New drug targets in depression: Inflammatory, cell-mediate immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. and new drug candidates-Nrf2 activators and GSK-3 inhibitors
Maes M.,Maes Clinics at TRIA |
Fisar Z.,Charles University |
Medina M.,Noscira |
Scapagnini G.,University of Molise |
And 3 more authors.
Inflammopharmacology | Year: 2012
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 cyto-kines, 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. © 2011 CARS.
Noscira and Neuropharma | Date: 2010-07-13
Chemicals used in industry and science. [ Pharmaceutical preparations, in particular preparation for the treatment of neuron and central nervous system diseases, sanitary preparations for medical purposes; dietetic products for medical purposes in the nature of dietetic foods adapted for medical use ]. Scientific and technological services, namely, consulting services in the fields of medicine and pharmaceuticals; scientific and technology research in the fields of medicine and pharmaceuticals.
Noscira and Neuropharma | Date: 2010-03-30
Chemicals used in industry and science. Pharmaceutical preparations, in particular preparations for the treatment of neuron and central nervous system diseases, sanitary preparations for medical purposes; dietetic products for medical purposes in the nature of dietetic foods adapted for medical use. Business operation, business management, business marketing for the goods and services in the medical, pharmaceutical, parapharmaceutical, nutrition, perfumery, hygiene and oral care fields; advertising, business management and business administration. Scientific and technological services, namely, scientific research and technological consultation in the technology field of medical equipment and pharmaceutical products; scientific and technology research in the fields of medicine and pharmaceuticals. Medical assistance; medical information on the internet; medical information about pharmaceuticals.
Trueba-Saiz A.,Cajal Institute CSIC |
Trueba-Saiz A.,CIBER ISCIII |
Cavada C.,Metropolitan Autonomous University |
Fernandez A.M.,Cajal Institute CSIC |
And 9 more authors.
Translational Psychiatry | Year: 2013
Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymptomatic AD mice this reduction is already manifested as a decreased brain input of serum IGF-I in response to environmental enrichment. To explore a potential diagnostic use of this early loss of IGF-I input, we monitored electrocorticogram (ECG) responses to systemic IGF-I in mice. Whereas control mice showed enhanced ECG activity after IGF-I, presymptomatic AD mice showed blunted ECG responses. Because nonhuman primates showed identically enhanced electroencephalogram (EEG) activity in response to systemic IGF-I, loss of the EEG signature of serum IGF-I may be exploited as a disease biomarker in AD patients.
Monte F.L.,TU Darmstadt |
Kramer T.,TU Darmstadt |
Bolander A.,TU Darmstadt |
Plotkin B.,Tel Aviv University |
And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011
The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC 50 = 140 nM) and the pyridylurea 62 (IC 50 = 98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC 50 = 330 nM) in our assays. © 2011 Elsevier Ltd. All rights reserved.