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Persico AM, Asta L, Chehbani F, Mirabelli S, Parlatini V, Cortese S, Arango C, Vitiello B. The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part II: The future. Prog Neuropsychopharmacol Biol Psychiatry 2025; 136:111176. [PMID: 39490514 DOI: 10.1016/j.pnpbp.2024.111176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/31/2024] [Accepted: 10/19/2024] [Indexed: 11/05/2024]
Abstract
Part I of this systematic review summarized the state-of-the-art of pediatric psychopharmacology for Autism Spectrum Disorder (ASD), a severe and lifelong neurodevelopmental disorder. The purpose of this Part II follow-up article is to provide a systematic overview of the experimental psychopharmacology of ASD. To this aim, we have first identified in the Clinicaltrials.gov website all the 157 pharmacological and nutraceutical compounds which have been experimentally tested in children and adolescents with ASD using the randomized placebo-controlled trial (RCT) design. After excluding 24 drugs already presented in Part I, a systematic review spanning each of the remaining 133 compounds was registered on Prospero (ID: CRD42023476555), performed on PubMed (August 8, 2024), and completed with EBSCO, PsycINFO (psychology and psychiatry literature) and the Cochrane Database of Systematic reviews, yielding a total of 115 published RCTs, including 57 trials for 23 pharmacological compounds and 48 trials for 17 nutraceuticals/supplements. Melatonin and oxytocin were not included, because recent systematic reviews have been already published for both these compounds. RCTs of drugs with the strongest foundation in preclinical research, namely arbaclofen, balovaptan and bumetanide have all failed to reach their primary end-points, although efforts to target specific patient subgroups do warrant further investigation. For the vast majority of compounds, including cannabidiol, vasopressin, and probiotics, insufficient evidence of efficacy and safety is available. However, a small subset of compounds, including N-acetylcysteine, folinic acid, l-carnitine, coenzyme Q10, sulforaphane, and metformin may already be considered, with due caution, for clinical use, because there is promising evidence of efficacy and a high safety profile. For several other compounds, such as secretin, efficacy can be confidently excluded, and/or the data discourage undertaking new RCTs. Part I and Part II summarize "drug-based" information, which will be ultimately merged to provide clinicians with a "symptom-based" consensus statement in a conclusive Part III, with the overarching aim to foster evidence-based clinical practices and to organize new strategies for future clinical trials.
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Affiliation(s)
- Antonio M Persico
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Child & Adolescent Neuropsychiatry Program, Modena University Hospital, Modena, Italy.
| | - Lisa Asta
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Fethia Chehbani
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Silvestro Mirabelli
- Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital, Messina, Italy
| | - Valeria Parlatini
- Center for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK
| | - Samuele Cortese
- Center for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK; Solent NHS Trust, Southampton, UK; Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York City, NY, USA; DiMePRe-J-Department of Precision and Regenerative Medicine-Jonic Area, University "Aldo Moro", Bari, Italy
| | - Celso Arango
- Child and Adolescent Psychiatry Department, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain
| | - Benedetto Vitiello
- Department of Public Health and Pediatric Sciences, Section of Child and Adolescent Neuropsychiatry, University of Turin, Turin, Italy
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Aishworiya R, Valica T, Hagerman R, Restrepo B. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. FOCUS (AMERICAN PSYCHIATRIC PUBLISHING) 2024; 22:198-211. [PMID: 38680976 PMCID: PMC11046717 DOI: 10.1176/appi.focus.24022006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD. Appeared originally in Neurotherapeutics 2022; 19:248-262.
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Affiliation(s)
- Ramkumar Aishworiya
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA (Aishworiya, Valica, Hagerman, Restrepo); Khoo Teck Puat-National University Children's Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore (Aishworiya); Association for Children With Autism, Chisinau, Moldova (Valica); Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA 95817, USA (Hagerman, Restrepo)
| | - Tatiana Valica
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA (Aishworiya, Valica, Hagerman, Restrepo); Khoo Teck Puat-National University Children's Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore (Aishworiya); Association for Children With Autism, Chisinau, Moldova (Valica); Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA 95817, USA (Hagerman, Restrepo)
| | - Randi Hagerman
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA (Aishworiya, Valica, Hagerman, Restrepo); Khoo Teck Puat-National University Children's Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore (Aishworiya); Association for Children With Autism, Chisinau, Moldova (Valica); Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA 95817, USA (Hagerman, Restrepo)
| | - Bibiana Restrepo
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA 95817, USA (Aishworiya, Valica, Hagerman, Restrepo); Khoo Teck Puat-National University Children's Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore (Aishworiya); Association for Children With Autism, Chisinau, Moldova (Valica); Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA 95817, USA (Hagerman, Restrepo)
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van Andel DM, Sprengers JJ, Königs M, de Jonge MV, Bruining H. Effects of Bumetanide on Neurocognitive Functioning in Children with Autism Spectrum Disorder: Secondary Analysis of a Randomized Placebo-Controlled Trial. J Autism Dev Disord 2024; 54:894-904. [PMID: 36626004 PMCID: PMC10907457 DOI: 10.1007/s10803-022-05841-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2022] [Indexed: 01/11/2023]
Abstract
We present the secondary-analysis of neurocognitive tests in the 'Bumetanide in Autism Medication and Biomarker' (BAMBI;EUDRA-CT-2014-001560-35) study, a randomized double-blind placebo-controlled (1:1) trial testing 3-months bumetanide treatment (≤ 1 mg twice-daily) in unmedicated children 7-15 years with ASD. Children with IQ ≥ 70 were analyzed for baseline deficits and treatment-effects on the intention-to-treat-population with generalized-linear-models, principal component analysis and network analysis. Ninety-two children were allocated to treatment and 83 eligible for analyses. Heterogeneous neurocognitive impairments were found that were unaffected by bumetanide treatment. Network analysis showed higher modularity after treatment (mean difference:-0.165, 95%CI:-0.317 to - 0.013,p = .034) and changes in the relative importance of response inhibition in the neurocognitive network (mean difference:-0.037, 95%CI:-0.073 to - 0.001,p = .042). This study offers perspectives to include neurocognitive tests in ASD trials.
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Affiliation(s)
- Dorinde M van Andel
- Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Jan J Sprengers
- Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Marsh Königs
- Department of Paediatrics, Emma Neuroscience Group, Amsterdam UMC Emma Children's Hospital, Amsterdam, The Netherlands
| | - Maretha V de Jonge
- Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, The Netherlands
- Department Education and Child Studies, Faculty of Social and Behavioral Sciences, Leiden University, Leiden, The Netherlands
| | - Hilgo Bruining
- Department of Psychiatry, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, The Netherlands.
- Child and Adolescent Psychiatry and Psychosocial Care, Emma Children's Hospital, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
- N=You Neurodevelopmental Precision Center, Amsterdam Neuroscience, Amsterdam Reproduction and Development, Amsterdam UMC, Amsterdam, Netherlands.
- Levvel, Center for Child and Adolescent Psychiatry, Amsterdam, Netherlands.
