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Şenol B, Ekinci RN, Arat O, Uzdoğan EA, Göka E. Serum adenosine deaminase levels in antipsychotic-naïve first-episode psychosis patients are comparable to healthy controls. Asian J Psychiatr 2024; 102:104262. [PMID: 39378757 DOI: 10.1016/j.ajp.2024.104262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/10/2024]
Affiliation(s)
- Bedirhan Şenol
- University of Health Sciences, Ankara City Hospital, Department of Psychiatry, Ankara, Turkey.
| | - Rabia Nazik Ekinci
- University of Health Sciences, Ankara City Hospital, Department of Psychiatry, Ankara, Turkey
| | - Oğuzhan Arat
- University of Health Sciences, Ankara City Hospital, Department of Psychiatry, Ankara, Turkey
| | - Esma Andaç Uzdoğan
- University of Health Sciences, Ankara City Hospital, Department of Biochemistry, Ankara, Turkey
| | - Erol Göka
- University of Health Sciences, Ankara City Hospital, Department of Psychiatry, Ankara, Turkey
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2
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Singer P, Yee BK. The adenosine hypothesis of schizophrenia into its third decade: From neurochemical imbalance to early life etiological risks. Front Cell Neurosci 2023; 17:1120532. [PMID: 36998267 PMCID: PMC10043328 DOI: 10.3389/fncel.2023.1120532] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 02/15/2023] [Indexed: 03/17/2023] Open
Abstract
The adenosine hypothesis of schizophrenia was conceptualized about two decades ago in an attempt to integrate two prominent theories of neurochemical imbalance that attribute the pathogenesis of schizophrenia to hyperfunction of the mesocorticolimbic dopamine neurotransmission and hypofunction of cortical glutamate neurotransmission. Given its unique position as an endogenous modulator of both dopamine and glutamate signaling in the brain, adenosine was postulated as a potential new drug target to achieve multiple antipsychotic actions. This new strategy may offer hope for improving treatment, especially in alleviating negative symptoms and cognitive deficits of schizophrenia that do not respond to current medications. To date, however, the adenosine hypothesis has yet led to any significant therapeutic breakthroughs. Here, we address two possible reasons for the impasse. First, neither the presence of adenosine functional deficiency in people with schizophrenia nor its causal relationship to symptom production has been satisfactorily examined. Second, the lack of novel adenosine-based drugs also impedes progress. This review updates the latest preclinical and clinical data pertinent to the construct validity of the adenosine hypothesis and explores novel molecular processes whereby dysregulation of adenosine signaling could be linked to the etiology of schizophrenia. It is intended to stimulate and revitalize research into the adenosine hypothesis towards the development of a new and improved generation of antipsychotic drugs that has eluded us for decades.
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Affiliation(s)
- Philipp Singer
- Roche Diagnostics International AG, Rotkreuz, Switzerland
- *Correspondence: Philipp Singer Benjamin K. Yee
| | - Benjamin K. Yee
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- Mental Health Research Centre, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
- *Correspondence: Philipp Singer Benjamin K. Yee
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Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets. Int J Mol Sci 2022; 23:ijms23031219. [PMID: 35163142 PMCID: PMC8835915 DOI: 10.3390/ijms23031219] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 12/16/2022] Open
Abstract
Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.
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4
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Büki A, Kekesi G, Horvath G, Vécsei L. A Potential Interface between the Kynurenine Pathway and Autonomic Imbalance in Schizophrenia. Int J Mol Sci 2021; 22:10016. [PMID: 34576179 PMCID: PMC8467675 DOI: 10.3390/ijms221810016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023] Open
Abstract
Schizophrenia is a neuropsychiatric disorder characterized by various symptoms including autonomic imbalance. These disturbances involve almost all autonomic functions and might contribute to poor medication compliance, worsened quality of life and increased mortality. Therefore, it has a great importance to find a potential therapeutic solution to improve the autonomic disturbances. The altered level of kynurenines (e.g., kynurenic acid), as tryptophan metabolites, is almost the most consistently found biochemical abnormality in schizophrenia. Kynurenic acid influences different types of receptors, most of them involved in the pathophysiology of schizophrenia. Only few data suggest that kynurenines might have effects on multiple autonomic functions. Publications so far have discussed the implication of kynurenines and the alteration of the autonomic nervous system in schizophrenia independently from each other. Thus, the coupling between them has not yet been addressed in schizophrenia, although their direct common points, potential interfaces indicate the consideration of their interaction. The present review gathers autonomic disturbances, the impaired kynurenine pathway in schizophrenia, and the effects of kynurenine pathway on autonomic functions. In the last part of the review, the potential interaction between the two systems in schizophrenia, and the possible therapeutic options are discussed.
