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Cadeddu R, Branca C, Braccagni G, Musci T, Piras IS, Anderson CJ, Capecchi MR, Huentelman MJ, Moos PJ, Bortolato M. Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D 3 dopamine receptors. Mol Psychiatry 2025:10.1038/s41380-025-02970-w. [PMID: 40155412 DOI: 10.1038/s41380-025-02970-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/05/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
The gene CELSR3 (Cadherin EGF LAG Seven-pass-G-type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.
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Affiliation(s)
- Roberto Cadeddu
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Caterina Branca
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Giulia Braccagni
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Teresa Musci
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Collin J Anderson
- Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA
- School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
- School of Biomedical Engineering, University of Sydney, Camperdown, NSW, Australia
| | - Mario R Capecchi
- Department of Human Genetics, College of Medicine, University of Utah, Salt Lake City, UT, USA
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA
| | - Philip J Moos
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
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Zhao Z, Qian Y, Du Y, Chen H, He J, Chen Y, Wang X, Mai J, Sun S, Wang H, Jiao F. Efficacy of Clonidine Adhesive Patch for Patients With Tourette Syndrome: A Randomized, Double-blind, Placebo-Controlled, Multicenter Clinical Trial. Clin Neuropharmacol 2024; 47:150-156. [PMID: 39258554 PMCID: PMC11446511 DOI: 10.1097/wnf.0000000000000605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2024]
Abstract
OBJECTIVE This study aimed to explore the efficacy of the clonidine adhesive patch for participants with Tourette syndrome (TS). METHODS This randomized, double-blind, placebo-controlled, multicenter phase IV clinical trial included participants with TS at 20 centers between May 2012 and March 2015. Treatment efficacy at week 8 was the primary outcome. The Clinical Global Impression-Severity scale and Improvement scale were the secondary endpoints. RESULTS This trial included 488 participants, with 121 participants in the 2.0-mg/wk group, 119 participants in the 1.5-mg/wk group, 126 participants in the 1.0-mg/wk group, and 122 participants in the placebo group. For Yale Global Tic Severity Scale score reduction rate, compared with the placebo group (39.60 ± 25.56), those of the 2.0-mg/wk group (63.21 ± 32.60) and the 1.5-mg/wk group (68.16 ± 25.88) were statistically significantly different (all P < 0.001). For total Yale Global Tic Severity Scale score, compared with the placebo group (17.0 ± 8.03), the score for the 2.0-mg/wk group was 9.9 ± 8.36 ( P < 0.001); 1.5-mg/wk group, 9.6 ± 8.03 ( P < 0.001); and 1.0-mg/wk group, 10.5 ± 9.28 ( P < 0.001). The Clinical Global Impression-Severity scale and Improvement scale scores were statistically significantly different in the 3 clonidine (or experimental) groups compared with the placebo group (all P < 0.001). CONCLUSIONS Larger doses of the clonidine adhesive patch such as 1.5 and 2.0 mg/wk are effective in improving the symptoms and overall function of participants with TS.
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Affiliation(s)
- Zhimin Zhao
- Department of Child and Adolescent Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai
| | - Yun Qian
- Department of Child and Adolescent Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai
| | - Yasong Du
- Department of Child and Adolescent Psychiatry, Shanghai Mental Health Center, Shanghai Jiaotong University, Shanghai
| | - Hong Chen
- The First Affiliated Hospital of Dalian Medical University, Dalian
| | - Jie He
- China National Pharmaceutical Group Shanxi Rfl Pharmaceutical Co Ltd, Taiyuan
| | - Yanhui Chen
- Fujian Medical University Union Hospital, Fuzhou
| | - Xiuxia Wang
- The Second Hospital of Hebei Medical University, Shijiazhuang
| | - Jianning Mai
- Guangzhou Women and Children's Medical Center, Guangzhou
| | - Suzhen Sun
- Children's Hospital of Hebei Province, Shijiazhuang
| | | | - Fuyong Jiao
- Shanxi Provincial People's Hospital, Xi'an, China
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Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol 2023; 29:2571-2599. [PMID: 37213397 PMCID: PMC10198058 DOI: 10.3748/wjg.v29.i17.2571] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
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Affiliation(s)
- Fernanda Villarruel-Melquiades
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - María Eugenia Mendoza-Garrido
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - Claudia M García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Julio Isael Pérez-Carreón
- Instituto Nacional de Medicina Genómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
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Bai Y, Niu L, Li S, Le W. Psychopharmacotherapy in Patients with Tics and Other Motor Disorders. NEUROPSYCHOPHARMACOTHERAPY 2022:4271-4301. [DOI: 10.1007/978-3-030-62059-2_257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Roessner V, Eichele H, Stern JS, Skov L, Rizzo R, Debes NM, Nagy P, Cavanna AE, Termine C, Ganos C, Münchau A, Szejko N, Cath D, Müller-Vahl KR, Verdellen C, Hartmann A, Rothenberger A, Hoekstra PJ, Plessen KJ. European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: pharmacological treatment. Eur Child Adolesc Psychiatry 2022; 31:425-441. [PMID: 34757514 PMCID: PMC8940878 DOI: 10.1007/s00787-021-01899-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 10/24/2021] [Indexed: 12/18/2022]
Abstract
In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.
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Affiliation(s)
- Veit Roessner
- Department of Child and Adolescent Psychiatry, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
| | - Heike Eichele
- Department of Biological and Medical Psychology, Faculty of Psychology, University of Bergen, Bergen, Norway , Regional Resource Center for Autism, ADHD, Tourette Syndrome and Narcolepsy Western Norway, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
| | - Jeremy S. Stern
- Department of Neurology, St George’s Hospital, St George’s University of London, London, UK
| | - Liselotte Skov
- Paediatric Department, Herlev University Hospital, Herlev, Denmark
| | - Renata Rizzo
- Child and Adolescent Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | | | - Péter Nagy
- Vadaskert Child Psychiatric Hospital and Outpatient Clinic, Budapest, Hungary
| | - Andrea E. Cavanna
- Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
| | - Cristiano Termine
- Child Neuropsychiatry Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Christos Ganos
- Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander Münchau
- Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
| | - Natalia Szejko
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland ,Department of Bioethics, Medical University of Warsaw, Warsaw, Poland ,Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT USA
| | - Danielle Cath
- Department of Psychiatry, University Medical Center Groningen, Rijks Universiteit Groningen, GGZ Drenthe Mental Health Institution, Assen, The Netherlands
| | - Kirsten R. Müller-Vahl
- Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
| | - Cara Verdellen
- PsyQ Nijmegen, Parnassia Group, Nijmegen, The Netherlands ,TicXperts, Heteren, The Netherlands
| | - Andreas Hartmann
- Department of Neurology, Sorbonne Université, Pitié-Salpetriere Hospital, Paris, France ,National Reference Center for Tourette Disorder, Pitié Salpetiere Hospital, Paris, France
| | - Aribert Rothenberger
- Clinic for Child and Adolescent Psychiatry and Psychotherapy, University Medical Center Gottingen, Gottingen, Germany
| | - Pieter J. Hoekstra
- Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Kerstin J. Plessen
- Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland ,Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark
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Lin L, Lan Y, Zhu H, Yu L, Wu S, Wan W, Shu Y, Xiang H, Hou T, Zhang H, Ma Y, Su W, Li M. Effects of Chemogenetic Inhibition of D1 or D2 Receptor-Containing Neurons of the Substantia Nigra and Striatum in Mice With Tourette Syndrome. Front Mol Neurosci 2021; 14:779436. [PMID: 34955745 PMCID: PMC8696039 DOI: 10.3389/fnmol.2021.779436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/09/2021] [Indexed: 01/02/2023] Open
Abstract
As tourette syndrome (TS) is a common neurobehavioral disorder, the primary symptoms of which include behavioral stereotypies. Dysfunction of the substantia nigra-striatum network could be the main pathogenesis of TS, which is closely associated with dopamine (DA) and its receptors. TS is often resistant to conventional treatments. Therefore, it is necessary to investigate the neurobiological mechanisms underlying its pathogenesis. In this study, we investigated whether chemogenetic activation or inhibition of dopaminergic D1 receptor (D1R)- or D2 receptor (D2R)-containing neurons in the substantia nigra pars compacta (SNpc) or dorsal striatum (dSTR) affected the stereotyped behavior and motor functions of TS mice. Intraperitoneal injection of 3,3'-iminodipropionitrile (IDPN) was used to induce TS in mice. Stereotyped behavior test and open-field, rotarod, and grip strength tests were performed to evaluate stereotyped behavior and motor functions, respectively. Immunofluorescence labeling was used to detect the co-labeling of virus fluorescence and D1R or D2R. We found that chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies and motor functions in TS mice. Chemogenetic activation of D1R-containing neurons in the dSTR aggravated behavioral stereotypies and motor functions in vehicle-treated mice, but neither was aggravated in TS mice. In conclusion, chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies of TS, providing a new treatment target for TS. Moreover, the activation of D1R-containing neurons in the dSTR may contribute to the pathogenesis of TS, which can be chosen as a more precise target for treatment.