- Department of Child and Adolescent Psychiatry, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
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Shaker E, El Agami O, Salamah A. Bumetanide, a Diuretic That Can Help Children with Autism Spectrum Disorder. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:536-542. [PMID: 37021422 DOI: 10.2174/1871527322666230404114911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 01/17/2023] [Accepted: 01/25/2023] [Indexed: 04/08/2023]
Abstract
BACKGROUND Autism Spectrum Disorder (ASD) is a common child neurodevelopmental disorder, whose pathogenesis is not completely understood. Until now, there is no proven treatment for the core symptoms of ASD. However, some evidence indicates a crucial link between this disorder and GABAergic signals which are altered in ASD. Bumetanide is a diuretic that reduces chloride, shifts gamma-amino-butyric acid (GABA) from excitation to inhibition, and may play a significant role in the treatment of ASD. OBJECTIVE The objective of this study is to assess the safety and efficacy of bumetanide as a treatment for ASD. METHODS Eighty children, aged 3-12 years, with ASD diagnosed by Childhood Autism Rating Scale (CARS), ⩾ 30 were included in this double-blind, randomized, and controlled study. Group 1 received Bumetanide, Group 2 received a placebo for 6 months. Follow-up by CARS rating scale was performed before and after 1, 3, and 6 months of treatment. RESULTS The use of bumetanide in group 1 improved the core symptoms of ASD in a shorter time with minimal and tolerable adverse effects. There was a statistically significant decrease in CARS and most of its fifteen items in group 1 versus group 2 after 6 months of treatment (p-value <0.001). CONCLUSION Bumetanide has an important role in the treatment of core symptoms of ASD.
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Affiliation(s)
- Esraa Shaker
- Department of Pediatrics, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Osama El Agami
- Department of Pediatrics, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Abeer Salamah
- Department of Pediatrics, Faculty of Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
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Nguyen TD, Ishibashi M, Sinha AS, Watanabe M, Kato D, Horiuchi H, Wake H, Fukuda A. Astrocytic NKCC1 inhibits seizures by buffering Cl - and antagonizing neuronal NKCC1 at GABAergic synapses. Epilepsia 2023; 64:3389-3403. [PMID: 37779224 DOI: 10.1111/epi.17784] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/29/2023] [Accepted: 09/29/2023] [Indexed: 10/03/2023]
Abstract
OBJECTIVE A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl- importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl- concentration ([Cl- ]i ) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl- ]i with NKCC1, and this gradient promotes Cl- efflux via the astrocytic GABAA receptor (GABAA R). This Cl- efflux buffers the synaptic cleft Cl- concentration to maintain the postsynaptic Cl- gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models. METHODS We used the astrocyte-specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABAA R-mediated depolarization was evaluated by applying the GABAA R antagonist bicuculline. The pilocarpine-induced seizure in vivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild-type (WT) mice were compared. RESULTS The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAA R-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both in vitro and in vivo. SIGNIFICANCE Astrocytic NKCC1 inhibits GABA-mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.
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Affiliation(s)
- Trong Dao Nguyen
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masaru Ishibashi
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Adya Saran Sinha
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Miho Watanabe
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Daisuke Kato
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Horiuchi
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Wake
- Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Hirst K, Zamzow RM, Stichter JP, Beversdorf DQ. A Pilot Feasibility Study Assessing the Combined Effects of Early Behavioral Intervention and Propranolol on Autism Spectrum Disorder (ASD). CHILDREN (BASEL, SWITZERLAND) 2023; 10:1639. [PMID: 37892301 PMCID: PMC10605265 DOI: 10.3390/children10101639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/20/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023]
Abstract
Autism spectrum disorder (ASD), a neurodevelopmental disorder typified by differences in social communication as well as restricted and repetitive behaviors, is often responsive to early behavioral intervention. However, there is limited information on whether such intervention can be augmented with pharmacological approaches. We conducted a double-blinded, placebo-controlled feasibility trial to examine the effects of the β-adrenergic antagonist propranolol combined with early intensive behavioral intervention (EIBI) for children with ASD. Nine participants with ASD, ages three to ten, undergoing EIBI were enrolled and randomized to a 12-week course of propranolol or placebo. Blinded assessments were conducted at baseline, 6 weeks, and 12 weeks. The primary outcome measures focusing on social interaction were the General Social Outcome Measure-2 (GSOM-2) and Social Responsiveness Scale-Second Edition (SRS-2). Five participants completed the 12-week visit. The sample size was insufficient to evaluate the treatment efficacy. However, side effects were infrequent, and participants were largely able to fully participate in the procedures. Conducting a larger clinical trial to investigate propranolol's effects on core ASD features within the context of behavioral therapy will be beneficial, as this will advance and individualize combined therapeutic approaches to ASD intervention. This initial study helps to understand feasibility constraints on performing such a study.
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Affiliation(s)
- Kathy Hirst
- Thompson Center for Autism and Neurodevelopment, University of Missouri, Columbia, MO 65211, USA; (K.H.); (J.P.S.)
| | - Rachel M. Zamzow
- Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO 65211, USA;
| | - Janine P. Stichter
- Thompson Center for Autism and Neurodevelopment, University of Missouri, Columbia, MO 65211, USA; (K.H.); (J.P.S.)
| | - David Q. Beversdorf
- Thompson Center for Autism and Neurodevelopment, University of Missouri, Columbia, MO 65211, USA; (K.H.); (J.P.S.)
- Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO 65211, USA;
- Departments of Radiology, Neurology, and Psychological Sciences, William and Nancy Thompson Endowed Chair in Radiology, University of Missouri, Columbia, MO 65211, USA
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Boyarko B, Podvin S, Greenberg B, Momper JD, Huang Y, Gerwick WH, Bang AG, Quinti L, Griciuc A, Kim DY, Tanzi RE, Feldman HH, Hook V. Evaluation of bumetanide as a potential therapeutic agent for Alzheimer's disease. Front Pharmacol 2023; 14:1190402. [PMID: 37601062 PMCID: PMC10436590 DOI: 10.3389/fphar.2023.1190402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/28/2023] [Indexed: 08/22/2023] Open
Abstract
Therapeutics discovery and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and the underlying pathogenic processes. Recent drug discovery approaches have utilized in silico computational strategies for drug candidate selection which has opened the door to repurposing drugs for AD. Computational analysis of gene expression signatures of patients stratified by the APOE4 risk allele of AD led to the discovery of the FDA-approved drug bumetanide as a top candidate agent that reverses APOE4 transcriptomic brain signatures and improves memory deficits in APOE4 animal models of AD. Bumetanide is a loop diuretic which inhibits the kidney Na+-K+-2Cl- cotransporter isoform, NKCC2, for the treatment of hypertension and edema in cardiovascular, liver, and renal disease. Electronic health record data revealed that patients exposed to bumetanide have lower incidences of AD by 35%-70%. In the brain, bumetanide has been proposed to antagonize the NKCC1 isoform which mediates cellular uptake of chloride ions. Blocking neuronal NKCC1 leads to a decrease in intracellular chloride and thus promotes GABAergic receptor mediated hyperpolarization, which may ameliorate disease conditions associated with GABAergic-mediated depolarization. NKCC1 is expressed in neurons and in all brain cells including glia (oligodendrocytes, microglia, and astrocytes) and the vasculature. In consideration of bumetanide as a repurposed drug for AD, this review evaluates its pharmaceutical properties with respect to its estimated brain levels across doses that can improve neurologic disease deficits of animal models to distinguish between NKCC1 and non-NKCC1 mechanisms. The available data indicate that bumetanide efficacy may occur at brain drug levels that are below those required for inhibition of the NKCC1 transporter which implicates non-NKCC1 brain mechansims for improvement of brain dysfunctions and memory deficits. Alternatively, peripheral bumetanide mechanisms may involve cells outside the central nervous system (e.g., in epithelia and the immune system). Clinical bumetanide doses for improved neurological deficits are reviewed. Regardless of mechanism, the efficacy of bumetanide to improve memory deficits in the APOE4 model of AD and its potential to reduce the incidence of AD provide support for clinical investigation of bumetanide as a repurposed AD therapeutic agent.