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Affiliation(s)
- Alexandra Büki
- Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 10., H-6720 Szeged, Hungary; (A.B.); (G.K.); (G.H.)
| | - Gabriella Kekesi
- Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 10., H-6720 Szeged, Hungary; (A.B.); (G.K.); (G.H.)
| | - Gyongyi Horvath
- Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, Dóm tér 10., H-6720 Szeged, Hungary; (A.B.); (G.K.); (G.H.)
| | - László Vécsei
- Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6., H-6725 Szeged, Hungary
- MTA-SZTE Neuroscience Research Group, H-6725 Szeged, Hungary
- Interdisciplinary Excellence Center, Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6., H-6725 Szeged, Hungary
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5
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Nascimento FP, Macedo-Júnior SJ, Lapa-Costa FR, Cezar-Dos-Santos F, Santos ARS. Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor? Front Neurosci 2021; 15:703783. [PMID: 34504414 PMCID: PMC8421806 DOI: 10.3389/fnins.2021.703783] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/20/2021] [Indexed: 11/13/2022] Open
Abstract
Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.
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Affiliation(s)
- Francisney Pinto Nascimento
- Programa de Pós-Graduação em Biociências, Laboratório de Neurofarmacologia Clínica, Faculdade de Medicina, Universidade Federal da Integração Latino-Americana, Foz do Iguaçu, Brazil
| | | | | | - Fernando Cezar-Dos-Santos
- Programa de Pós-Graduação em Biociências, Laboratório de Neurofarmacologia Clínica, Faculdade de Medicina, Universidade Federal da Integração Latino-Americana, Foz do Iguaçu, Brazil
| | - Adair R S Santos
- Programa de Pós-Graduação em Neurociências, Laboratório de Neurobiologia da Dor e Inflamação, Universidade Federal de Santa Catarina, Florianópolis, Brazil
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6
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Li J, Tang F, Si S, Wang B, Xue F. Integration analysis of GWAS and expression quantitative trait loci to identify candidate genes and pathways for clozapine-related neutropaenia. Br J Clin Pharmacol 2021; 88:1904-1912. [PMID: 34409637 DOI: 10.1111/bcp.15043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/30/2021] [Accepted: 08/06/2021] [Indexed: 12/23/2022] Open
Abstract
AIMS Little is known about the genetic basis of clozapine-related neutropaenia. This study aims to explore candidate genes and pathways involved in clozapine-related neutropaenia. METHODS This study conducted a two-stage integrative analysis of the summary statistics from the genome-wide association study (GWAS, n = 552) of the lowest absolute neutrophil count (ANC) during clozapine treatment and the summary data of the expressed quantitative trait locus (eQTL). First, we use the probabilistic Mendelian randomization (PMR-Egger) to identify genes whose expression is causally related to ANC, and then use Bayesian co-localization analysis to investigate whether there are shared causal variants between them [posterior probability for hypotheses 4 (PP.H4) > 0.80]. Finally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore the pathways that may be associated with ANC during clozapine treatment. RESULTS PMR-Egger analysis identified 146 genes that may be causally associated with ANC after Bonferroni correction (P-value < 3.25e-6). Bayesian co-localization analysis identified six further genes whose gene expression shared common variants with ANC, including NT5E (PP.H4 = 0.96), GLDC (PP.H4 = 0.82), NUDT17 (PP.H4 = 0.88), MSH4 (PP.H4 = 0.88), PTER (PP.H4 = 0.89) and SERPINB6 (PP.H4 = 0.83). Enrichment analysis identified 52 GO terms and seven pathways associated with ANC, such as NAD metabolic process, drug catabolic process and glyoxylate and dicarboxylate metabolism. CONCLUSION This study identified multiple candidate genes and pathways that may be involved in clozapine-related neutropaenia, providing novel clues for the mechanism of clozapine-related neutropaenia.
