARα/δ) increases skeletal muscle expression of kynurenine aminotransferases, has protective properties with regards to stress-induced depressive symptoms, in particular as a reduction in kynurenine brain accumulation levels can protect the brain from stress-induced changes that are related to depressive symptoms (Reference Agudelo, Femenía and Orhan3). More precisely, an increased peripheral conversion of kynurenine into its metabolite kynurenic acid (which cannot overcome the blood–brain barrier) has been discussed as a main mechanism of action with regards to this process. Recent research carried out in rodents showed that skeletal muscle-specific PGC-1α1 transgenic mice were resistant to displaying depressive-like behaviours induced via kynurenine administration or exposure to chronic mild stress (Reference Agudelo, Femenía and Orhan3). As a consequence, changes in tryptophan metabolism and the closely related kynurenine pathway that impact skeletal muscle function via the PGC-1α1-PPAR could be explored as a new translational strategy for intervention, in particular with regards to the inflammatory properties that are thought to be related to depressive symptoms. Moreover, as outlined by Kiecolt-Glaser et al. (Reference Kiecolt-Glaser, Derry and Fagundes1), the gut microbiome as a factor potentially impacting systemic inflammation (i.e. as regards intestinal permeability) needs to be mentioned, in particular given the fact that the gut microbiome has been discussed to affect the availability of tryptophan and kynurenine (Reference Kiecolt-Glaser, Derry and Fagundes1,Reference O’Mahony, Clarke, Borre, Dinan and Cryan4). Such a mechanism could serve as an important regulating factor, in particular with regards to crosstalk within the brain–gut axis serving as a bidirectional communication system between the brain and the gastrointestinal tractus (Reference Kiecolt-Glaser, Derry and Fagundes1,Reference O’Mahony, Clarke, Borre, Dinan and Cryan4).

Besides the points highlighted, a further important aspect that needs to be outlined in the context of immunological processes that can be linked to depressive symptoms in humans is antiphospholipid syndrome. In patients with this particular syndrome, antibodies against phospholipids that are comparable with those detected in patients with systemic lupus (also known as lupus anticoagulant) can bind to proteins and cell membrane-based phospholipids and can be related to depressive symptoms (Reference Zepf and Stewart5Reference Mackworth-Young7). These particular antiphospholipid antibodies hold an important position in conditions such as depression, psychosis and dementia, and have recently been discussed in the context of suicidal ideation (Reference Zepf and Stewart5Reference Mackworth-Young7).

In summary, in the light of the outlined factors, we like to propose that research into inflammatory and immunological mechanisms as well as stress-related factors underpinning depressive symptoms needs to be fostered, in particular as regards the above-mentioned factors and mechanisms as well as their relationship to features of depressive symptoms in different populations.

Acknowledgements

F.D.Z. was the recipient of an unrestricted award donated by the American Psychiatric Association, the American Psychiatric Institute for Research and Education and AstraZeneca (Young Minds in Psychiatry Award). He has also received research support from the German Federal Ministry for Economics and Technology, the European Union, the German Society for Social Pediatrics and Adolescent Medicine, the Paul and Ursula Klein Foundation, the Dr. August Scheidel Foundation, the IZKF Fund of the University Hospital of RWTH Aachen University and a travel stipend donated by the GlaxoSmithKline Foundation. He is the recipient of an unrestricted educational grant, travel support and speaker honoraria by Shire Pharmaceuticals, Germany. In addition, he has received support from the Raine Foundation for Medical Research (Raine Visiting Professorship), and editorial fees from Co-Action Publishing (Sweden). The other authors have nothing to report or to disclose.

References

1. Kiecolt-Glaser, JK, Derry, HM, Fagundes, CP et al. Inflammation: depression fans the flames and feasts on the heat. Am J Psychiatry 2015;172:10751091.CrossRefGoogle ScholarPubMed
2. Wegner, M, Helmich, I, Machado, S, Nardi, AE, Arias-Carrion, O, Budde, H. Effects of exercise on anxiety and depression disorders: review of meta-analyses and neurobiological mechanisms. CNS Neurol Disord Drug Targets 2014;13:10021014.CrossRefGoogle ScholarPubMed
3. Agudelo, LZ, Femenía, T, Orhan, F et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 2014;159:3345.CrossRefGoogle Scholar
4. O’Mahony, SM, Clarke, G, Borre, YE, Dinan, TG, Cryan, JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 2015;277:3248.CrossRefGoogle ScholarPubMed
5. Zepf, FD, Stewart, RM. Inflammation, immunity and suicidality: a potential role for autoantibodies against neurotransmitters and antiphospholipid syndrome? Acta Psychiatr Scand 2015. doi:10.1111/acps.12508. [Epub ahead of print].Google ScholarPubMed
6. Rege, S, Mackworth-Young, C. Antiphospholipid antibodies as biomarkers in psychiatry: review of psychiatric manifestations in antiphospholipid syndrome. Transl Dev Psychiatry 2015;3:25452. http://dx.doi.org/10.3402/tdp.v3.25452.CrossRefGoogle Scholar
7. Mackworth-Young, CG. Antiphospholipid syndrome: multiple mechanisms. Clin Exp Immunol 2004;136:393401.CrossRefGoogle ScholarPubMed
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