PhD ceremony Ms. N. Dobos: Neuroinflammation in depression

PhD ceremony: Ms. N. Dobos

Dissertation: Neuroinflammation in depression

Promotor(s): prof. U.L.M. Eisel, prof. P.G.M. Luiten, prof. J.A. den Boer

Faculty: Medical Sciences

Major depression (MD) is a devastating disease with a high lifetime prevalence worldwide. There have been several hypotheses proposed for MD, however, to date, none of them can meet all criteria to explain the pathogenesis of the disorder. Among others, neuroinflammation has been pointed out to be a key component of depression; therefore the rationale of the present thesis was to investigate the role of neuroinflammation in depression.

Immune activation, either in the periphery or in the central nervous system generates an inflammatory cascade, which might be responsible for altered brain functioning and behavioral changes. Inflammation-induced cytokine production and subsequent activation of the kynurenine pathway has been implicated in the pathophysiology of depression. Along the kynurenine pathway, tryptophan is metabolized and several neuroactive compounds are produced. The reduction of tryptophan levels may lead to serotonin depletion, which is believed to be one of the main causes of MD. Moreover, neurotoxic metabolites can further contribute to excitotoxicity and immune activation. The first and rate-limiting step of the kynurenine pathway is mediated by indoleamine 2,3 dioxygenase (IDO). We could demonstrate that neuroinflammation-induced depressive-like behavior is dependent on the activation of IDO what we could further confirm using a competitive IDO-inhibitor.

In the present thesis, novel findings support the neuroinflammatory theory of depression and evidence are provided for the involvement of the kynurenine pathway and the upregulation of IDO in major depression. The results presented here can contribute to open a new avenue in novel antidepressant therapies.