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Affiliation(s)
- Ben Boyarko
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Sonia Podvin
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Barry Greenberg
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jeremiah D. Momper
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
| | - Yadong Huang
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, United States
- Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA, United States
| | - William H. Gerwick
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
- Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, United States
| | - Anne G. Bang
- Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys, San Diego, CA, United States
| | - Luisa Quinti
- Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Ana Griciuc
- Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Doo Yeon Kim
- Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Rudolph E. Tanzi
- Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
| | - Howard H. Feldman
- Department of Neurosciences and Department of Pharmacology, University of California, San Diego, San Diego, United States
- Alzheimer’s Disease Cooperative Study, University of California, San Diego, La Jolla, CA, United States
| | - Vivian Hook
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, United States
- Department of Neurosciences and Department of Pharmacology, University of California, San Diego, San Diego, United States
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Pressey JC, de Saint-Rome M, Raveendran VA, Woodin MA. Chloride transporters controlling neuronal excitability. Physiol Rev 2023; 103:1095-1135. [PMID: 36302178 DOI: 10.1152/physrev.00025.2021] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Synaptic inhibition plays a crucial role in regulating neuronal excitability, which is the foundation of nervous system function. This inhibition is largely mediated by the neurotransmitters GABA and glycine that activate Cl--permeable ion channels, which means that the strength of inhibition depends on the Cl- gradient across the membrane. In neurons, the Cl- gradient is primarily mediated by two secondarily active cation-chloride cotransporters (CCCs), NKCC1 and KCC2. CCC-mediated regulation of the neuronal Cl- gradient is critical for healthy brain function, as dysregulation of CCCs has emerged as a key mechanism underlying neurological disorders including epilepsy, neuropathic pain, and autism spectrum disorder. This review begins with an overview of neuronal chloride transporters before explaining the dependent relationship between these CCCs, Cl- regulation, and inhibitory synaptic transmission. We then discuss the evidence for how CCCs can be regulated, including by activity and their protein interactions, which underlie inhibitory synaptic plasticity. For readers who may be interested in conducting experiments on CCCs and neuronal excitability, we have included a section on techniques for estimating and recording intracellular Cl-, including their advantages and limitations. Although the focus of this review is on neurons, we also examine how Cl- is regulated in glial cells, which in turn regulate neuronal excitability through the tight relationship between this nonneuronal cell type and synapses. Finally, we discuss the relatively extensive and growing literature on how CCC-mediated neuronal excitability contributes to neurological disorders.
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Affiliation(s)
- Jessica C Pressey
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Miranda de Saint-Rome
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Vineeth A Raveendran
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Melanie A Woodin
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
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9
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Savardi A, Patricelli Malizia A, De Vivo M, Cancedda L, Borgogno M. Preclinical Development of the Na-K-2Cl Co-transporter-1 (NKCC1) Inhibitor ARN23746 for the Treatment of Neurodevelopmental Disorders. ACS Pharmacol Transl Sci 2023; 6:1-11. [PMID: 36654749 PMCID: PMC9841778 DOI: 10.1021/acsptsci.2c00197] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Indexed: 01/06/2023]
Abstract
Alterations in the expression of the Cl- importer Na-K-2Cl co-transporter-1 (NKCC1) and the exporter K-Cl co-transporter 2 (KCC2) lead to impaired intracellular chloride concentration in neurons and imbalanced excitation/inhibition in the brain. These alterations have been observed in several neurological disorders (e.g., Down syndrome and autism). Recently, we have reported the discovery of the selective NKCC1 inhibitor "compound ARN23746" for the treatment of Down syndrome and autism in mouse models. Here, we report on an extensive preclinical characterization of ARN23746 toward its development as a clinical candidate. ARN23746 shows an overall excellent metabolism profile and good brain penetration. Moreover, ARN23746 is effective in rescuing cognitive impairment in Down syndrome mice upon per os administration, in line with oral treatment of neurodevelopmental disorders. Notably, ARN23746 does not present signs of toxicity or diuresis even if administered up to 50 times the effective dose. These results further support ARN23746 as a solid candidate for clinical trial-enabling studies.
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Affiliation(s)
| | | | - Marco De Vivo
- IAMA
Therapeutics, via Filippo
Turati 2/9, 16128 Genoa, Italy
- Molecular
Modeling & Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Laura Cancedda
- IAMA
Therapeutics, via Filippo
Turati 2/9, 16128 Genoa, Italy
- Brain
Development & Disease Laboratory, Istituto
Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Marco Borgogno
- IAMA
Therapeutics, via Filippo
Turati 2/9, 16128 Genoa, Italy
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10
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Carnovale C, Perrotta C, Baldelli S, Cattaneo D, Montrasio C, Barbieri SS, Pompilio G, Vantaggiato C, Clementi E, Pozzi M. Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects. Cardiovasc Res 2022; 119:647-667. [PMID: 35895876 PMCID: PMC10153433 DOI: 10.1093/cvr/cvac110] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 11/14/2022] Open
Abstract
A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette's syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.
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Affiliation(s)
- Carla Carnovale
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università degli Studi di Milano, 20157 Milano, Italy
| | - Cristiana Perrotta
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università degli Studi di Milano, 20157 Milano, Italy
| | - Sara Baldelli
- Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, 20157 Milano, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, 20157 Milano, Italy
| | - Cristina Montrasio
- Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, 20157 Milano, Italy
| | - Silvia S Barbieri
- Unit of Brain-Heart axis: cellular and molecular mechanisms - Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine - Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy.,Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
| | | | - Emilio Clementi
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università degli Studi di Milano, 20157 Milano, Italy.,Scientific Institute IRCCS Eugenio Medea, Bosisio Parini (LC), Italy
| | - Marco Pozzi
- Scientific Institute IRCCS Eugenio Medea, Bosisio Parini (LC), Italy
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11
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He X, Yu Y, Ouyang Y. Evaluation and Analysis of the Intervention Effect of Systematic Parent Training Based on Computational Intelligence on Child Autism. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:7746374. [PMID: 35720038 PMCID: PMC9200578 DOI: 10.1155/2022/7746374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/11/2022] [Accepted: 05/16/2022] [Indexed: 11/30/2022]
Abstract
Autism, also known as pervasive developmental disorder or autism spectrum disorder, is a group of clinical syndromes of developmental delay or impairment. Social impairment, verbal communication impairment, and behavioral impairment are the three conditions for the diagnosis of autism spectrum disorder, according to the American Psychiatric Association's Diagnostic and Statistical Manual. According to relevant statistics, about 1 in 100 children is now diagnosed with autism, and their rehabilitation treatment is also valued by people from all walks of life. In the rehabilitation training of autistic children, it is found that the rehabilitation training of autistic children should pay attention to the role of parents and family environment. It is crucial that parents receive systematic training and act as partners in the development of the intervention plan. Research shows that a specific structured education and skills training program for parents of children with autism can be beneficial in improving behavioral problems, functional communication, and symptoms of autism in children with autism. To this end, this paper has completed the following work: Secondly, a portion of the systematic training of CA parents is discussed, followed by an explanation of the structure and principles of BPNN. Finally, the BPNN is utilized to create a model for assessing the impact of systematic parent instruction on CA. The experimental findings suggest that the proposed BPNN outperforms the competition.