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Affiliation(s)
- Lixue Lin
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Rehabilitation, Wuhan No.1 Hospital, Wuhan, China
| | - Yuye Lan
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - He Zhu
- Institute of Clinical Medicine, Zhanjiang Central People's Hospital, Zhanjiang, China
| | - Lingling Yu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Wu
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wangyixuan Wan
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Shu
- Department of Central Laboratory, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hongchun Xiang
- Department of Acupuncture and Moxibustion, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tengfei Hou
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Zhang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Ma
- Department of Rehabilitation, Wuhan No.1 Hospital, Wuhan, China
| | - Wen Su
- Department of Pediatrics, Wuhan No.1 Hospital, Wuhan, China
| | - Man Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Kahl CK, Swansburg R, Kirton A, Pringsheim T, Wilcox G, Zewdie E, Harris A, Croarkin PE, Nettel-Aguirre A, Chenji S, MacMaster FP. Targeted Interventions in Tourette's using Advanced Neuroimaging and Stimulation (TITANS): study protocol for a double-blind, randomised controlled trial of transcranial magnetic stimulation (TMS) to the supplementary motor area in children with Tourette's syndrome. BMJ Open 2021; 11:e053156. [PMID: 34952879 PMCID: PMC8712978 DOI: 10.1136/bmjopen-2021-053156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Tourette's syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette's syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures). METHODS AND ANALYSIS This study will recruit 50 youth with TS, aged 6-18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2-6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette's symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers. ETHICS AND DISSEMINATION Ethical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub. TRIAL REGISTRATION NCT03844919.
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Affiliation(s)
- Cynthia K Kahl
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Rose Swansburg
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Adam Kirton
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Tamara Pringsheim
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
- Community Health Sciences, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Gabrielle Wilcox
- School and Applied Child Psychology, Werklund School of Education, University of Calgary, Calgary, Alberta, Canada
| | - Ephrem Zewdie
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Ashley Harris
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Department of Radiology, University of Calgary, Calgary, Alberta, Canada
| | - Paul E Croarkin
- Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Alberto Nettel-Aguirre
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Community Health Sciences, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Sneha Chenji
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
| | - Frank P MacMaster
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
- Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
- Provincial Addictions and Mental Health, Alberta Health Services, Calgary, Alberta, Canada
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Lee H, Shim S, Kong JS, Kim MJ, Park S, Lee SS, Kim A. Overexpression of dopamine receptor D2 promotes colorectal cancer progression by activating the β-catenin/ZEB1 axis. Cancer Sci 2021; 112:3732-3743. [PMID: 34118099 PMCID: PMC8409418 DOI: 10.1111/cas.15026] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/08/2021] [Accepted: 06/11/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a recurring cancer that is often resistant to conventional therapies and therefore requires the development of molecular-based therapeutic approaches. Dopamine receptor D2 (DRD2) is associated with the growth of many types of tumors, but its oncogenic role in CRC is unclear. Here, we observed that elevated DRD2 expression was associated with a poor survival rate among patients with CRC. Depletion of DRD2 suppressed CRC cell growth and motility by downregulating β-catenin/ZEB signaling in vitro and in vivo, whereas overexpression of DRD2 promoted CRC cell progression. Inhibition of DRD2 by the antagonist pimozide inhibited tumor growth and lymph node metastasis in vivo and enhanced the cytotoxic effects of conventional agents in vitro. Taken together, our findings indicate that targeting the DRD2/β-catenin/ZEB1 signaling axis is a potentially promising therapeutic strategy for patients with CRC.
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Affiliation(s)
- Hyunjung Lee
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea
| | - Sehwan Shim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea
| | - Joon Seog Kong
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea.,Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Science, Seoul, Korea
| | - Min-Jung Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea
| | - Sunhoo Park
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea.,Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Science, Seoul, Korea
| | - Seung-Sook Lee
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea.,Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Science, Seoul, Korea
| | - Areumnuri Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Seoul, Korea
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Ashurova M, Budman C, Coffey BJ. Ticked Off: Anger Outbursts and Aggressive Symptoms in Tourette Disorder. Child Adolesc Psychiatr Clin N Am 2021; 30:361-373. [PMID: 33743944 DOI: 10.1016/j.chc.2020.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Tourette disorder is a complex neuropsychiatric syndrome of childhood onset characterized by multiple motor and phonic tics and is associated with high rates of psychiatric comorbidity. Symptoms of impulsive aggression (explosive outbursts or "rage") are commonly encountered in the clinical setting, cause significant morbidity, and pose diagnostic and treatment challenges. These symptoms may be multifactorial in etiology and result from a complex interplay of illness severity and psychosocial factors. Treatment strategies require careful differential diagnostic evaluation and include both behavioral and pharmacologic interventions.