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Affiliation(s)
- Jiqing Li
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.,Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Fang Tang
- Center for Big Data Research in Health and Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shucheng Si
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.,Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Bojie Wang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.,Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Fuzhong Xue
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.,Healthcare Big Data Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
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7
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Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine. iScience 2019; 17:325-333. [PMID: 31325771 PMCID: PMC6642228 DOI: 10.1016/j.isci.2019.06.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/17/2019] [Accepted: 06/28/2019] [Indexed: 11/23/2022] Open
Abstract
Dopamine transporter (SLC6A3) deficiency causes infantile Parkinson disease, for which there is no effective therapy. We have explored the effects of genetically deleting SLC6A3 in zebrafish. Unlike the wild-type, slc6a3−/− fish hover near the tank bottom, with a repetitive digging-like behavior. slc6a3−/− fish manifest pruning and cellular loss of particular tyrosine hydroxylase-immunoreactive neurons in the midbrain. Clozapine, an effective therapeutic for treatment-resistant schizophrenia, rescues the abnormal behavior of slc6a3−/− fish. Clozapine also reverses the abnormalities in the A8 region of the mutant midbrain. By RNA sequencing analysis, clozapine increases the expression of erythropoietin pathway genes. Transgenic over-expression of erythropoietin in neurons of slc6a3−/− fish partially rescues the mutant behavior, suggesting a potential mechanistic basis for clozapine's efficacy.
DAT mutation in zebrafish causes digging behavior and loss of specific midbrain neurons Clozapine restores normal behavior and neuronal morphology of mutant fish Clozapine increases expression of erythropoietin pathway genes Transgenic expression of erythropoietin partially rescues the mutant behavior
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Cell-subtype-specific changes in adenosine pathways in schizophrenia. Neuropsychopharmacology 2018; 43:1667-1674. [PMID: 29483661 PMCID: PMC6006250 DOI: 10.1038/s41386-018-0028-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/01/2018] [Accepted: 02/05/2018] [Indexed: 12/22/2022]
Abstract
Prior work in animal models implicates abnormalities of adenosine metabolism in astrocytes as a possible pathophysiological mechanism underlying the symptoms of schizophrenia. In the present study, we sought to reverse-translate these findings back to the human brain in schizophrenia, focusing on the following questions: (1) Which components of the adenosine system are dysregulated in schizophrenia, and (2) are these changes limited to astrocytes? To address these questions, we captured enriched populations of DLPFC pyramidal neurons and astrocytes from schizophrenia and control subjects using laser capture microdissection and assessed expression of adenosine system components using qPCR. Interestingly, we found changes in enriched populations of astrocytes and neurons spanning metabolic and catabolic pathways. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) and ENTPD2 mRNA levels were significantly decreased (p < 0.05, n = 16 per group) in enriched populations of astrocytes; in pyramidal neurons equilibrative nucleoside transporter 1 (ENT1) and adenosine A1 receptor mRNA levels were significantly decreased, with an increase in adenosine deaminase (ADA) (p < 0.05, n = 16 per group). Rodent studies suggest that some of our findings (A1R and ENTPD2) may be due to treatment with antipsychotics. Our findings suggest changes in expression of genes involved in regulating metabolism of ATP in enriched populations of astrocytes, leading to lower availability of substrates needed to generate adenosine. In pyramidal neurons, changes in ENT1 and ADA mRNA may suggest increased catabolism of adenosine. These results offer new insights into the cell-subtype-specific pathophysiology of the adenosine system in this illness.
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9
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Yuan S, Zhang ZW, Li ZL. Antacids' side effect hyperuricaemia could be alleviated by long-term aerobic exercise via accelerating ATP turnover rate. Biomed Pharmacother 2018; 99:18-24. [PMID: 29324308 DOI: 10.1016/j.biopha.2018.01.052] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/20/2017] [Accepted: 01/05/2018] [Indexed: 01/31/2023] Open
Abstract
Hyperuricemia is the term for an abnormally high serum uric acid level. Many factors contribute to hyperuricemia, however no definite correlation between proton pump inhibitors (PPIs) and hyperuricemia has been reported before. Physical exercise also decreases serum uric acid levels. However, the detailed biochemical-regulatory mechanisms remain unknown. Here we found that adenylate deaminase activities are much higher in hyperuricemia patients than in the healthy people. Therefore, the patients have higher levels of adenosine metabolites hypoxanthine and uric acid. Acid-inhibitory drugs (antacids) significantly increased serum uric acid level and may lead to gout in the hyperuricemia patient. Long-term aerobic exercise significantly increased serum phosphorus and decreased serum ATP and its metabolites, and therefore decreased serum uric acid. Antacids slow down the ATP turnover rate and result in serum uric acid elevation subsequently. While the long-term aerobic exercise decreases serum uric acid levels by accelerating ATP turnover rate. The results imply that long-term aerobic exercise may be a useful strategy to prevent and treat hyperuricaemia.