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Affiliation(s)
- Xuejin He
- The Wuhan University School of Nursing, Wuhan, Hubei 430000, China
- Tongji Hospital Affiliated to Tongji Medical College HUST, Wuhan, Hubei 430000, China
| | - Yinzhen Yu
- Tongji Hospital Affiliated to Tongji Medical College HUST, Wuhan, Hubei 430000, China
| | - Yanqiong Ouyang
- The Wuhan University School of Nursing, Wuhan, Hubei 430000, China
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12
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Li Q, Zhang L, Shan H, Yu J, Dai Y, He H, Li WG, Langley C, Sahakian BJ, Yao Y, Luo Q, Li F. The immuno-behavioural covariation associated with the treatment response to bumetanide in young children with autism spectrum disorder. Transl Psychiatry 2022; 12:228. [PMID: 35660740 PMCID: PMC9166783 DOI: 10.1038/s41398-022-01987-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 05/21/2022] [Accepted: 05/25/2022] [Indexed: 11/09/2022] Open
Abstract
Bumetanide, a drug being studied in autism spectrum disorder (ASD) may act to restore gamma-aminobutyric acid (GABA) function, which may be modulated by the immune system. However, the interaction between bumetanide and the immune system remains unclear. Seventy-nine children with ASD were analysed from a longitudinal sample for a 3-month treatment of bumetanide. The covariation between symptom improvements and cytokine changes was calculated and validated by sparse canonical correlation analysis. Response patterns to bumetanide were revealed by clustering analysis. Five classifiers were used to test whether including the baseline information of cytokines could improve the prediction of the response patterns using an independent test sample. An immuno-behavioural covariation was identified between symptom improvements in the Childhood Autism Rating Scale (CARS) and the cytokine changes among interferon (IFN)-γ, monokine induced by gamma interferon and IFN-α2. Using this covariation, three groups with distinct response patterns to bumetanide were detected, including the best (21.5%, n = 17; Hedge's g of improvement in CARS = 2.16), the least (22.8%, n = 18; g = 1.02) and the medium (55.7%, n = 44; g = 1.42) responding groups. Including the cytokine levels significantly improved the prediction of the best responding group before treatment (the best area under the curve, AUC = 0.832) compared with the model without the cytokine levels (95% confidence interval of the improvement in AUC was [0.287, 0.319]). Cytokine measurements can help in identifying possible responders to bumetanide in ASD children, suggesting that immune responses may interact with the mechanism of action of bumetanide to enhance the GABA function in ASD.
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Affiliation(s)
- Qingyang Li
- Department of Computational Biology, School of Life Sciences, Fudan University, 200438, Shanghai, China
| | - Lingli Zhang
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Haidi Shan
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Juehua Yu
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
- Center for Experimental Studies and Research, The First Affiliated Hospital of Kunming Medical University, 650032, Kunming, China
| | - Yuan Dai
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Hua He
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
| | - Wei-Guang Li
- Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Christelle Langley
- Department of Psychiatry and the Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB21TN, UK
| | - Barbara J Sahakian
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China
- Department of Psychiatry and the Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB21TN, UK
- National Clinical Research Center for Aging and Medicine at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science and Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, 200433, Shanghai, China
| | - Yin Yao
- Department of Computational Biology, School of Life Sciences, Fudan University, 200438, Shanghai, China
- Human Phenome Institute, Fudan University, 201203, Shanghai, China
| | - Qiang Luo
- National Clinical Research Center for Aging and Medicine at Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science and Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, 200433, Shanghai, China.
- Human Phenome Institute, Fudan University, 201203, Shanghai, China.
- Center for Computational Psychiatry, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired, Research Institute of Intelligent Complex Systems, Fudan University, 200040, Shanghai, China.
| | - Fei Li
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 200092, Shanghai, China.
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13
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Tian J, Gao X, Yang L. Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics. Front Neurosci 2022; 16:780407. [PMID: 35310097 PMCID: PMC8924045 DOI: 10.3389/fnins.2022.780407] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/09/2022] [Indexed: 01/28/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social communication, social interaction, and repetitive restricted behaviors (RRBs). It is usually detected in early childhood. RRBs are behavioral patterns characterized by repetition, inflexibility, invariance, inappropriateness, and frequent lack of obvious function or specific purpose. To date, the classification of RRBs is contentious. Understanding the potential mechanisms of RRBs in children with ASD, such as neural connectivity disorders and abnormal immune functions, will contribute to finding new therapeutic targets. Although behavioral intervention remains the most effective and safe strategy for RRBs treatment, some promising drugs and new treatment options (e.g., supplementary and cell therapy) have shown positive effects on RRBs in recent studies. In this review, we summarize the latest advances of RRBs from mechanistic to therapeutic approaches and propose potential future directions in research on RRBs.
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Affiliation(s)
| | | | - Li Yang
- Peking University Sixth Hospital, Peking University Institute of Mental Health, National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Beijing, China
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14
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Auberry K. Educating behavior clinicians in a community behavior care center for children with autism spectrum disorder: Medication administration a pilot study in the United States. JOURNAL OF INTELLECTUAL DISABILITIES : JOID 2022; 26:166-184. [PMID: 33190595 DOI: 10.1177/1744629520967176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Autism Spectrum Disorder (ASD) is a multifaceted developmental disability requiring specialized supports. Due to the growing diagnoses of ASD, the demand for behavior treatment centers has also grown. These centers offer a wide range of beneficial services to children with ASD, including medication administration and management. While centers may employ highly educated and certified employees, there may be a gap in education related to medication administration and medication management knowledge. Using an evidence based education tool, this study sought to explore if clinicians in a behavior care center could gain knowledge in their ability to accurately administer and manage medications for children with ASD, and postulate if existing post-secondary curricula for behavior clinicians should be enriched to include medication administration and management training. This comprised two separate day long sessions of an implementation pilot study of best practice education in medication administration and medication management for behavior clinicians employed at a community behavior care center for children with ASD in the United States. Using the Statistical Package for the Social Sciences, 25 (SPSS), the paired samples t-test was applied for analysis. The quantitative results demonstrated the skill level treatment effect was statistically significant (p < .001). On the basis of the results the author makes recommendations regarding how to include medication administration and medication management education into existing behavior clinician curricula in the United States.
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15
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Ben-Ari Y, Cherubini E. The GABA Polarity Shift and Bumetanide Treatment: Making Sense Requires Unbiased and Undogmatic Analysis. Cells 2022; 11:396. [PMID: 35159205 PMCID: PMC8834580 DOI: 10.3390/cells11030396] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 12/17/2022] Open
Abstract
GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl-]i) levels. The control of [Cl-]i levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials.