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Affiliation(s)
- Marianna Ashurova
- Zucker Hillside Hospital, ACP Building Basement, 75-59 263rd Street, Glen Oaks, NY 11004, USA; Child & Adolescent Psychiatry Consultation Liaison Service, Cohens Children's Medical Center, 268-01 76th Avenue, New Hyde Park, NY 11040, USA.
| | - Cathy Budman
- Long Island Center for Tourette, 1615 Northern Boulevard, Suite #306, Manhasset, NY 11030, USA; Zucker School of Medicine, 500 Hofstra Boulevard, Hempstead, NY 11549, USA
| | - Barbara J Coffey
- Department of Psychiatry and Behavioral Sciences, Child and Adolescent Psychiatry, Tourette Association Center of Excellence, University of Miami Miller School of Medicine, 1120 Northwest Fourteenth Street, Suite 1442, Miami, FL 33136, USA
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10
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Wang Y, Zhao L, Li AY. Gastrodin - A potential drug used for the treatment of Tourette Syndrome. J Pharmacol Sci 2021; 145:289-295. [PMID: 33602510 DOI: 10.1016/j.jphs.2021.01.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 09/29/2020] [Accepted: 01/18/2021] [Indexed: 10/22/2022] Open
Abstract
Gastrodin (Gas) represents the major active component of Gastrodia elata, a Chinese herb. Clinically, Gas is widely used for its sedative, anticonvulsive and neuroprotective properties. This work aimed to assess Gas for its efficacy in Tourette Syndrome (TS) treatment. Twenty-four rats were randomized to the blank control (n = 6) and experimental (n = 18) groups. The experimental group was administered continuous injection of 3, 3'-iminodipropionitrile (IDPN) intraperitoneally for 7 days, and subdivided into the IDPN + NS, IDPN + Hal, and IDPN + Gas groups (n = 6). The control and IDPN + NS groups received saline intragastrically, while the IDPN + Hal and IDPN + Gas groups were administered Gas and Haloperidol, respectively, for 8 weeks. Then, micro-positron emission tomography (PET) was performed for measuring the density and brain distribution of dopamine D2 receptors (D2Rs), dopamine transporters (DATs), 5-HT2A receptors (5-HT2ARs) and 5-HT transporters (SERTs). According to stereotypical behavior experiments, IDPN significantly induced abnormal stereotypical behaviors in rats in comparison with control animals. In addition, micro-PET revealed that by reducing the amounts of D2Rs and increasing those of DATs, Gas could significantly reduce stereotypical TS-like behaviors in this rat model system. Furthermore, Gas treatment reduced the density of SERTs, which could indirectly decrease DA release. The current study demonstrated that Gas could be effective in treating TS.
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Affiliation(s)
- Yuan Wang
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Lin Zhao
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
| | - An-Yuan Li
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
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11
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Xu D, Liu L, Li H, Sun L, Yang L, Qian Q, Wang Y. Potential Role of ADRA2A Genetic Variants in the Etiology of ADHD Comorbid With Tic Disorders. J Atten Disord 2021; 25:33-43. [PMID: 29482474 DOI: 10.1177/1087054718757646] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Objective: To evaluate the role of the adrenergic receptor alpha-2A gene (ADRA2A) in the genetic etiology of ADHD comorbid with tic disorders (ADHD+TD). Method: Two single nucleotide polymorphisms (SNPs) of ADRA2A were genotyped and analyzed in 936 normal controls and 1,815 ADHD probands, including 1,249 trios. Approximately 16% of the ADHD probands also had a diagnosis of TD. Results: No significant association was found between ADRA2A and ADHD in general. Case-control analyses indicated different allelic and genotypic distributions of rs553668 between ADHD+TD and controls in males. Family-based association tests showed that the G allele of rs1800544, the A allele of rs553668, and the GA haplotype consisting of these two SNPs were overtransmitted in the ADHD+TD trios, especially in males. Moreover, the allelic/genotypic distribution and allelic transmission were different between ADHD+TD and ADHD without TD. Conclusion:ADRA2A may be associated with ADHD+TD, especially in males.
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Affiliation(s)
- Defeng Xu
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Lu Liu
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Haimei Li
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Li Sun
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Li Yang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Qiujin Qian
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Yufeng Wang
- Peking University Sixth Hospital/Institute of Mental Health, Beijing, China.,National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
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12
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Okubo R, Hasegawa T, Fukuyama K, Shiroyama T, Okada M. Current Limitations and Candidate Potential of 5-HT7 Receptor Antagonism in Psychiatric Pharmacotherapy. Front Psychiatry 2021; 12:623684. [PMID: 33679481 PMCID: PMC7930824 DOI: 10.3389/fpsyt.2021.623684] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022] Open
Abstract
Several mood-stabilizing atypical antipsychotics and antidepressants weakly block serotonin (5-HT) receptor type-7 (5-HT7R); however, the contributions of 5-HT7R antagonism to clinical efficacy and pathophysiology are yet to be clarified. A novel mood-stabilizing antipsychotic agent, lurasidone exhibits predominant binding affinity to 5-HT7R when compared with other monoamine receptors. To date, we have failed to discover the superior clinical efficacy of lurasidone on schizophrenia, mood, or anxiety disorders when compared with conventional mood-stabilizing atypical antipsychotics; however, numerous preclinical findings have indicated the possible potential of 5-HT7R antagonism against several neuropsychiatric disorders, as well as the generation of novel therapeutic options that could not be expected with conventional atypical antipsychotics. Traditional experimental techniques, electrophysiology, and microdialysis have demonstrated that the effects of 5-HT receptor type-1A (5-HT1AR) and 5-HT7R on neurotransmission are in contrast, but the effect of 5-HT1AR is more predominant than that of 5-HT7R, resulting in an insufficient understanding of the 5-HT7R function in the field of psychopharmacology. Accumulating knowledge regarding the pharmacodynamic profiles of 5-HT7R suggests that 5-HT7R is one of the key players in the establishment and remodeling of neural development and cytoarchitecture during the early developmental stage to the mature brain, and dysfunction or modulation of 5-HT7R is linked to the pathogenesis/pathophysiology of neuropsychiatric and neurodevelopmental disorders. In this review, to explore candidate novel applications for the treatment of several neuropsychiatric disorders, including mood disorders, schizophrenia, and other cognitive disturbance disorders, we discuss perspectives of psychopharmacology regarding the effects of 5-HT7R antagonism on transmission and intracellular signaling systems, based on preclinical findings.
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Affiliation(s)
- Ruri Okubo
- Division of Neuroscience, Laboratory Department of Neuropsychiatry, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Toshiki Hasegawa
- Division of Neuroscience, Laboratory Department of Neuropsychiatry, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Kouji Fukuyama
- Division of Neuroscience, Laboratory Department of Neuropsychiatry, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Takashi Shiroyama
- Division of Neuroscience, Laboratory Department of Neuropsychiatry, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Motohiro Okada
- Division of Neuroscience, Laboratory Department of Neuropsychiatry, Graduate School of Medicine, Mie University, Tsu, Japan
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13
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Erb HHH, Bodenbender J, Handle F, Diehl T, Donix L, Tsaur I, Gleave M, Haferkamp A, Huber J, Fuessel S, Juengel E, Culig Z, Thomas C. Assessment of STAT5 as a potential therapy target in enzalutamide-resistant prostate cancer. PLoS One 2020; 15:e0237248. [PMID: 32790723 PMCID: PMC7425943 DOI: 10.1371/journal.pone.0237248] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/22/2020] [Indexed: 12/18/2022] Open
Abstract
Despite enzalutamide's efficacy in delaying the progression of metastatic castration-resistant prostate cancer (CRPC), resistance to this anti-androgen inevitably occurs. Several studies have revealed that the signal transducer and activator of transcription (STAT) 5 plays a role in tumour progression and development of drug resistance such as enzalutamide. Data mining revealed heterogeneous expression of STAT5 in enzalutamide-treated mCRPC patients and enzalutamide-resistant prostate cancer (PCa). Isobologram analysis revealed that the STAT5 inhibitor pimozide combined with enzalutamide has? additive and synergistic inhibitory effects on cell viability in the used models. Functional analysis with siRNA-mediated STAT5 knockdown yielded divergent results. The LNCaP-derived cell line MR49F could be resensitised to enzalutamide by siRNA-mediated STAT5b-knock-down. In contrast, neither STAT5a nor STAT5b knockdown resensitised enzalutamide-resistant LAPC4-EnzaR cells to enzalutamide. In conclusion, our results indicate that STAT5 may be a possible target in a subgroup of enzalutamide-resistant PCa. However, based on the data presented here, a general role of STAT5 in enzalutamide-resistance and its potential as a therapeutic target could not be shown.