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Affiliation(s)
- Shu Yuan
- College of Resources, Sichuan Agricultural University, Chengdu, China.
| | - Zhong-Wei Zhang
- College of Resources, Sichuan Agricultural University, Chengdu, China
| | - Zi-Lin Li
- Department of Internal Medicine, Xijing Hospital, Medical University of the Air Force, Xi'an, China
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Gadelha A, Zugman A, Calzavara MB, de Mendonça Furtado RH, Scorza FA, Bressan RA. Is adenosine associated with sudden death in schizophrenia? A new framework linking the adenosine pathway to risk of sudden death. Neurosci Biobehav Rev 2018; 84:29-34. [DOI: 10.1016/j.neubiorev.2017.10.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 09/25/2017] [Accepted: 10/22/2017] [Indexed: 11/29/2022]
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Sasidharan A, Kumar S, John JP, Philip M, Subramanian S, Jain S, Kutty BM. Elevated serum adenosine deaminase levels in neuroleptic-naïve patients with recent-onset schizophrenia. Asian J Psychiatr 2017; 29:13-15. [PMID: 29061410 DOI: 10.1016/j.ajp.2017.03.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Revised: 03/12/2017] [Accepted: 03/13/2017] [Indexed: 12/18/2022]
Abstract
The present study examined serum levels of adenosine deaminase (ADA), an adenosine metabolizing enzyme, in neuroleptic-naive patients with recent-onset schizophrenia and age-matched healthy comparison subjects. ADA levels were found to be higher among patients, and revealed a possible link between evening rise and severity of auditory hallucinations as well as morning rise and severity of avolition-apathy in patients with schizophrenia. These findings suggest the potential utility of serum ADA as a peripheral biomarker of schizophrenia.
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Affiliation(s)
- Arun Sasidharan
- Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India; Multimodal Brain Image Analysis Laboratory (MBIAL), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Sunil Kumar
- Multimodal Brain Image Analysis Laboratory (MBIAL), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India; Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - John P John
- Multimodal Brain Image Analysis Laboratory (MBIAL), National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India; Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India; Department of Clinical Neuroscience, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India.
| | - Mariamma Philip
- Department of Biostatistics, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Sarada Subramanian
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Sanjeev Jain
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India; Molecular Genetics Laboratory, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
| | - Bindu M Kutty
- Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India
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12
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Sasidharan A, Kumar S, Nair AK, Lukose A, Marigowda V, John JP, Kutty BM. Further evidences for sleep instability and impaired spindle-delta dynamics in schizophrenia: a whole-night polysomnography study with neuroloop-gain and sleep-cycle analysis. Sleep Med 2017; 38:1-13. [DOI: 10.1016/j.sleep.2017.02.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 02/03/2017] [Accepted: 02/09/2017] [Indexed: 02/04/2023]
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Moscoso-Castro M, Gracia-Rubio I, Ciruela F, Valverde O. Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice. Eur Neuropsychopharmacol 2016; 26:1227-40. [PMID: 27133030 DOI: 10.1016/j.euroneuro.2016.04.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/14/2016] [Accepted: 04/14/2016] [Indexed: 12/12/2022]
Abstract
Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2AR) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2AR knockout (KO) mice with complete and specific inactivation of A2AR, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2AR KO animals. Hyperlocomotion induced by d-amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2AR KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia.
