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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 March 2013, Vol.110(12), pp.4804-9
    Description: Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
    Keywords: Acetylcarnitine -- Pharmacology ; Antidepressive Agents -- Pharmacology ; Epigenesis, Genetic -- Drug Effects ; Hippocampus -- Metabolism ; Nerve Tissue Proteins -- Biosynthesis ; Prefrontal Cortex -- Metabolism ; Receptors, Metabotropic Glutamate -- Biosynthesis
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, March 19, 2013, Vol.110(12), p.4804(6)
    Description: Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-kB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action. doi/10.1073/pnas.1216100110
    Keywords: Antidepressants -- Research ; Antidepressants -- Analysis ; Depression (Mood disorder) -- Research ; Depression (Mood disorder) -- Analysis
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
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  • 3
    In: Neuropsychopharmacology, 2011, Vol.37(4), p.929
    Description: Prenatal exposure to restraint stress causes long-lasting changes in neuroplasticity that likely reflect pathological modifications triggered by early-life stress. We found that the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (here named 'prenatal restraint stress mice' or 'PRS mice') developed a schizophrenia-like phenotype, characterized by a decreased expression of brain-derived neurotrophic factor and glutamic acid decarboxylase 67, an increased expression of type-1 DNA methyl transferase (DNMT1) in the frontal cortex, and a deficit in social interaction, locomotor activity, and prepulse inhibition. PRS mice also showed a marked decrease in metabotropic glutamate 2 (mGlu2) and mGlu3 receptor mRNA and protein levels in the frontal cortex, which was manifested at birth and persisted in adult life. This decrease was associated with an increased binding of DNMT1 to CpG-rich regions of mGlu2 and mGlu3 receptor promoters and an increased binding of MeCP2 to the mGlu2 receptor promoter. Systemic treatment with the selective mGlu2/3 receptor agonist LY379268 (0.5 mg/kg, i.p., twice daily for 5 days), corrected all the biochemical and behavioral abnormalities shown in PRS mice. Our data show for the first time that PRS induces a schizophrenia-like phenotype in mice, and suggest that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress.
    Keywords: Medicine ; Pharmacy, Therapeutics, & Pharmacology ; Anatomy & Physiology;
    ISSN: 0893-133X
    E-ISSN: 1740634X
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  • 4
    Language: English
    In: Biological Psychiatry, 15 March 2015, Vol.77(6), pp.589-596
    Description: Prenatal stress (PRS) is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that PRS induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ, including the gene for brain-derived neurotrophic factor (BDNF). Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1, ten-eleven-translocation hydroxylases, methyl CpG binding protein 2, histone deacetylases, and histone methyltransferases and demethylase in the frontal cortex and hippocampus. We also measured the expression of BDNF. Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to changes seen in postmortem brains of patients with SZ. This includes a significant increase in DNA methyltransferase 1 and ten-eleven-translocation hydroxylase 1 in the frontal cortex and hippocampus but not in cerebellum; no changes in histone deacetylases, histone methyltransferases and demethylases, or methyl CpG binding protein 2, and a significant decrease in messenger RNA variants. The decrease of the corresponding transcript level was accompanied by an enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at gene regulatory regions. In addition, the expression of transcripts (IV and IX) correlated positively with social approach in both PRS mice and nonstressed mice. Because patients with psychosis and PRS mice show similar epigenetic signature, PRS mice may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with SZ.
    Keywords: Bdnf ; DNA Methylation ; Dnmt ; Prenatal Stress ; Schizophrenia ; Tet ; Medicine ; Biology ; Chemistry
    ISSN: 0006-3223
    E-ISSN: 1873-2402
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 19 March 2013, Vol.110(12), pp.4804-4809
    Description: Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a welltolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-KB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-κB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
    ISSN: 00278424
    Source: Archival Journals (JSTOR)
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  • 6
    In: Neuropsychopharmacology, 2011, Vol.37(2), p.531
    Description: Aberrant neocortical DNA methylation has been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort. We find an increase in GADD45b mRNA and protein in patients with psychosis. In immunohistochemistry experiments using samples from the Harvard Brain Tissue Resource Center, we report an increased number of GADD45b-stained cells in prefrontal cortical layers II, III, and V in psychotic patients. Brain-derived neurotrophic factor IX (BDNF IXabcd) was selected as a readout gene to determine the effects of GADD45b expression and promoter binding. We find that there is less GADD45b binding to the BDNF IXabcd promoter in psychotic subjects. Further, there is reduced BDNF IXabcd mRNA expression, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine at its promoter. On the basis of these results, we conclude that GADD45b may be increased in psychosis compensatory to its inability to access gene promoter regions.