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Affiliation(s)
- Holger H. H. Erb
- Department of Urology, Technische Universität Dresden, Dresden, Germany
| | - Julia Bodenbender
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
| | - Florian Handle
- Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Tamara Diehl
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
| | - Lukas Donix
- Department of Urology, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Igor Tsaur
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
| | - Martin Gleave
- The Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
| | - Axel Haferkamp
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
| | - Johannes Huber
- Department of Urology, Technische Universität Dresden, Dresden, Germany
| | - Susanne Fuessel
- Department of Urology, Technische Universität Dresden, Dresden, Germany
| | - Eva Juengel
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
| | - Zoran Culig
- Experimental Urology, Department of Urology, University of Innsbruck, Innsbruck, Austria
| | - Christian Thomas
- Department of Urology, Technische Universität Dresden, Dresden, Germany
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14
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Hou YB, Zhang LN, Wang HN, Zhao ZF, Sun YT, Ji K, Chen JJ. The antipsychotic drug pimozide inhibits IgE-mediated mast cell degranulation and migration. Int Immunopharmacol 2020; 84:106500. [PMID: 32311669 DOI: 10.1016/j.intimp.2020.106500] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND Mast cells (MCs) mediate a key role in allergic diseases. Detailed studies of how the neuroleptic drug pimozide affects MC activity are lacking. The aim of this study was to investigate pimozide inhibition of immunoglobulin E (IgE)-mediated MC activation and MC-mediated allergic responses. METHOD MCs were stimulated with anti-dinitrophenyl (DNP) IgE antibodies and DNP-horse serum albumin (HSA) antigen (Ag), and anti-allergic pimozide effects were detected by measuring β-hexosaminidase levels. Morphological changes were observed histologically. In vivo pimozide effects were assessed in passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-sensitized active systemic anaphylaxis mouse (ASA) model experiments. Levels of phosphorylated (p-) SYK (spleen tyrosine kinase) and MAPKs (mitogen-activated protein kinases) were detected in western blots. RESULTS We found that pimozide inhibited MC degranulation, reduced MC release of β-hexosaminidase dose-dependently in activated RBL-2H3 (IC50: 13.52 μM) and bone marrow derived MC (BMMC) (IC50: 42.42 μM), and reduced MC morphological changes. The IgE/Ag-induced migration effect was suppressed by pimozide treatment dose-dependently. Pimozide down-regulated IgE/Ag-induced phosphorylation of SYK and MAPKs in activated MCs. Moreover, pimozide attenuated allergic reactions in PCA and ASA model mice, and decreased MC populations among splenic cells. CONCLUSIONS The antipsychotic drug pimozide can suppress IgE-mediated MC activation in vitro and in vivo and should be considered for repurposing to suppress MC-mediated diseases.
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Affiliation(s)
- Yi-Bo Hou
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China
| | - Li-Na Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China
| | - Hui-Na Wang
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China
| | - Zhen-Fu Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Yue-Tong Sun
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China
| | - Kunmei Ji
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Jia-Jie Chen
- Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China.
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15
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Kim U, Kim CY, Lee JM, Ryu B, Kim J, Shin C, Park JH. Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species. Front Pharmacol 2020; 10:1517. [PMID: 32009948 PMCID: PMC6976539 DOI: 10.3389/fphar.2019.01517] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/25/2019] [Indexed: 12/11/2022] Open
Abstract
The United States Food and Drug Administration-approved antipsychotic drug, pimozide, has anticancer activities. However, the role of reactive oxygen species (ROS) in its effect on prostate cancer is not well-known. We examined cell proliferation, colony formation, migration, ROS production, and the expression of antioxidant-related genes after treatment of human prostate cancer PC3 and DU145 cells with pimozide. In addition, histopathology, ROS production, and superoxide dismutase (SOD) activity were analyzed after administering pimozide to TRAMP, a transgenic mouse with prostate cancer. Pimozide increased the generation of ROS in both cell lines and inhibited cell proliferation, migration, and colony formation. Oxidative stress induced by pimozide caused changes in the expression of antioxidant enzymes (SOD1, peroxiredoxin 6, and glutathione peroxidase 2) and CISD2. Co-treatment with glutathione, an antioxidant, reduced pimozide-induced ROS levels, and counteracted the inhibition of cell proliferation. Administration of pimozide to TRAMP mice reduced the progression of prostate cancer with increased ROS generation and decreased SOD activity. These results suggest that the antipsychotic drug, pimozide, has beneficial effects in prostate cancer in vivo and in vitro. The mechanism of pimozide may be related to augmenting ROS generation. We recommend pimozide as a promising anticancer agent.
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Affiliation(s)
- Ukjin Kim
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - C-Yoon Kim
- Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, South Korea
| | - Ji Min Lee
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Bokyeong Ryu
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Jin Kim
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Changsoo Shin
- Department of Energy Resources Engineering, Seoul National University, Seoul, South Korea
| | - Jae-Hak Park
- Department of Laboratory Animal Medicine, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
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16
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Lin L, Yu L, Xiang H, Hu X, Yuan X, Zhu H, Li H, Zhang H, Hou T, Cao J, Wu S, Su W, Li M. Effects of Acupuncture on Behavioral Stereotypies and Brain Dopamine System in Mice as a Model of Tourette Syndrome. Front Behav Neurosci 2019; 13:239. [PMID: 31680895 PMCID: PMC6803462 DOI: 10.3389/fnbeh.2019.00239] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 09/23/2019] [Indexed: 12/23/2022] Open
Abstract
Tourette syndrome (TS), a developmental neurobehavioral disorder, is characterized by involuntary behavioral stereotypies. Clinical studies have confirmed the positive effect of acupuncture on treating TS, but the underlying mechanisms are not fully understood. In the present study, we used behavioral tests, Western blotting, double-immunofluorescence labeling, and fluorescence spectrophotometry to investigate whether acupuncture performed at acupoints "Baihui" (GV20) and "Yintang" (GV29) affected behavioral stereotypies and regulated the dopamine (DA) system in three different brain regions in Balb/c mice injected with 3,3'-iminodipropionitrile (IDPN) as a model for TS. We found that acupuncture alleviated behavioral stereotypies, down-regulated the expression of D1R and D2R in the striatum (STR) and substantia nigra pars compacta (SNpc), and decreased the concentration of DA in the STR, SNpc, and prefrontal cortex (PFC) as well. Moreover, acupuncture reduced the expression of tyrosine hydroxylase (TH) in the SNpc. Conclusively, acupuncture ameliorated behavioral stereotypies by regulating the DA system in the STR, SNpc, and PFC. Our findings provide novel evidence for the therapeutic effect of acupuncture on TS.