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Affiliation(s)
- Maria Moscoso-Castro
- Neurobiology of Behavior Research Group (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Irene Gracia-Rubio
- Neurobiology of Behavior Research Group (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Francisco Ciruela
- Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, Barcelona, Spain; Department of Biochemistry and Microbiology, Faculty of Sciences, University of Ghent, Gent, Belgium
| | - Olga Valverde
- Neurobiology of Behavior Research Group (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Neuroscience Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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Lai CY, Scarr E, Udawela M, Everall I, Chen WJ, Dean B. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World J Psychiatry 2016; 6:102-17. [PMID: 27014601 PMCID: PMC4804259 DOI: 10.5498/wjp.v6.i1.102] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/20/2015] [Accepted: 12/17/2015] [Indexed: 02/05/2023] Open
Abstract
Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophrenia-associated phenotype. We sorted the studies into six categories which include: (1) brain-derived neurotrophic factor; (2) inflammation and immune function; (3) neurochemistry; (4) oxidative stress response and metabolism; (5) epigenetics and microRNA; and (6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, blood oriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.
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Boison D, Aronica E. Comorbidities in Neurology: Is adenosine the common link? Neuropharmacology 2015; 97:18-34. [PMID: 25979489 PMCID: PMC4537378 DOI: 10.1016/j.neuropharm.2015.04.031] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 04/24/2015] [Accepted: 04/27/2015] [Indexed: 12/13/2022]
Abstract
Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the 'adenosine hypothesis of comorbidities' implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic 'comorbidity model', in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain co-morbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.
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Affiliation(s)
- Detlev Boison
- Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232, USA.
| | - Eleonora Aronica
- Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, The Netherlands; Stichting Epilepsie Instellingen (SEIN) Nederland, Heemstede, The Netherlands
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Demirci K, Özçankaya R, Yilmaz HR, Yiğit A, Uğuz AC, Karakuş K, Demirdaş A, Akpınar A. Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism. Redox Rep 2015; 20:170-6. [PMID: 25545018 PMCID: PMC6837464 DOI: 10.1179/1351000214y.0000000122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE The treatment of schizophrenia is multifactorial, with antipsychotic medications comprising a major part of treatment. Paliperidone is a newly commercialized antipsychotic whose formulation includes the principal active metabolite risperidone, 9-hydroxyrisperidone. Ever since the relationship between schizophrenia and oxidative stress was first demonstrated, many studies have been conducted in order to probe the potential protective effects of antipsychotic drugs on the oxidant-antioxidant system and lipid peroxidation. The basic aim of this study is to determine the effects of the newly marketed drug paliperidone on the activities of the enzymes adenosine deaminase (ADA), xanthine oxidase (XO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) as well as on malondialdehyde (MDA) and nitric oxide (NO) levels in rat brain tissues. METHODS Twenty male Sprague-Dawley rats were used for the study, which were divided into two equal groups. The first was the control group (n = 10) and the second was the paliperidone group (n = 10). Saline was administered once daily for 14 days in the control group. In the paliperidone group, paliperidone was administered once daily with a dose of 1 mg/kg for 14 days. All rats were sacrificed at the end of the fourteenth day. Brain samples were collected and then analyzed. RESULTS Our results demonstrated that paliperidone significantly decreased the activities of ADA (P = 0.015), XO (P = 0.0001), and CAT (P = 0.004) while insignificantly increasing the activity of SOD (P = 0.49), MDA (P = 0.71), and NO (P = 0.26) levels in rat brain tissues. In addition, paliperidone insignificantly decreased the activity of GSH-Px (P = 0.30) compared to the control group in rat brain tissues. DISCUSSION In conclusion, the data obtained in this study suggest that paliperidone can positively alter antioxidant status and, accordingly, can offer positive outcomes in the treatment of schizophrenia by reducing activity in the enzymes ADA and XO, which are associated with purine metabolism. We believe that such a comprehensive approach used with other antipsychotic drugs warrants further study.
