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Caraci F.,University of Catania | Caraci F.,Institute for Research on Mental Retardation and Brain Aging | Di Sciascio G.,University of Bari
Journal of Psychopathology | Year: 2015

Recent evidence, such as that from the STAR-D study, have demonstrated that several unmet needs are still present in the treatment of major depression. The "classical" approach adopted to develop new antidepressants drugs, based on selectivity, did not result in increased remission rates in clinical practice, whereas multi-modality represents a new approach to develop novel antidepressants endowed with multiple actions that affect several pharmacological targets. Multimodal antidepressants, developed in the last three years, act through at least two pharmacological modes of action (serotonin reuptake inhibition, agonist/antagonists on neurotransmitter receptors) on at least two or more pharmacologic targets. Vortioxetine is a novel multimodal antidepressant that exerts its antidepressant efficacy in animal models of depression through a combination of two pharmacological modes of action: reuptake inhibition and receptor activity. In vitro studies indicate that vortioxetine is antagonist of 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist of 5-HT1B receptors, an agonist of 5-HT1A receptors, and inhibitor of the serotonin transporter. The combination of 5-HT1A agonism with 5-HT3 antagonism can explain the rapid 5-HT cell firing induced by vortioxetine compared to SSRIs such as fluoxetine. Vortioxetine is also able to activate the glutamatergic system in the rat frontal cortex through antagonism at 5-HT3, 5-HT7 receptors. All these pharmacological modes of action can contribute to explain the increased clinical efficacy of vortioxetine in the treatment of cognitive symptoms of depression. Cognitive deficits in depression are often associated with both a suboptimal response to antidepressants and reduced remission rates. Vortioxetine is the first multimodal antidepressant available for the treatment of depression with a specific, positive impact on cognitive symptoms. Source

Caraci F.,University of Catania | Battaglia G.,I.N.M. Neuromed | Bruno V.,I.N.M. Neuromed | Bosco P.,Institute for Research on Mental Retardation and Brain Aging | And 8 more authors.
CNS Neuroscience and Therapeutics | Year: 2011

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease-modifying drugs. Recently, a specific impairment of transforming-growth-factor-β1 (TGF-β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF-β1 signaling has been shown to increase both Aβ accumulation and Aβ-induced neurodegeneration in AD models. The loss of function of TGF-ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF-β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF-β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ-induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF-β1 in AD, and discuss the TGF-β1 signaling pathway as a new pharmacological target for the treatment of AD. © 2009 Blackwell Publishing Ltd. Source

Malaguarnera G.,University of Catania | Gagliano C.,University of Catania | Salomone S.,University of Catania | Giordano M.,University of Turin | And 7 more authors.
Clinical Ophthalmology | Year: 2015

Background: Folate deficiency is associated with cardiovascular disease, megaloblastic anemia, and with hyperhomocysteinemia. This study has been undertaken to investigate the role of folate status during the progression of the diabetic retinopathy. Methods: We measured the plasma levels of homocysteine, folic acid, and red cell folate in 70 diabetic type 2 patients with nonproliferative diabetic retinopathy (NPDR), 65 with proliferative diabetic retinopathy (PDR), 96 without diabetic retinopathy, and 80 healthy subjects used as a control group. Results: We found higher plasma levels of homocysteine in the NPDR group compared to the control group (P<0.001) and in the PDR group compared to control group (P<0.001) and NPDR group (P<0.01). The severity of diabetic retinopathy was associated with lower folic acid and red cell folate levels, and a significant difference was observed between PDR and NPDR groups (P<0.05). Conclusion: The folate status could play a role in the development and progression of diabetic retinopathy. © 2015 Malaguarnera et al. Source

di Nuzzo L.,University of Rome La Sapienza | Orlando R.,Institute for Research on Mental Retardation and Brain Aging | Nasca C.,University of Rome La Sapienza | Nicoletti F.,University of Rome La Sapienza
Drug Design, Development and Therapy | Year: 2014

New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood-brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism. © 2014 di Nuzzo et al. Source

Caraci F.,University of Catania | Spampinato S.,University of Catania | Sortino M.A.,University of Catania | Bosco P.,Institute for Research on Mental Retardation and Brain Aging | And 7 more authors.
Cell and Tissue Research | Year: 2012

Alzheimer's disease (AD) is a neurodegenerative disorder that affects about 35 million people worldwide. Current drugs for AD only treat the symptoms and do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Identification of the molecular determinants underlying Aβ-induced neurodegeneration is an essential step for the development of disease-modifying drugs. Recently, an impairment of the transforming growth factor-β1 (TGF-β1) signaling pathway has been demonstrated to be specific to the AD brain and, particularly, to the early phase of the disease. TGF-β1 is a neurotrophic factor responsible for the initiation and maintenance of neuronal differentiation and synaptic plasticity. The deficiency of TGF-β1 signaling is associated with Aβ pathology and neurofibrillary tangle formation in AD animal models. Reduced TGF-β1 signaling seems to contribute both to microglial activation and to ectopic cell-cycle re-activation in neurons, two events that contribute to neurodegeneration in the AD brain. The neuroprotective features of TGF-β1 indicate the advantage of rescuing TGF-β1 signaling as a means to slow down the neurodegenerative process in AD. © Springer-Verlag 2011. Source

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