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Affiliation(s)
- Yehezkel Ben-Ari
- Neurochlore, Batiment Beret Delaage, Campus Scientifique de Luminy, 13009 Marseille, France
| | - Enrico Cherubini
- European Brain Research Institute (EBRI)-Rita Levi-Montalcini, 00161 Roma, Italy;
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16
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Cherubini E, Di Cristo G, Avoli M. Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance. Front Cell Neurosci 2022; 15:813441. [PMID: 35069119 PMCID: PMC8766311 DOI: 10.3389/fncel.2021.813441] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 11/30/2021] [Indexed: 01/01/2023] Open
Abstract
The construction of the brain relies on a series of well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt to the external environment. Disruption of these processes leads to neurological and psychiatric disorders, which in many cases are manifest already early in postnatal life. GABA, the main inhibitory neurotransmitter in the adult brain is one of the major players in the early assembly and formation of neuronal circuits. In the prenatal and immediate postnatal period GABA, acting on GABAA receptors, depolarizes and excites targeted cells via an outwardly directed flux of chloride. In this way it activates NMDA receptors and voltage-dependent calcium channels contributing, through intracellular calcium rise, to shape neuronal activity and to establish, through the formation of new synapses and elimination of others, adult neuronal circuits. The direction of GABAA-mediated neurotransmission (depolarizing or hyperpolarizing) depends on the intracellular levels of chloride [Cl−]i, which in turn are maintained by the activity of the cation-chloride importer and exporter KCC2 and NKCC1, respectively. Thus, the premature hyperpolarizing action of GABA or its persistent depolarizing effect beyond the postnatal period, leads to behavioral deficits associated with morphological alterations and an excitatory (E)/inhibitory (I) imbalance in selective brain areas. The aim of this review is to summarize recent data concerning the functional role of GABAergic transmission in building up and refining neuronal circuits early in development and its dysfunction in neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia and epilepsy. In particular, we focus on novel information concerning the mechanisms by which alterations in cation-chloride co-transporters (CCC) generate behavioral and cognitive impairment in these diseases. We discuss also the possibility to re-establish a proper GABAA-mediated neurotransmission and excitatory (E)/inhibitory (I) balance within selective brain areas acting on CCC.
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Affiliation(s)
- Enrico Cherubini
- European Brain Research Institute (EBRI)-Rita Levi-Montalcini, Roma, Italy
- *Correspondence: Enrico Cherubini
| | - Graziella Di Cristo
- Neurosciences Department, Université de Montréal and CHU Sainte-Justine Research Center, Montreal, QC, Canada
| | - Massimo Avoli
- Montreal Neurological Institute-Hospital and Departments of Neurology and Neurosurgery and of Physiology, McGill University, Montreal, QC, Canada
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17
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Wang L, Feng J, Zhang Y, Wang T. Effect of the Early Start Denver Model on Children With Autism Spectrum Disorder Syndrome of Different Traditional Chinese Medicine Types in Northeast China. Front Pediatr 2022; 10:851109. [PMID: 35425726 PMCID: PMC9002090 DOI: 10.3389/fped.2022.851109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 03/03/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The clinical presentation of children with autism spectrum disorder (ASD) is heterogeneous, and there are little data available on the treatment of children with different types of ASD. We sought to explore which traditional Chinese medicine (TCM) syndrome type was more effective for children with ASD after 3 months of Early Denver Model intervention and to analyze the reasons for its efficacy from the perspective of TCM. METHODS This was a retrospective study. The subjects were children with ASD who were first diagnosed at the Developmental Behavioral Pediatrics, the First Hospital of Jilin University, between December 2018 and September 2019. Eighty-nine children were divided into a kidney jing deficiency group, a liver qi stagnation group, and a group with deficiency of both the heart and spleen. RESULTS After treatment, the total Autism Behavior Checklist (ABC), Autism Treatment Evaluation Checklist, and Childhood Autism Rating Scale scores were significantly reduced in the three groups (p < 0.05) compared to before treatment. Significant improvements were seen in all five domains of the Griffiths Development Scales-Chinese version in the LQ group (p < 0.05). After intervention, the LQ group showed greater improvements compared to the other two groups in the language, eye-hand coordination, body and object use, social and self-help, and total ABC scores. CONCLUSION Our study showed that Early Denver Model intervention is effective in the treatment of three syndrome types of children with ASD, with the LQ group experiencing the most significant effects.
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Affiliation(s)
- Lili Wang
- Developmental Behavioral Pediatrics, The First Hospital of Jilin University, Jilin, China
| | - Junyan Feng
- Developmental Behavioral Pediatrics, The First Hospital of Jilin University, Jilin, China
| | - Yu Zhang
- Developmental Behavioral Pediatrics, The First Hospital of Jilin University, Jilin, China
| | - Tiantian Wang
- Developmental Behavioral Pediatrics, The First Hospital of Jilin University, Jilin, China
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18
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Aishworiya R, Valica T, Hagerman R, Restrepo B. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. Neurotherapeutics 2022; 19:248-262. [PMID: 35029811 PMCID: PMC9130393 DOI: 10.1007/s13311-022-01183-1] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2022] [Indexed: 01/05/2023] Open
Abstract
While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.
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Affiliation(s)
- Ramkumar Aishworiya
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA
- Khoo Teck Puat-National University Children's Medical Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore
- Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore, 119228, Singapore
| | - Tatiana Valica
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA
- Association for Children With Autism, Chisinau, Moldova
| | - Randi Hagerman
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA.
- Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA, 95817, USA.
| | - Bibiana Restrepo
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA
- Department of Pediatrics, University of California Davis School of Medicine, 4610 X St, Sacramento, CA, 95817, USA
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19
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Aykan S, Puglia MH, Kalaycıoğlu C, Pelphrey KA, Tuncalı T, Nalçacı E. Right Anterior Theta Hypersynchrony as a Quantitative Measure Associated with Autistic Traits and K-Cl Cotransporter KCC2 Polymorphism. J Autism Dev Disord 2022; 52:61-72. [PMID: 33635423 DOI: 10.1007/s10803-021-04924-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2021] [Indexed: 10/22/2022]
Abstract
Our aim was to use theta coherence as a quantitative trait to investigate the relation of the polymorphisms in NKCC1 (rs3087889) and KCC2 (rs9074) channel protein genes to autistic traits (AQ) in neurotypicals. Coherence values for candidate connection regions were calculated from eyes-closed resting EEGs in two independent groups. Hypersynchrony within the right anterior region was related to AQ in both groups (p < 0.05), and variability in this hypersynchrony was related to the rs9074 polymorphism in the total group (p < 0.05). In conclusion, theta hypersynchrony within the right anterior region during eyes-closed rest can be considered a quantitative measure for autistic traits. Replicating our findings in two independent populations with different backgrounds strengthens the validity of the current study.
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Affiliation(s)
- Simge Aykan
- Department of Physiology, Ankara University School of Medicine, Ankara, Turkey.
| | - Meghan H Puglia
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
- Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Canan Kalaycıoğlu
- Department of Physiology, Ankara University School of Medicine, Ankara, Turkey
| | - Kevin A Pelphrey
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
| | - Timur Tuncalı
- Department of Medical Genetics, Ankara University School of Medicine, Ankara, Turkey
| | - Erhan Nalçacı
- Department of Physiology, Ankara University School of Medicine, Ankara, Turkey
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20
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Canitano R, Palumbi R. Excitation/Inhibition Modulators in Autism Spectrum Disorder: Current Clinical Research. Front Neurosci 2021; 15:753274. [PMID: 34916897 PMCID: PMC8669810 DOI: 10.3389/fnins.2021.753274] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 11/08/2021] [Indexed: 11/13/2022] Open
Abstract
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication abnormalities. Heterogeneity in the expression and severity of the core and associated symptoms poses difficulties in classification and the overall clinical approach. Synaptic abnormalities have been observed in preclinical ASD models. They are thought to play a major role in clinical functional abnormalities and might be modified by targeted interventions. An imbalance in excitatory to inhibitory neurotransmission (E/I imbalance), through altered glutamatergic and GABAergic neurotransmission, respectively, is thought to be implicated in the pathogenesis of ASD. Glutamatergic and GABAergic agents have been tested in clinical trials with encouraging results as to efficacy and tolerability. Further studies are needed to confirm the role of E/I modulators in the treatment of ASD and on the safety and efficacy of the current agents.