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Affiliation(s)
- Lixue Lin
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingling Yu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongchun Xiang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuefei Hu
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaocui Yuan
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - He Zhu
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongping Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong Zhang
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tengfei Hou
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Cao
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuang Wu
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Su
- Department of Pediatrics, Wuhan No. 1 Hospital, Wuhan, China
| | - Man Li
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Callari A, Miniati M. Clinical and Therapeutic Challenges when Psychiatric Disorders Occur in Neurological Diseases: A Narrative Review. CURRENT PSYCHIATRY RESEARCH AND REVIEWS 2019. [DOI: 10.2174/1573400515666190411142109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:Over the course of the 20th century, neurology and psychiatry diverged and became two separate disciplines. Subsequently, the continuous progress of neurosciences confused their boundaries. However, with ‘the splitting’ and ‘the lumping’ approaches, relevant difficulties remain in targeting clinical and therapeutic goals, when psychiatric signs and symptoms co-occur with neurological diseases.Objective:The study summarize current evidence on psychiatric signs and symptoms comorbid with neurological diseases, with the aim to provide information on diagnostic problems and available therapeutic options.Methods:Finding from searches of publications on ‘PsycInfo’, ‘Medline’, and ‘Science Direct’, from January 1993 to December 2018 (25 years) is summarized in a narrative manner on six main neurological areas: congenital neurological illnesses (n=16), dementias (n=15), basal ganglia diseases (n=30), epilepsy (n=22), strokes/focal brain injuries (n=29), and neurological neoplastic/paraneoplastic diseases (n=15).Results:Clinical phenotypes of psychiatric syndromes are frequently described in neurological studies. Little evidence is provided on the most adequate therapeutic approaches.Conclusion:Psychiatric syndromes in comorbidity with neurological diseases are heterogeneous and severe; evidence-based treatments are scarce. Despite a model supporting an equal approach between psychiatric and neurological syndromes, psychiatric syndromes in neurological diseases have been described, to a relevant degree, as less important, leading to a hierarchical primate of the neurological manifestations, and thus, in our opinion, limiting the systematic studies on psychopharmacological treatments in this area.
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Affiliation(s)
| | - Mario Miniati
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy
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18
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Wang Y, Li A. Regulatory effects of Ningdong granule on dopaminergic and serotonergic neurotransmission in a rat model of Tourette syndrome assessed by PET. Mol Med Rep 2019; 20:191-197. [PMID: 31115527 DOI: 10.3892/mmr.2019.10243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 03/20/2019] [Indexed: 11/06/2022] Open
Abstract
Dysfunctions in dopamine (DA) and serotonin (5‑HT) metabolism have been widely implicated in Tourette syndrome (TS); however, the exact nature of these dysfunctions remains unclear. The objective of the present study was to investigate the variation in DA and 5‑HT metabolism in a rat model of TS, and to evaluate the therapeutic effect of Ningdong granule (NDG), a traditional Chinese medicine (TCM) preparation used specifically for the treatment of TS. Rats were treated with 3,3'‑iminodipropionitrile for 7 days to induce the model of TS, and were then intragastrically administered NDG each day. After 8 weeks of treatment, micro‑positron emission tomography was used to measure the binding of DA D2 receptors (D2Rs), DA transporters (DATs), 5‑HT2A receptors (5‑HT2ARs) and 5‑HT transporters (SERTs) in brain regions of interest. The results indicated that NDG could significantly reduce the typical characteristics of TS in the rat model. Decreased D2R binding and increased DAT binding were detected in the striatum compared with the binding activities in untreated rats. The density of 5‑HT2AR was also significantly increased in the striatum following NDG treatment; however, SERT levels were decreased in certain brain regions, including the striatum, cortex, nucleus accumbens and amygdala. Taken together, the current results demonstrated that NDG may be effective in treating patients with TS.
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Affiliation(s)
- Yuan Wang
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Anyuan Li
- Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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19
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Pinares-Garcia P, Stratikopoulos M, Zagato A, Loke H, Lee J. Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders. Brain Sci 2018; 8:E154. [PMID: 30104506 PMCID: PMC6120011 DOI: 10.3390/brainsci8080154] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/08/2018] [Accepted: 08/10/2018] [Indexed: 12/11/2022] Open
Abstract
Males and females sometimes significantly differ in their propensity to develop neurological disorders. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD) and autism. Despite this, biological sex is rarely considered when making treatment decisions in neurological disorders. A better understanding of the molecular mechanism(s) underlying sex differences in the healthy and diseased brain will help to devise diagnostic and therapeutic strategies optimal for each sex. Thus, the aim of this review is to discuss the available evidence on sex differences in neuropsychiatric and neurodegenerative disorders regarding prevalence, progression, symptoms and response to therapy. We also discuss the sex-related factors such as gonadal sex hormones and sex chromosome genes and how these might help to explain some of the clinically observed sex differences in these disorders. In particular, we highlight the emerging role of the Y-chromosome gene, SRY, in the male brain and its potential role as a male-specific risk factor for disorders such as PD, autism, and ADHD in many individuals.
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Affiliation(s)
- Paulo Pinares-Garcia
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
| | - Marielle Stratikopoulos
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
| | - Alice Zagato
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
| | - Hannah Loke
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
| | - Joohyung Lee
- Brain and Gender laboratory, Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
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20
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Jia H, Ren W, Feng Y, Wei T, Guo M, Guo J, Zhao J, Song X, Wang M, Zhao T, Wang H, Feng Z, Tian Z. The enhanced antitumour response of pimozide combined with the IDO inhibitor L‑MT in melanoma. Int J Oncol 2018; 53:949-960. [PMID: 30015838 PMCID: PMC6065445 DOI: 10.3892/ijo.2018.4473] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 06/06/2018] [Indexed: 12/12/2022] Open
Abstract
Melanoma is one of the most fatal and therapy-resistant types of cancer; therefore, identifying novel therapeutic candidates to improve patient survival is an ongoing effort. Previous studies have revealed that pimozide is not sufficient to treat melanoma; therefore, enhancing the treatment is necessary. Indoleamine 2, 3‑dioxygenase (IDO) is an immunosuppressive, intracellular rate-limiting enzyme, which contributes to immune tolerance in various tumours, including melanoma, and inhibition of IDO may be considered a novel therapeutic strategy when combined with pimozide. The present study aimed to assess the antitumour activities of pimozide in vitro, and to investigate the effects of pimozide combined with L‑methyl-tryptophan (L‑MT) in vivo. For in vitro analyses, the B16 melanoma cell line was used. Cell cytotoxicity assay, cell viability assay, wound‑healing assay and western blotting were conducted to analyse the effects of pimozide on B16 cells. Furthermore, B16 cell-bearing mice were established as the animal model. Haematoxylin and eosin staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labelling staining, western blotting and flow cytometry were performed to determine the effects of monotherapy and pimozide and L‑MT cotreatment on melanoma. The results demonstrated that pimozide exhibited potent antitumour activity via the regulation of proliferation, apoptosis and migration. Furthermore, the antitumour effects of pimozide were enhanced when combined with L‑MT, not only via regulation of proliferation, apoptosis and migration, but also via immune modulation. Notably, pimozide may regulate tumour immunity through inhibiting the activities of signal transducer and activator of transcription (Stat)3 and Stat5. In conclusion, the present study proposed the use of pimozide in combination with the IDO inhibitor, L‑MT, as a potential novel therapeutic strategy for the treatment of melanoma.