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Affiliation(s)
- Kadir Demirci
- Department of PsychiatryFaculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Ramazan Özçankaya
- Department of PsychiatryFaculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - H. Ramazan Yilmaz
- Department of Medical BiologyFaculty of Medicine, Mevlana University, Konya, Turkey
| | - Ayşe Yiğit
- Department of Medical GeneticsFaculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | | | - Kadir Karakuş
- Deparment of Psychiatry, Isparta State Hospital, Turkey
| | - Arif Demirdaş
- Department of PsychiatryFaculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Abdullah Akpınar
- Department of PsychiatryFaculty of Medicine, Suleyman Demirel University, Isparta, Turkey
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Villar-Menéndez I, Díaz-Sánchez S, Blanch M, Albasanz JL, Pereira-Veiga T, Monje A, Planchat LM, Ferrer I, Martín M, Barrachina M. Reduced striatal adenosine A2A receptor levels define a molecular subgroup in schizophrenia. J Psychiatr Res 2014; 51:49-59. [PMID: 24433848 DOI: 10.1016/j.jpsychires.2013.12.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 11/13/2013] [Accepted: 12/20/2013] [Indexed: 01/02/2023]
Abstract
Schizophrenia (SZ) is a mental disorder of unknown origin. Some scientific evidence seems to indicate that SZ is not a single disease entity, since there are patient groups with clear symptomatic, course and biomarker differences. SZ is characterized by a hyperdopaminergic state related to high dopamine D2 receptor activity. It has also been proposed that there is a hypoadenosynergic state. Adenosine is a nucleoside widely distributed in the organism with neuromodulative and neuroprotective activity in the central nervous system. In the brain, the most abundant adenosine receptors are A1R and A2AR. In the present report, we characterize the presence of both receptors in human postmortem putamens of patients suffering SZ with real time TaqMan PCR, western blotting and radioligand binding assay. We show that A1R levels remain unchanged with respect to age-matched controls, whereas nearly fifty percent of patients have reduced A2AR, at the transcriptional and translational levels. Moreover, we describe how DNA methylation plays a role in the pathological A2AR levels with the bisulfite-sequencing technique. In fact, an increase in 5-methylcytosine percentage in the 5' UTR region of ADORA2A was found in those SZ patients with reduced A2AR levels. Interestingly, there was a relationship between the A2A/β-actin ratio and motor disturbances as assessed with some items of the PANSS, AIMS and SAS scales. Therefore, there may be a subgroup of SZ patients with reduced striatal A2AR levels accompanied by an altered motor phenotype.
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Affiliation(s)
- Izaskun Villar-Menéndez
- Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Sara Díaz-Sánchez
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencia y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain; Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain
| | - Marta Blanch
- Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain
| | - José Luis Albasanz
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencia y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain; Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain
| | - Thais Pereira-Veiga
- Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Alfonso Monje
- Banc de Teixits Neurològics-Parc Sanitari Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Spain
| | - Luis Maria Planchat
- Banc de Teixits Neurològics-Parc Sanitari Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Spain
| | - Isidre Ferrer
- Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain; Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Spain
| | - Mairena Martín
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencia y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain; Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain
| | - Marta Barrachina
- Institute of Neuropathology, Bellvitge University Hospital-ICS, [Bellvitge Biomedical Research Institute-] IDIBELL, L'Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Spain.
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Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the "adenosine hypothesis". Purinergic Signal 2013; 9:599-608. [PMID: 23771238 DOI: 10.1007/s11302-013-9370-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 05/31/2013] [Indexed: 01/12/2023] Open
Abstract
Schizophrenia (SZ) is a major chronic neuropsychiatric disorder characterized by a hyperdopaminergic state. The hypoadenosinergic hypothesis proposes that reduced extracellular adenosine levels contribute to dopamine D2 receptor hyperactivity. ATP, through the action of ecto-nucleotidases, constitutes a main source of extracellular adenosine. In the present study, we examined the activity of ecto-nucleotidases (NTPDases, ecto-5'-nucleotidase, and alkaline phosphatase) in the postmortem putamen of SZ patients (n = 13) compared with aged-matched controls (n = 10). We firstly demonstrated, by means of artificial postmortem delay experiments, that ecto-nucleotidase activity in human brains was stable up to 24 h, indicating the reliability of this tissue for these enzyme determinations. Remarkably, NTPDase-attributable activity (both ATPase and ADPase) was found to be reduced in SZ patients, while ecto-5'-nucleotidase and alkaline phosphatase activity remained unchanged. In the present study, we also describe the localization of these ecto-enzymes in human putamen control samples, showing differential expression in blood vessels, neurons, and glial cells. In conclusion, reduced striatal NTPDase activity may contribute to the pathophysiology of SZ, and it represents a potential mechanism of adenosine signalling impairment in this illness.