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Affiliation(s)
- Roberto Canitano
- Division of Child and Adolescent Neuropsychiatry, University Hospital of Siena, Siena, Italy
| | - Roberto Palumbi
- Division of Child and Adolescent Neuropsychiatry, Basic Medical Sciences, Neuroscience and Sense Organs Department, University Hospital of Bari, Bari, Italy
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21
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Wang T, Shan L, Miao C, Xu Z, Jia F. Treatment Effect of Bumetanide in Children With Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Front Psychiatry 2021; 12:751575. [PMID: 34867539 PMCID: PMC8634163 DOI: 10.3389/fpsyt.2021.751575] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/04/2021] [Indexed: 11/13/2022] Open
Abstract
Background: The therapeutic effect of bumetanide on autism spectrum disorder (ASD) seems to be controversial. To obtain better evidence on the efficacy of bumetanide, a systematic review and meta-analysis were performed. Methods: Randomized, placebo-controlled trials (RCTs) of bumetanide treatment in children with ASD were identified through systematic review from database inception to January 17, 2021. Subsequently, a meta-analysis was carried out to examine the effect of bumetanide on the severity of symptoms of ASD as assessed by the Childhood Autism Rating Scale (CARS) and Social Responsive Scale (SRS); core symptoms according to criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 of the American Psychiatric Association [social affect (SA), restricted, repetitive patterns of behavior, interests, or activities (RRB) and sensory symptoms]; and the therapeutic effect as assessed by Clinical Global Impressions-Efficacy (CGI-E). Results: In total, six RCTs involving 496 participants with ASD were identified in our study. The results showed that bumetanide could significantly improve the severity of the ASD symptoms measured by CARS and SRS. There was also evidence that bumetanide had positive effect on the core symptoms of ASD such as the SA and RRB, but there was no statistically significant effect on sensory symptoms. A significant positive effect on CGI-E scores in ASD patients was also observed. Conclusion: Our meta-analysis provided some support that bumetanide could improve the symptoms of children with ASD. However, additional large-scale longitudinal studies that provide clearer information and better control for confounding factors are needed to confirm our findings.
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Affiliation(s)
- Tiantian Wang
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ling Shan
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Chunyue Miao
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zhida Xu
- Department of Psychiatry, GGz Centraal, Amersfoort, Netherlands
| | - Feiyong Jia
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China
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22
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London EB, Yoo JH. From Research to Practice: Toward the Examination of Combined Interventions for Autism Spectrum Disorders. Brain Sci 2021; 11:1073. [PMID: 34439691 PMCID: PMC8391105 DOI: 10.3390/brainsci11081073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/25/2021] [Accepted: 08/06/2021] [Indexed: 12/04/2022] Open
Abstract
The use of biological (i.e., medications) in conjunction with applied behavior analysis is relatively common among people with ASD, yet research examining its benefit is scarce. This paper provides a brief overview of the existing literature on the combined interventions, including promising developments, and examines the existing barriers that hinder research in this area, including the heavy reliance on RCTs. Recommendations for possible solutions, including the creation of health homes, are provided in order to move toward a more integrated approach.
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Affiliation(s)
- Eric Bart London
- Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road Staten Island, New York, NY 10314, USA;
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23
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Dai Y, Zhang L, Yu J, Zhou X, He H, Ji Y, Wang K, Du X, Liu X, Tang Y, Deng S, Langley C, Li WG, Zhang J, Feng J, Sahakian BJ, Luo Q, Li F. Improved symptoms following bumetanide treatment in children aged 3-6 years with autism spectrum disorder: a randomized, double-blind, placebo-controlled trial. Sci Bull (Beijing) 2021; 66:1591-1598. [PMID: 36654288 DOI: 10.1016/j.scib.2021.01.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 10/26/2020] [Accepted: 12/23/2020] [Indexed: 02/03/2023]
Abstract
With the current limited drug therapy for the core symptoms of autism spectrum disorder (ASD), we herein report a randomized, double-blind, placebo-controlled trial to investigate the efficacy, safety, and potential neural mechanism of bumetanide in children with ASD aged 3-6 years old. A total of 120 children were enrolled into the study and randomly assigned to either 0.5 mg bumetanide or placebo. In the final sample, 119 children received at least one dose of bumetanide (59 children) or placebo (60 children) were included in the final analysis. The primary outcome was a reduction in the Childhood Autism Rating Scale (CARS) score, and the secondary outcomes were the Clinical Global Impressions Scale (CGI) -Global Improvement (CGI-I) score at 3 months and the change from baseline to 3-month in the Autism Diagnostic Observation Schedule (ADOS). Magnetic resonance spectroscopy (MRS) was used to measure γ-aminobutyric acid (GABA) and glutamate neurotransmitter concentrations in the insular cortex (IC) before and after the treatment. As compared with the placebo, bumetanide treatment was significantly better in reducing the severity. No patient withdrew from the trial due to adverse events. The superiority of bumetanide to placebo in reducing insular GABA, measured using MRS, was demonstrated. The clinical improvement was associated with a decrease in insular GABA in the bumetanide group. In conclusion, this trial in a large group of young children with predominantly moderate and severe ASD demonstrated that bumetanide is safe and effective in improving the core symptoms of ASD. However, the clinical significance remains uncertain, and future multi-center clinical trials are required to replicate these findings and confirm the clinical significance using a variety of outcome measures.
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Affiliation(s)
- Yuan Dai
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lingli Zhang
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Juehua Yu
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Centre for Experimental Studies and Research, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Xin Zhou
- Clinical Research Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Hua He
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yiting Ji
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Kai Wang
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiujuan Du
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xin Liu
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yun Tang
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; The School of Psychology and Cognitive Science, East China Normal University, Shanghai 200062, China
| | - Shining Deng
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Christelle Langley
- Department of Psychiatry and the Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB21TN, UK
| | - Wei-Guang Li
- Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Zhang
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jianfeng Feng
- Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai 200433, China
| | - Barbara J Sahakian
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Psychiatry and the Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB21TN, UK; Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai 200433, China
| | - Qiang Luo
- Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education-Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence and Research and Research Institute of Intelligent Complex Systems, Fudan University, Shanghai 200433, China; State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
| | - Fei Li
- Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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24
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Crutel V, Lambert E, Penelaud PF, Albarrán Severo C, Fuentes J, Rosier A, Hervás A, Marret S, Oliveira G, Parellada M, Kyaga S, Gouttefangeas S, Bertrand M, Ravel D, Falissard B. Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials). J Autism Dev Disord 2021; 51:2959-2972. [PMID: 33151500 PMCID: PMC8254707 DOI: 10.1007/s10803-020-04709-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
There are currently no approved pharmacological treatments to improve social reciprocity and limit repetitive and rigid behaviors in autism spectrum disorder (ASD). We describe the design of two Phase III studies evaluating the efficacy/safety of bumetanide oral liquid formulation in ASD. These are international, multicenter, randomized, double-blind, placebo-controlled studies in children and adolescents with ASD aged 7 to 17 years (n = 200; study 1), or younger children with ASD aged 2 to 6 years (n = 200; study 2). The primary endpoint of each is change in Childhood Autism Rating Scale 2 total raw score after 6 months. These studies could contribute to the first pharmacological treatment to improve social reciprocity and limit repetitive and rigid behaviors in children and adolescents with ASD.