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Affiliation(s)
- Huijie Jia
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Wenjing Ren
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Yuchen Feng
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Tian Wei
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Mengmeng Guo
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Jing Guo
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Jingjing Zhao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Xiangfeng Song
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Mingyong Wang
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Tiesuo Zhao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Hui Wang
- Research Center for Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Zhiwei Feng
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
| | - Zhongwei Tian
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453000, P.R. China
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21
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Qi C, Ji X, Zhang G, Kang Y, Huang Y, Cui R, Li S, Cui H, Shi G. Haloperidol ameliorates androgen-induced behavioral deficits in developing male rats. J Endocrinol 2018; 237:193-205. [PMID: 29563235 DOI: 10.1530/joe-17-0642] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 03/21/2018] [Indexed: 01/06/2023]
Abstract
The purpose of present study was to infer the potential effects of testosterone increase in some male-based childhood-onset neuropsychiatric disorders, such as Tourette syndrome. Thus, the influence of early postnatal androgen exposure upon the neurobehaviors and its possible neural basis were investigated in the study. Male pup rats received consecutive 14-day testosterone propionate (TP) subcutaneous injection from postnatal day (PND) 7. The TP treatment produced the hyperactive motor behavior and grooming behavior as well as the increased levels of dopamine, tyrosine hydroxylase and dopamine transporter in the mesodopaminergic system and the elevated levels of serotonin in the nucleus accumbens, without affecting the levels of glutamate, γ-aminobutyric acid, norepinephrine and histamine in the caudate putamen and nucleus accumbens of PND21 and PND49 rats. Dopamine D2 receptor antagonist haloperidol was administered to the early postnatal TP-exposed PND21 and PND49 male rats 30 min prior to open field test. Haloperidol significantly ameliorated the motor behavioral and grooming behavioral defects induced by early postnatal TP exposure. The results demonstrated that early postnatal androgen exposure significantly disturbed the brain activity of developing male rats via enhancing the mesodopaminergic activity. It was suggested that abnormal increments of testosterone levels during the early postnatal development might be a potential risk factor for the incidence of some male-based childhood-onset neuropsychiatric disorders by affecting the mesodopaminergic system.
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Affiliation(s)
- Chunxiao Qi
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Xiaoming Ji
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Guoliang Zhang
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Yunxiao Kang
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Yuanxiang Huang
- Grade 2015 Eight-year Clinical Medicine ProgramSchool of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Rui Cui
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Shuangcheng Li
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
| | - Huixian Cui
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
- Neuroscience Research CenterHebei Medical University, Shijiazhuang, People's Republic of China
| | - Geming Shi
- Department of NeurobiologyHebei Medical University, Shijiazhuang, People's Republic of China
- Department of Human AnatomyHebei Medical University, Shijiazhuang, People's Republic of China
- Neuroscience Research CenterHebei Medical University, Shijiazhuang, People's Republic of China
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22
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Mogwitz S, Buse J, Wolff N, Roessner V. Update on the Pharmacological Treatment of Tics with Dopamine-Modulating Agents. ACS Chem Neurosci 2018; 9:651-672. [PMID: 29498507 DOI: 10.1021/acschemneuro.7b00460] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
More than 40 years of research and clinical practice have proven the effectiveness of dopamine receptor antagonists in the pharmacological treatment of tics. A blockade of the striatal dopamine-D2 receptors is mainly responsible for their tic-reducing effect. A broad spectrum of dopamine-modulating agents, such as typical and atypical antipsychotics, but also dopamine receptor agonists are used with an immanent discord between experts about which of them should be considered as first choice. The present Review outlines the state of the art on pharmacological treatment of tics with dopamine-modulating agents by giving an systematic overview of studies on their effectiveness and a critical discussion of their specific adverse effects. It is considered as an update of a previous review of our research group published in 2013. The Review closes with a description of the current resulting treatment recommendations including the results of a first published revised survey on European expert's prescription preferences. Based on the enormously growing evidence on its effectiveness and safety, aripiprazole currently seems to be the most promising agent in the pharmacological treatment of tics. Furthermore, benzamides (especially tiapride), which are commonly used in Europe, have proven their excellent effectiveness-tolerability profile over decades in clinical practice and are therefore also highly recommended for the treatment of tics. Nevertheless, pharmacological treatment of tics remains an indiviual choice depending on each patient's own specific needs.
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Affiliation(s)
- Sabine Mogwitz
- Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, 01307 Dresden, Germany
| | - Judith Buse
- Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, 01307 Dresden, Germany
| | - Nicole Wolff
- Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, 01307 Dresden, Germany
| | - Veit Roessner
- Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, 01307 Dresden, Germany
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23
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Saggu BM, Shad S, Barnes AA, Budman CL. Pharmacological Management of Tic Disorders in Youth. THE CLINICIAN'S GUIDE TO TREATMENT AND MANAGEMENT OF YOUTH WITH TOURETTE SYNDROME AND TIC DISORDERS 2018:71-100. [DOI: 10.1016/b978-0-12-811980-8.00004-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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24
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Chen JJ, Cai N, Chen GZ, Jia CC, Qiu DB, Du C, Liu W, Yang Y, Long ZJ, Zhang Q. The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma. Oncotarget 2017; 8:17593-17609. [PMID: 26061710 PMCID: PMC5392272 DOI: 10.18632/oncotarget.4307] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 05/13/2015] [Indexed: 12/23/2022] Open
Abstract
Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug resistance to chemotherapy, and the prognosis is poor due to the existence of liver cancer stem-like cells. In this study, we investigated the effect of the neuroleptic agent pimozide to inhibit stem-like cell maintenance and tumorigenicity in HCC. Our results showed that pimozide functioned as an anti-cancer drug in HCC cells or stem-like cells. Pimozide inhibited cell proliferation and sphere formation capacities in HCC cells by inducing G0/G1 phase cell cycle arrest, as well as inhibited HCC cell migration. Surprisingly, pimozide inhibited the maintenance and tumorigenicity of HCC stem-like cells, particularly the side population (SP) or CD133-positive cells, as evaluated by colony formation, sphere formation and transwell migration assays. Furthermore, pimozide was found to suppress STAT3 activity in HCC cells by attenuating STAT3-dependent luciferase activity and down-regulating the transcription levels of downstream genes of STAT3 signaling. Moreover, pimozide reversed the stem-like cell tumorigenic phenotypes induced by IL-6 treatment in HCC cells. Further, the antitumor effect of pimozide was also proved in the nude mice HCC xenograft model. In short, the anti-psychotic agent pimozide may act as a novel potential anti-tumor agent in treating advanced HCC.
