title: New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors.
abstract: This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.
authors.affiliation: Maes Clinics@TRIA, 998 Rimklongsamsen Road, Bangkok 10310, Thailand. dr.michaelmaes@hotmail.com
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
authors.forename: Zdenĕk
authors.initials: Z
authors.lastname: Fišar
authors.forename: Miguel
authors.initials: M
authors.lastname: Medina
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scapagnini
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D038362:Glycogen Synthase Kinase 3