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Shen HY, Singer P, Lytle N, Wei CJ, Lan JQ, Williams-Karnesky RL, Chen JF, Yee BK, Boison D. Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia. J Clin Invest 2012; 122:2567-77. [PMID: 22706302 DOI: 10.1172/jci62378] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 05/09/2012] [Indexed: 02/01/2023] Open
Abstract
An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.
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Affiliation(s)
- Hai-Ying Shen
- Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR, USA
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Ghaleiha A, Honarbakhsh N, Boroumand MA, Jafarinia M, Tabrizi M, Rezaei F, Raznahan M, Akhondzadeh S. Correlation of adenosinergic activity with superior efficacy of clozapine for treatment of chronic schizophrenia: a double blind randomised trial. Hum Psychopharmacol 2011; 26:120-4. [PMID: 21412846 DOI: 10.1002/hup.1176] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 01/12/2011] [Indexed: 12/12/2022]
Abstract
OBJECTIVE It has been proposed that a deficit of adenosinergic activity could contribute to the pathophysiology of schizophrenia. The authors undertook this study to further evaluate the level of adenosine deaminase (ADA) in patients with chronic schizophrenia treated with monotherapy of haloperidol, risperidone or clozapine and correlation between the ADA level with response to treatment. METHODS The trial was a prospective, 8-week, double blind study of parallel groups of patients with chronic schizophrenia. Eligible participants in the study were 51 patients with chronic schizophrenia with ages ranging from 20 to 45 years. All participants were inpatients, in the active phase of illness, and met DSM-IV-TR criteria for schizophrenia. Patients were randomly allocated (17 patients in each group) to risperidone (6 mg/day) or haloperidol 15 mg/day or clozapine (300 mg/day). Serum ADA activity was measured at baseline and week 8. RESULTS The plasma levels of ADA in patients with chronic schizophrenia who received clozapine were significantly higher than patients who received haloperidol. In addition, response to treatment was positively correlated with plasma levels of ADA only in the clozapine group (r = 0.46 and p = 0.04). CONCLUSION The results indicate an increased activity of the enzyme ADA in the serum of schizophrenic patients being treated with clozapine and this increase may be correlated with clozapine's superior antipsychotic efficacy.
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Affiliation(s)
- Ali Ghaleiha
- Research Center for Behavioral Disorders and Substance Abuse, Hamadan University of Medical Sciences, Hamadan, Iran
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Clozapine mobilizes CD34+ hematopoietic stem and progenitor cells and increases plasma concentration of interleukin 6 in patients with schizophrenia. J Clin Psychopharmacol 2010; 30:591-5. [PMID: 20814329 DOI: 10.1097/jcp.0b013e3181eeb7f7] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The blood of 8 European patients with schizophrenia without manifest comorbidity was studied whether the classical atypical antipsychotic drug clozapine altered the amount of circulating CD34(+) hematopoietic cells. As assessed by flow cytometry, the number of CD34(+) cells increased by 433% (from 1.49 ± 1.07 × 10(6)/L, mean ± SD pretreatment, to a peak of 6.45 ± 3.47 × 10(6)/L) following first-time therapy with clozapine for 12 weeks. The increase of CD34(+) cell, neutrophil, and leukocyte counts was statistically significant (P = 0.012). A transversal investigation of 23 long-term patients and 58 controls showed elevated neutrophil counts in the clozapine-monotreated group, whereas CD34(+) cell numbers were unaltered. A transversal investigation of 12 clozapine-monotreated long-term patients and 10 controls revealed a 1.3-fold elevation of plasma interleukin 6 levels in patients on clozapine (P = 0.017). In conclusion, clozapine treatment results in an initial mobilization of CD34(+) stem and progenitor cells into the peripheral blood and in a slight long-term elevation of interleukin 6.