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Affiliation(s)
- Jia-Jie Chen
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Nan Cai
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Guan-Zhong Chen
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Chang-Chang Jia
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Dong-Bo Qiu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Cong Du
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Wei Liu
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yang Yang
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Zi-Jie Long
- Department of Hematology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Qi Zhang
- Organ Transplantation Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.,Vaccine Research Institute of Sun Yat-Sen University, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
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25
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Wang S, Wei YZ, Yang J, Zhou Y, Zheng Y. Clonidine adhesive patch for the treatment of tic disorders: A systematic review and meta-analysis. Eur J Paediatr Neurol 2017; 21:614-620. [PMID: 28495246 DOI: 10.1016/j.ejpn.2017.03.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 02/04/2017] [Accepted: 03/11/2017] [Indexed: 01/08/2023]
Abstract
OBJECTIVE The aim of this study was to evaluate the efficacy and safety of clonidine adhesive patch for tic disorders (TDs). METHODS Medline, Embase, Cochrane central register of controlled trials and Chinese databases of CBM, CNKI were searched from inception to 08.2016 for randomized controlled studies (RCTs), open-label control studies of clonidine adhesive patch versus other medications or/and placebo for TDs. The cochrane Handbook for Systematic Reviews of Interventions was used to guide our study. RESULTS Six studies involving 1145 participants were included in this study. Among these studies, two study (N = 513 patients) used placebo as a control and four studies (N = 632 patients) used positive drug controls. The results of meta-analysis suggested that clonidine adhesive patch may be as effective as haloperidol or tiapride for TDs. Adverse events (AEs) were reported in all studies, and the most common AEs of clonidine adhesive patch were rash (8.9%), lightheadedness (8.0%), dry mouth (4.0%). The AEs of clonidine adhesive patch were slight. CONCLUSION These data provide moderate quality evidence that clonidine adhesive patch might be an effective and safe treatment option for TDs, and results from further trials are urgently needed to extend the evidence base.
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Affiliation(s)
- Shuai Wang
- Beijing Anding Hospital, Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders, Beijing 100001, China
| | - Yan-Zhao Wei
- Beijing Anding Hospital, Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders, Beijing 100001, China
| | - Jianhong Yang
- Beijing Anding Hospital, Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders, Beijing 100001, China
| | - Yuming Zhou
- Beijing Anding Hospital, Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders, Beijing 100001, China
| | - Yi Zheng
- Beijing Anding Hospital, Capital Medical University, Beijing, China; Beijing Institute for Brain Disorders, Beijing 100001, China.
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26
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Abstract
Tourette syndrome is a neuropsychiatric condition characterized by both motor and phonic tics over a period of at least 1 year with the onset in childhood or adolescence. Apart from the tics, most of the patients with Tourette syndrome have associated neuropsychiatric comorbidities consisting of attention deficit hyperactivity disorder, obsessive compulsive disorder, rage attacks, sleep issues, depression, and migraine. Patients may also have physical complications directly from violent motor tics which can rarely include cervical myelopathy, arterial dissection, and stroke. The purpose of this article is to review the associated neuropsychiatric comorbidities of Tourette syndrome with emphasis on recent research.
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27
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Zheng W, Li XB, Xiang YQ, Zhong BL, Chiu HFK, Ungvari GS, Ng CH, Lok GKI, Xiang YT. Aripiprazole for Tourette's syndrome: a systematic review and meta-analysis. Hum Psychopharmacol 2016; 31:11-8. [PMID: 26310194 DOI: 10.1002/hup.2498] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 04/23/2015] [Accepted: 07/02/2015] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To review the efficacy and safety of aripiprazole (ARI) for Tourette's syndrome (TS). METHODS This review included randomized controlled trials (RCTs) of children and adolescents (6-18 years) with TS comparing ARI monotherapy with another monotherapies in relation to clinical improvement and adverse events. RESULTS Six RCTs with a total of 528 subjects (ARI treatment group: n = 253; control group: n = 275) met the inclusion criteria. These included two RCTs (n = 255) that compared ARI monotherapy with tiapride (TIA). Tic symptoms control assessed by Yale Global Tic Severity Scale (Standard Mean Difference (SMD) = -0.38 (Confidence Interval (CI) = -1.32 to 0.56); I(2) = 90%, P = 0.42) revealed no significant differences between the two groups. Extrapyramidal symptoms were significantly different when ARI (1.5%) was compared with haloperidol (HAL) (43.5%). No significant group differences were found in the rates of nausea/vomiting, dizziness, and dry mouth between ARI and TIA (RR = 0.57 to 1.00 (95%CI = 0.14-4.20); I(2) = 0% to 69%, P = 0.35 to 1.00). CONCLUSION This review found that ARI has similar efficacy to TIA and HAL for TS, while extrapyramidal symptoms were significantly less with ARI than with HAL. ARI can be considered as an alternative treatment option for TS.
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Affiliation(s)
- Wei Zheng
- Beijing Anding Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Psychiatric Disorders, China
| | - Xian-Bin Li
- Beijing Anding Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Psychiatric Disorders, China
| | - Ying-Qiang Xiang
- Beijing Anding Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Psychiatric Disorders, China
| | - Bao-Liang Zhong
- Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Helen F K Chiu
- Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Gabor S Ungvari
- The University of Notre Dame Australia/Marian Centre, Perth, Australia.,School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia
| | - Chee H Ng
- Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
| | - Grace K I Lok
- Kiang Wu Nursing College of Macau, Macao, SRA, China
| | - Yu-Tao Xiang
- Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao, SAR, China
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28
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Jiao F, Zhang X, Zhang X, Wang J. Clinical observation on treatment of Tourette syndrome in Chinese children by clonidine adhesive patch. Eur J Paediatr Neurol 2016; 20:80-4. [PMID: 26602699 DOI: 10.1016/j.ejpn.2015.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 09/24/2015] [Accepted: 10/04/2015] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To evaluate the therapeutic effectiveness and safety of clonidine adhesive patch in treating Tourette syndrome (TS). METHODS From July 2010 to July 2014,a total of 261 children, who met the Chinese Classification of Mental Disorders (third edition) diagnostic criteria for TS, aged 5-12 years, were referred to the department of Pediatrics, Shaanxi Provincial People's Hospital. The patients were divided randomly into a treatment group (clonidine adhesive patch, n = 128) and a control group (haloperidol, n = 116), 17cases dropped out. The clinical effectiveness was assessed by the Yale Global Tic Severity Scale (YGTSS) at the end of fourth week. The short-term effectiveness and adverse reaction to the treatment were assessed at the end of treatment. RESULTS The YGTSS score in both groups decreased after 4 weeks of treatment, but the clonidine adhesive patch group showed a higher reduction in the overall tic symptom scores (40.05 ± 3.44%) than that of the control group (17.88 ± 4.40%; P < 0.05). In the clonidine adhesive patch group, the effectiveness was 81.3% (effective in 104 patients), while it was 66.4% in the control group (effective in 77 patients). The overall effectiveness rate showed no statistical significance between the two groups (p > 0.05). There were no severe adverse events in both groups, but mild side effects (decrease of blood pressure and dizziness) were observed in 3 patients in the clonidine adhesive patch group. 2 had mild cervical muscle tension and 4 had mild drowsiness and fatigue in the control group. CONCLUSION In the treatment of TS in children and adolescents, the clonidine adhesive patch is superior to the standard treatment with haloperidol with a safer and better-tolerated profile.
