Serotonin – kynurenine hypothesis of depression: historical overview and recent developments

摘要

In the late 60^th - early 70^th of the last century Prof. IP Lapin (June 26, 1930 – August 23, 2012) suggested that “intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component” while “activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect”. He suggested that in depression cortisol-inducible activation of liver enzyme, tryptophan 2,3-dioxygenase (TDO), shunted “metabolism of tryptophan away from serotonin production towards kynurenine production” leading to serotonin deficiency. He was the first to suggest and discover that kynurenine and its metabolites affect brain functions, and propose the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect. Further major developments of serotonin-kynurenine hypothesis include the discovery of antidepressant and cognition-enhancing effects of post-serotonin metabolite, N-acetylserotonin, an agonist to tyrosine kinase B(TrkB) receptors of brain derived neurotrophic factor. The discovery of indoleamine 2,3–dioxygenase (IDO), another rate-limiting enzyme of TRY – KYN metabolism, located in brain and inducible by pro-inflammatory cytokines, suggested the link between depression and aging/aging-associated medical (e.g., insulin resistance, obesity, cardiovascular), psychiatric (e.g., vascular cognitive impairment) and other disorders associated with chronic inflammation (e.g., hepatitis virus C, psoriasis) disorders.