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Affiliation(s)
- Véronique Crutel
- Neuro Immuno-Inflammation Therapeutic Area, Institut de Recherches Internationales Servier, Suresnes, France
| | - Estelle Lambert
- Neuro Immuno-Inflammation Therapeutic Area, Institut de Recherches Internationales Servier, Suresnes, France
| | - Pierre-François Penelaud
- Neuro Immuno-Inflammation Therapeutic Area, Institut de Recherches Internationales Servier, Suresnes, France
| | - Cristina Albarrán Severo
- Neuro Immuno-Inflammation Therapeutic Area, Institut de Recherches Internationales Servier, Suresnes, France
| | - Joaquin Fuentes
- Child & Adolescent Psychiatry Service, Policlínica Gipuzkoa & GAUTENA Autism Society, San Sebastián, Spain
| | - Antoine Rosier
- Department of Neonatal Pediatrics, CHU de Rouen and CHU Le Rouvray, Sotteville les Rouen, France
| | - Amaia Hervás
- Child and Adolescent Mental Health Service, Hospital Universitari Mútua de Terrassa, and Global Institute of Neurodevelopment Integrated Care (IGAIN), Barcelona, Spain
| | - Stéphane Marret
- Department of Neonatal Pediatrics, Intensive Care, and Neuropediatrics, Rouen University Hospital, Rouen, France
- INSERM U 1245 team 4 Neovasc, School of Medicine, Normandy University, Rouen, France
| | - Guiomar Oliveira
- Neurodevelopmental and Autism Unit from Child Developmental Center and Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Faculty of Medicine, University Clinic of Pediatrics, University of Coimbra, Coimbra, Portugal
| | - Mara Parellada
- Servicio de Psiquiatría del Niño y del Adolescente Hospital General Universitario Gregorio Marañón, CIBERSAM, IiSGM, Ibiza 43, Madrid, Spain
| | - Simon Kyaga
- Global Medical and Patient Affairs, Servier, 35 rue de Verdun, 92284, Suresnes cedex, Suresnes, France.
| | - Sylvie Gouttefangeas
- Neuro Immuno-Inflammation Therapeutic Area, Institut de Recherches Internationales Servier, Suresnes, France
| | - Marianne Bertrand
- Neuro Immuno-Inflammation Therapeutic Area, Institut de Recherches Internationales Servier, Suresnes, France
| | | | - Bruno Falissard
- University Paris-Sud, Univ. Paris-Descartes, AP-HP, INSERM U1178, Paris, France
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25
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Treating Autism With Bumetanide: Are Large Multicentric and Monocentric Trials on Selected Populations Complementary? J Am Acad Child Adolesc Psychiatry 2021; 60:937-938. [PMID: 33385505 DOI: 10.1016/j.jaac.2020.09.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 08/26/2020] [Accepted: 12/23/2020] [Indexed: 12/31/2022]
Abstract
In their article in the Journal, Sprengers et al.1 conclude that bumetanide does not attenuate autism spectrum disorder (ASD) despite a nominally significant treatment effect in repetitive behaviors, which is a core symptom of ASD but was defined as a secondary measure in this trial. Four earlier studies performed by 3 independent institutes, including 2 studies2,3 not mentioned by Sprengers et al., testing a total of 169 children (versus 122 placebo) showed a significant amelioration of ASD symptoms. Bumetanide also significantly attenuated behavioral features of patients with tuberous sclerosis according to another study by Sprengers' same group.4.
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26
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Sprengers JJ, van Andel DM, Bruining H. Dr. Sprengers et al. Reply. J Am Acad Child Adolesc Psychiatry 2021; 60:938-939. [PMID: 33450401 DOI: 10.1016/j.jaac.2020.12.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/23/2020] [Indexed: 10/22/2022]
Abstract
Before we elaborate on the postulated discrepancies between our trial and previous bumetanide in autism spectrum disorder (ASD) trials, we would like to acknowledge the crucial pioneering work on the γ-aminobutyric acid (GABA) developmental sequence by Dr. Ben-Ari and colleagues. Chloride dysregulation and altered GABA polarity have been implicated in neurological and neurodevelopmental disorders, including some forms of ASD. Etiologies underlying ASD are profoundly heterogeneous, and an important challenge is to link the optimal treatment to individual patients. Indeed, ASD animal models indicate reversed GABA polarity as a treatment target in some,1,2 but not all, studies.3 The aim of the Bumetanide in Autism Medication and Biomarker (BAMBI) trial was to replicate previous trial findings and to develop stratification biomarkers that may help to understand expected variability in treatment response.
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Affiliation(s)
- Jan J Sprengers
- UMC Utrecht Brain Centre, University Medical Centre Utrecht, The Netherlands
| | - Dorinde M van Andel
- UMC Utrecht Brain Centre, University Medical Centre Utrecht, The Netherlands
| | - Hilgo Bruining
- UMC Utrecht Brain Centre, University Medical Centre Utrecht, The Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, N=You centre, Amsterdam Neuroscience, Amsterdam Reproduction and Development, The Netherlands.
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27
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Kipnis PA, Kadam SD. Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures. Aging Dis 2021; 12:1056-1069. [PMID: 34221549 PMCID: PMC8219493 DOI: 10.14336/ad.2021.0129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/29/2021] [Indexed: 12/12/2022] Open
Abstract
Epilepsy is associated with a multitude of acquired or genetic neurological disorders characterized by a predisposition to spontaneous recurrent seizures. An estimated 15 million patients worldwide have ongoing seizures despite optimal management and are classified as having refractory epilepsy. Early-life seizures like those caused by perinatal hypoxic ischemic encephalopathy (HIE) remain a clinical challenge because although transient, they are difficult to treat and associated with poor neurological outcomes. Pediatric epilepsy syndromes are consistently associated with intellectual disability and neurocognitive comorbidities. HIE and arterial ischemic stroke are the most common causes of seizures in term neonates and account for 7.5-20% of neonatal seizures. Standard first-line treatments such as phenobarbital (PB) and phenytoin fail to curb seizures in ~50% of neonates. In the long-term, HIE can result in hippocampal sclerosis and temporal lobe epilepsy (TLE), which is the most common adult epilepsy, ~30% of which is associated with refractory seizures. For patients with refractory TLE seizures, a viable option is the surgical resection of the epileptic foci. Novel insights gained from investigating the developmental role of Cl- cotransporter function have helped to elucidate some of the mechanisms underlying the emergence of refractory seizures in both HIE and TLE. KCC2 as the chief Cl- extruder in neurons is critical for enabling strong hyperpolarizing synaptic inhibition in the brain and has been implicated in the pathophysiology underlying both conditions. More recently, KCC2 function has become a novel therapeutic target to combat refractory seizures.
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Affiliation(s)
- Pavel A Kipnis
- Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
| | - Shilpa D Kadam
- Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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28
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Novel treatments for autism spectrum disorder based on genomics and systems biology. Pharmacol Ther 2021; 230:107939. [PMID: 34174273 DOI: 10.1016/j.pharmthera.2021.107939] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with a complex underlying genetic architecture. There are currently no known pharmacologic treatments for the core ASD symptoms of social deficits and restricted/ repetitive behavior. However, there are dozens of clinical trials currently underway that are testing the impact of novel and existing agents on core and associated symptoms in ASD. METHODS We present a narrative synthesis of the historical and contemporary challenges to drug discovery in ASD. We then provide an overview of novel treatments currently under investigation from a genomics and systems biology perspective. RESULTS Data driven network and cluster analyses suggest alterations in transcriptional regulation, chromatin remodelling, synaptic transmission, neuropeptide signalling, and/or immunological mechanisms may contribute to or underlie the development of ASD. Agents and upcoming trials targeting each of the above listed systems are reviewed. CONCLUSION Identifying effective pharmacologic treatments for the core and associated symptom domains in ASD will require further collaboration and innovation in the areas of outcome measurement, biomarker research, and genomics, as well as systematic efforts to identify and treat subgroups of individuals with ASD who may be differentially responsive to specific treatments.