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Affiliation(s)
- Fuyong Jiao
- Department of Pediatrics, Shaanxi Provincial People's Hospital (3rd Affiliated Hospital of Xi'an, Jiaotong University), Xi'an 710068, China.
| | - Xiaoyan Zhang
- Department of Pediatrics, Shaanxi Provincial People's Hospital (3rd Affiliated Hospital of Xi'an, Jiaotong University), Xi'an 710068, China
| | - Xipin Zhang
- Department of Pediatrics, Shaanxi Provincial People's Hospital (3rd Affiliated Hospital of Xi'an, Jiaotong University), Xi'an 710068, China
| | - Jing Wang
- Department of Pediatrics, Shaanxi Provincial People's Hospital (3rd Affiliated Hospital of Xi'an, Jiaotong University), Xi'an 710068, China
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29
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ZHOU WEI, CHEN MINGKUN, YU HAOTAO, ZHONG ZHIHONG, CAI NAN, CHEN GUANZHONG, ZHANG PING, CHEN JIAJIE. The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation. Int J Oncol 2015; 48:322-8. [DOI: 10.3892/ijo.2015.3229] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 09/28/2015] [Indexed: 11/06/2022] Open
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30
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Abstract
Tourette Syndrome is a disorder characterized by tics. It typically begins in childhood and often improves in adult life. Tics are best described as voluntary movements made automatically so that volition is not ordinarily appreciated. There is frequently an urge, sometimes in the form of a specific sensory feeling (sensory tic), that precedes the tic. Patients say that they make the tic in order to reduce the urge, although shortly after the tic, the urge recurs. The sensory feeling may arise due to defective sensory habituation. Since tics relieve the urge, this can be considered rewarding, and repetition of this behavior may perpetuate the tic as a habit. Tourette Syndrome affects boys more than girls and is associated with attention deficit hyperactivity disorder and obsessive compulsive disorder. Although Tourette Syndrome often appears to be autosomal recessive in inheritance, it has been difficult to find any abnormal genes. There is a loss of inhibition in these patients and recent studies show abnormalities in brain GABA. Certainly there is also an abnormality in dopamine function and dopamine blocking agents are effective therapy. In severe drug-refractory patients, deep brain stimulation can be effective.
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Affiliation(s)
- Mark HALLETT
- Human Motor Control Section, National Institute of Neurological Disorders and Stroke
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31
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El Malhany N, Gulisano M, Rizzo R, Curatolo P. Tourette syndrome and comorbid ADHD: causes and consequences. Eur J Pediatr 2015; 174:279-88. [PMID: 25224657 DOI: 10.1007/s00431-014-2417-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 08/27/2014] [Accepted: 09/01/2014] [Indexed: 12/17/2022]
Abstract
UNLABELLED Attention deficit hyperactivity disorder (ADHD) is the most common comorbid condition in patients with Tourette syndrome (TS). The co-occurrence of ADHD and TS is in most cases associated with a higher social and psychopathological impairment. Comorbidity between Tourette and ADHD appears to have a complex and partially known pathogenesis in which genetic, environmental, and neurobiological factors can be implicated. Genetic studies have revealed an involvement of dopaminergic, catecholaminergic, and GABAergic genes that modulated the activity of neurotransmitters. Furthermore, there are a lot of networks implicated in the development of ADHD and TS, involving cortical and striatal areas and basal ganglia. Although a large number of studies tried to find a common pathogenesis, the complex pathways responsible are not clear. The genes implicated in both disorders are currently unidentified, but it is probable that epigenetic factors associated with neural modifications can represent a substrate for the development of the diseases. CONCLUSION In this paper, recent advances in neurobiology of ADHD and TS are reviewed, providing a basis for understanding the complex common pathogenesis underlying the frequent co-occurrence of the two conditions and the therapeutic choices.
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Affiliation(s)
- N El Malhany
- Section of Child Neuropsychiatry, Department of Neurosciences, Tor Vergata University, Viale Oxford 81, 00133, Rome, Italy,
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32
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Goglia AG, Delsite R, Luz AN, Shahbazian D, Salem AF, Sundaram RK, Chiaravalli J, Hendrikx PJ, Wilshire JA, Jasin M, Kluger HM, Glickman JF, Powell SN, Bindra RS. Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors. Mol Cancer Ther 2015; 14:326-42. [PMID: 25512618 PMCID: PMC4326563 DOI: 10.1158/1535-7163.mct-14-0765] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA-damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radiosensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules that selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits that potently inhibit DSB repair, and we have validated their functional activity in a comprehensive panel of orthogonal secondary assays. A selection of these inhibitors was found to radiosensitize cancer cell lines in vitro, which suggests that they may be useful as novel chemo- and radio sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker mibefradil dihydrochloride, that demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a phase I clinical trial testing mibefradil as a glioma radiosensitizer.
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Affiliation(s)
- Alexander G Goglia
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Robert Delsite
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Antonio N Luz
- High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York
| | - David Shahbazian
- Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut
| | - Ahmed F Salem
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
| | - Ranjini K Sundaram
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
| | - Jeanne Chiaravalli
- High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York
| | - Petrus J Hendrikx
- Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer A Wilshire
- Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria Jasin
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Harriet M Kluger
- Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut
| | - J Fraser Glickman
- High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, New York
| | - Simon N Powell
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Ranjit S Bindra
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.
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Godar SC, Mosher LJ, Di Giovanni G, Bortolato M. Animal models of tic disorders: a translational perspective. J Neurosci Methods 2014; 238:54-69. [PMID: 25244952 DOI: 10.1016/j.jneumeth.2014.09.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/09/2014] [Accepted: 09/11/2014] [Indexed: 12/30/2022]
Abstract
Tics are repetitive, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive premonitory urges. The most severe tic disorder, Tourette syndrome (TS), is a childhood-onset condition featuring multiple motor and at least one phonic tic for a duration longer than 1 year. The pharmacological treatment of TS is mainly based on antipsychotic agents; while these drugs are often effective in reducing tic severity and frequency, their therapeutic compliance is limited by serious motor and cognitive side effects. The identification of novel therapeutic targets and development of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove extremely useful to test hypotheses on the etiology and neurobiological bases of TS and related conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater focus on endophenotypes and quantitative indices, rather than qualitative descriptors. Given the complex and multifactorial nature of TS and other tic disorders, the selection of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on genetic mutations, environmental interventions as well as pharmacological manipulations. Furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant progress in the identification of novel therapeutic targets for tic disorders.
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Affiliation(s)
- Sean C Godar
- Department of Pharmacology and Toxicology, School of Pharmacy; University of Kansas, Lawrence, KS, USA
| | - Laura J Mosher
- Department of Pharmacology and Toxicology, School of Pharmacy; University of Kansas, Lawrence, KS, USA
| | - Giuseppe Di Giovanni
- Department of Physiology and Biochemistry, University of Malta, Msida, Malta; School of Biosciences, Cardiff University, Cardiff, UK
| | - Marco Bortolato
- Department of Pharmacology and Toxicology, School of Pharmacy; University of Kansas, Lawrence, KS, USA; Consortium for Translational Research on Aggression and Drug Abuse (ConTRADA), University of Kansas, Lawrence, KS, USA.
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