    Keywords: 5-Methylcytosine–Metabolism ; Adult–Biosynthesis ; Antigens, Differentiation–Metabolism ; Antigens, Differentiation–Metabolism ; Brain-Derived Neurotrophic Factor–Analogs & Derivatives ; Case-Control Studies–Metabolism ; Cytosine–Genetics ; Cytosine–Physiology ; DNA Methylation–Metabolism ; Female–Metabolism ; Gene Expression–Genetics ; Humans–Genetics ; Male–Metabolism ; Middle Aged–Metabolism ; Parietal Lobe–Metabolism ; Prefrontal Cortex–Metabolism ; Promoter Regions, Genetic–Metabolism ; Psychotic Disorders–Metabolism ; Psychotic Disorders–Metabolism ; Antigens, Differentiation ; Brain-Derived Neurotrophic Factor ; Gadd45b Protein, Human ; 5-Hydroxymethylcytosine ; 5-Methylcytosine ; Cytosine;
    ISSN: 0893-133X
    E-ISSN: 1740634X
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  • 7
    In: Neuropsychopharmacology, 2012, Vol.37(9), p.2173
    ISSN: 0893-133X
    E-ISSN: 1740634X
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  • 8
    In: Journal of Neurochemistry, June 2013, Vol.125(5), pp.649-656
    Description: The αδ subunit of voltage‐sensitive calcium channels (s) is the molecular target of pregabalin and gabapentin, two drugs marked for the treatment of focal epilepsy, neuropathic pain, and anxiety disorders. Expression of the αδ subunit is up‐regulated in the dorsal horns of the spinal cord in models of neuropathic pain, suggesting that plastic changes in the αδ subunit are associated with pathological states. Here, we examined the expression of the αδ‐1 subunit in the amygdala, hippocampus, and frontal cortex in the trimethyltiazoline () mouse model of innate anxiety. is a volatile molecule present in the feces of the rodent predator, red fox. Mice that show a high defensive behavior during exposure developed anxiety‐like behavior in the following 72 h, as shown by the light–dark test. Anxiety was associated with an increased expression of the αδ‐1 subunit of s in the amygdaloid complex at all times following exposure (4, 24, and 72 h). No changes in the αδ‐1 protein levels were seen in the hippocampus and frontal cortex of mice exposed to . Pregabalin (30 mg/kg, i.p.) reduced anxiety‐like behavior in ‐exposed mice, but not in control mice. These data offer the first demonstration that the αδ‐1 subunit of s undergoes plastic changes in a model of innate anxiety, and supports the use of pregabalin as a disease‐dependent drug in the treatment of anxiety disorders. Changes in αδ subunit expression in anxiety modelThe αδ subunit is the molecular target for pregabalin, which is used in humans for the treatment of anxiety disorders. We found that αδ subunit was up‐regulated in the amygdala in a mouse model of innate anxiety where pregabalin was proved to be effective. These findings suggest that pregabalin acts as ‘disease‐dependent’ drug in the treatment of anxiety.
    Keywords: Αδ‐1 Subunit ; Amygdala ; Innate Anxiety ; Tmt ; Voltage‐Sensitive Calcium Channels
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 9
    Language: English
    In: Neuropharmacology, March, 2013, Vol.66, p.40(13)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.neuropharm.2012.05.022 Byline: Shigeyuki Chaki (a), Yukio Ago (b), Agnieszka Palucha-Paniewiera (c), Francesco Matrisciano (d)(e), Andrzej Pilc (c)(f) Abstract: Major depressive disorder is among the most prevalent forms of mental illness. All currently available antidepressant medications have stemmed from study of the mechanisms of serendipitously discovered drugs, and only 30-50% of patients exhibit remission and frequently at least 3-4 weeks are required for manifestation of significant therapeutic effects. To overcome these drawbacks, discovering novel neuronal mechanisms of pathophysiology of depression as well as more effective treatments are necessary. This review focuses on the metabotropic glutamate (mGlu) receptors and their potential for drug targets for the treatment of depression. In particular, accumulating evidence has indicated the potential importance and usefulness of agents acting on mGlu2/3 and mGlu5 receptors. Preclinical and clinical evidence of mGlu2/3 receptor ligands and mGlu5 receptor antagonists are described. Moreover, their potential in clinic will be discussed in the context of neuronal mechanisms of ketamine, an agent recently demonstrated a robust effect for patients with treatment-resistant depression. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. Author Affiliation: (a) Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan (b) Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan (c) Institute of Pharmacology, Polish Academy of Sciences, SmAtna 12, 31-343 Krakow, Poland (d) The Psychiatric Institute, Department of Psychiatry, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA (e) Department of Physiology and Pharmacology, University of Rome 'Sapienza', Piazzale Aldo Moro 5, 00185 Rome, Italy (f) Collegium Medicum, Jagiellonian University, Krakow, Poland Article History: Received 4 February 2012; Revised 27 April 2012; Accepted 15 May 2012
    Keywords: Tricyclic Antidepressants -- Physiological Aspects ; Neurons -- Physiological Aspects ; Medical Schools -- Physiological Aspects ; Glutamate -- Physiological Aspects ; Depression (Mood disorder) -- Physiological Aspects
    ISSN: 0028-3908
    Source: Cengage Learning, Inc.
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  • 10
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(1), p.e16447
    Description: The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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