Neuroinflammation in Mood Disorders: Mechanisms and Drug Targets

• Autores: Allent T. Hopper, Kenneth A. Jones, Brian M. Campbell, Guiying Li
• Localización: Annual reports in medicinal chemistry, ISSN 0065-7743, Vol 48, 2013, págs. 317-331
• Idioma: inglés
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• Resumen

  • Abstract Several clinical observations point to a role of chronic inflammation in the progression of major depressive disorder. Attention is therefore shifting away from drugs that regulate monoamines to interventions that normalize an imbalance of inflammatory mediators such as cytokines and metabolites of tryptophan that participate in the central nervous system response to inflammation. Regulation of interleukin-1beta (IL-1β) biosynthesis is of interest since this is the key cytokine for initiating the innate immune response. In this respect, drug discovery efforts are focusing on two important components of the inflammasome: the purinergic receptor P2X7 and the cysteine protease caspase-1. Downstream of proinflammatory cytokine release, kynurenine metabolism is disturbed during inflammation, resulting in metabolism favoring production of quinolinic acid over kynurenic acid. This imbalance has been reported after both acute and chronic inflammation stimuli to induce mood disturbances in animal models. Inhibition of IDO (indolamine 2,3-dioxygenase) or KMO (kynurenine 3-monooxygenase) normalizes these disturbances providing support for these enzymes as potential drug discovery targets.