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Dutra GP, Ottoni GL, Lara DR, Bogo MR. Lower frequency of the low activity adenosine deaminase allelic variant (ADA1*2) in schizophrenic patients. REVISTA BRASILEIRA DE PSIQUIATRIA 2010; 32:275-8. [DOI: 10.1590/s1516-44462010005000003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2009] [Accepted: 10/01/2009] [Indexed: 11/22/2022]
Abstract
OBJECTIVE: Adenosine may play a role in the pathophysiology of schizophrenia, since it modulates the release of several neurotransmitters such as glutamate, dopamine, serotonin and acetylcholine, decreases neuronal activity by pos-synaptic hyperpolarization and inhibits dopaminergic activity. Adenosine deaminase participates in purine metabolism by converting adenosine into inosine. The most frequent functional polymorphism of adenosine deaminase (22G→A) (ADA1*2) exhibits 20-30% lower enzymatic activity in individuals with the G/A genotype than individuals with the G/G genotype. The aim of this study was to evaluate the ADA polymorphism 22G→A (ADA1*2) in schizophrenic patients and healthy controls. METHOD: The genotypes of the ADA 22G→A were identified with allele-specific PCR strategy in 152 schizophrenic patients and 111 healthy individuals. RESULTS: A significant decrease in the frequency of the G/A genotype was seen in schizophrenic patients (7/152 - 4.6%) relative to controls (13/111 - 11.7%, p = 0.032, OR = 2.6). CONCLUSION: These results suggest that the G/A genotype associated with low adenosine deaminase activity and, supposingly, with higher adenosine levels is less frequent among schizophrenic patients.
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Affiliation(s)
| | | | - Diogo R. Lara
- Pontifícia Universidade Católica do Rio Grande do Sul, Brazil
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Antipsychotic drugs inhibit nucleotide hydrolysis in zebrafish (Danio rerio) brain membranes. Toxicol In Vitro 2008; 23:78-82. [PMID: 18996465 DOI: 10.1016/j.tiv.2008.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2008] [Revised: 10/15/2008] [Accepted: 10/16/2008] [Indexed: 11/20/2022]
Abstract
Haloperidol (HAL), olanzapine (OLZ), and sulpiride (SULP) are antipsychotic drugs widely used in the pharmacotherapy of psychopathological symptoms observed in schizophrenia or mood-related psychotic symptoms in affective disorders. Here, we tested the in vitro effects of different concentrations of a typical (HAL) and two atypical (OLZ and SULP) antipsychotic drugs on ectonucleotidase activities from zebrafish brain membranes. HAL inhibited ATP (28.9%) and ADP (26.5%) hydrolysis only at 250 microM. OLZ decreased ATPase activity at all concentrations tested (23.8-60.7%). SULP did not promote significant changes on ATP hydrolysis but inhibited ADP hydrolysis at 250 microM (25.6%). All drugs tested, HAL, OLZ, and SULP, did not promote any significant changes on 5'-nucleotidase activity in the brain membranes of zebrafish. These findings demonstrated that antipsychotic drugs could inhibit NTPDase activities whereas did not change 5'-nucleotidase. Such modulation can alter the adenosine levels, since the ectonucleotidase pathway is an important source of extracellular adenosine. Thus, it is possible to suggest that changes promoted by antipsychotic drugs in the bilayer membrane could alter the NTPDase activities, modulating extracellular ATP and adenosine levels.
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Salimi S, Fotouhi A, Ghoreishi A, Derakhshan MK, Khodaie-Ardakani MR, Mohammadi MR, Noorbala AA, Ahmadi-Abhari SA, Hajiazim M, Abbasi SH, Akhondzadeh S. A placebo controlled study of the propentofylline added to risperidone in chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:726-32. [PMID: 18096287 DOI: 10.1016/j.pnpbp.2007.11.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Revised: 11/09/2007] [Accepted: 11/17/2007] [Indexed: 11/28/2022]
Abstract
Impaired activity of the purinergic system is a plausible common factor that could be responsible for many aspects of schizophrenia. Based on purinegic hypothesis of schizophrenia, pharmacological treatments enhancing adenosine activity could be effective treatment in schizophrenia. Propentofylline is a novel xantine derivative which is being developed for treatment of degenerative and vascular dementia. It enhances extracellular adenosine level via inhibition of adenosine uptake. The purpose of the present investigation was to assess the efficacy of propentofylline as an adjuvant agent in the treatment of chronic schizophrenia in an 8-week double blind and placebo controlled trial. Eligible participants in this study were 50 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion, 25 to risperidone 6 mg/day plus propentofylline 900 mg/day (300 mg TDS) and 25 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and propentofylline showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the propentofylline group over the trial. However, the differences were not significant. The present study indicates propentofylline as a potential adjunctive treatment strategy for chronic schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendation for a broad clinical application can be made.
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Affiliation(s)
- Samarand Salimi
- Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran
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