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29
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Borgogno M, Savardi A, Manigrasso J, Turci A, Portioli C, Ottonello G, Bertozzi SM, Armirotti A, Contestabile A, Cancedda L, De Vivo M. Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome. J Med Chem 2021; 64:10203-10229. [PMID: 34137257 PMCID: PMC8311653 DOI: 10.1021/acs.jmedchem.1c00603] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Intracellular chloride concentration [Cl-]i is defective in several neurological disorders. In neurons, [Cl-]i is mainly regulated by the action of the Na+-K+-Cl- importer NKCC1 and the K+-Cl- exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 (ARN24092) as a backup/follow-up lead with in vivo efficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.
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Affiliation(s)
- Marco Borgogno
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Annalisa Savardi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Dulbecco Telethon Institute, 38123 Rome, Italy
| | - Jacopo Manigrasso
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Alessandra Turci
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Università degli Studi di Genova, via Balbi, 5, 16126 Genoa, Italy
| | - Corinne Portioli
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Giuliana Ottonello
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Sine Mandrup Bertozzi
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Armirotti
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Contestabile
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Laura Cancedda
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Dulbecco Telethon Institute, 38123 Rome, Italy
| | - Marco De Vivo
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
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30
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Fernell E, Gustafsson P, Gillberg C. Bumetanide for autism: Open-label trial in six children. Acta Paediatr 2021; 110:1548-1553. [PMID: 33336381 PMCID: PMC8248373 DOI: 10.1111/apa.15723] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 12/27/2022]
Abstract
Aim Bumetanide, a diuretic agent, that reduces intracellular chloride—thereby reinforcing GABAergic inhibition—has been reported to improve core symptoms of autism in children. Given the positive results reported from French trials of bumetanide in children with autism, we decided to evaluate its effects in a small‐scale pilot study, in advance of a larger randomised controlled study (RCT). Methods This was an open‐label three‐month trial of bumetanide on six children (five boys), aged 3–14 years with autism. Ratings according to the Parental Satisfaction Survey (PASS) were used after four and twelve weeks to assess symptom change. Blood electrolyte status was monitored. Results Improvement in the PASS domain “Communicative and cognitive abilities” was marked or very marked in four children, and two had some improvements. Few negative side effects were reported. Conclusion Our small cohort responded well to bumetanide, particularly with regard to “Communicative and cognitive abilities”. Taken with the evidence from larger‐scale RCTs, we suggest that bumetanide should be considered for inclusion in ethically approved treatment/management trials for children with autism, subject to rigorous follow‐up in large‐scale RCTs.
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Affiliation(s)
- Elisabeth Fernell
- Gillberg Neuropsychiatry Centre Institute of Neuroscience and Physiology Sahlgrenska AcademyGothenburg University Gothenburg Sweden
- Child Neuropsychiatry ClinicSahlgrenska University Hospital Gothenburg Sweden
| | - Peik Gustafsson
- Child and Adolescent Psychiatry Department of Clinical Sciences Lund Medical Faculty Lund University Lund Sweden
- Neuropsychiatry unitDepartment of Child and Adolescent Psychiatry in Malmö Region Skåne Sweden
| | - Christopher Gillberg
- Gillberg Neuropsychiatry Centre Institute of Neuroscience and Physiology Sahlgrenska AcademyGothenburg University Gothenburg Sweden
- Child Neuropsychiatry ClinicSahlgrenska University Hospital Gothenburg Sweden
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31
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Ben-Ari Y, Delpire E. Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details. Epilepsia 2021; 62:935-940. [PMID: 33534145 PMCID: PMC8035263 DOI: 10.1111/epi.16830] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/21/2022]
Abstract
Kaila, Löscher, and colleagues report that phenobarbital (PHB) and midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. However, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to γ-aminobutyric acidergic (GABAergic) mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of antiepileptic drugs (AEDs) to treat this severe life-threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM efficiently attenuates autism symptomatology notably in patients with tuberous sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.
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Affiliation(s)
- Yehezkel Ben-Ari
- Neurochlore, Fundamental Research Department, Ben-Ari Institute of Neuroarcheology (IBEN), Marseille, France.,Correspondence should be addressed to Dr. Yehezkel Ben-Ari, , Address: Neurochlore, Parc Scientifique et Technologique de Luminy, Bâtiment Beret-Delaage, Zone Luminy Biotech Entreprises, Case 922, 163 avenue de Luminy, 13288 Marseille Cedex 9. Phone number: +33 (0)4 86 94 85 02
| | - Eric Delpire
- Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN 37232, USA
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Salcedo-Arellano MJ, Cabal-Herrera AM, Punatar RH, Clark CJ, Romney CA, Hagerman RJ. Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments. Neurotherapeutics 2021; 18:265-283. [PMID: 33215285 PMCID: PMC8116395 DOI: 10.1007/s13311-020-00968-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2020] [Indexed: 02/06/2023] Open
Abstract
Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.
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Affiliation(s)
- Maria Jimena Salcedo-Arellano
- Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA.
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDHS, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA.
| | - Ana Maria Cabal-Herrera
- Group on Congenital Malformations and Dysmorphology, Faculty of Health, Universidad del Valle, Cali, 00000, Colombia
| | - Ruchi Harendra Punatar
- Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDHS, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA
| | - Courtney Jessica Clark
- Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDHS, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA
| | - Christopher Allen Romney
- Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDHS, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA
| | - Randi J Hagerman
- Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA.
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDHS, University of California Davis, 2825 50th Street, Sacramento, CA, 95817, USA.
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Savardi A, Borgogno M, Narducci R, La Sala G, Ortega JA, Summa M, Armirotti A, Bertorelli R, Contestabile A, De Vivo M, Cancedda L. Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders. Chem 2020; 6:2073-2096. [PMID: 32818158 PMCID: PMC7427514 DOI: 10.1016/j.chempr.2020.06.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/14/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023]
Abstract
Aberrant expression ratio of Cl− transporters, NKCC1 and KCC2, is implicated in several brain conditions. NKCC1 inhibition by the FDA-approved diuretic drug, bumetanide, rescues core symptoms in rodent models and/or clinical trials with patients. However, bumetanide has a strong diuretic effect due to inhibition of the kidney Cl− transporter NKCC2, creating critical drug compliance issues and health concerns. Here, we report the discovery of a new chemical class of selective NKCC1 inhibitors and the lead drug candidate ARN23746. ARN23746 restores the physiological intracellular Cl− in murine Down syndrome neuronal cultures, has excellent solubility and metabolic stability, and displays no issues with off-target activity in vitro. ARN23746 recovers core symptoms in mouse models of Down syndrome and autism, with no diuretic effect, nor overt toxicity upon chronic treatment in adulthood. ARN23746 is ready for advanced preclinical/manufacturing studies toward the first sustainable therapeutics for the neurological conditions characterized by impaired Cl− homeostasis.
NKCC1 is a promising target for the treatment of brain disorders The newly discovered ARN23746 presents selective NKCC1 versus NKCC2 and KCC2 inhibition ARN23746 restores altered neuronal chloride homeostasis in vitro ARN23746 rescues core behaviors in DS and ASD mice with no diuretic effect or toxicity In the last few decades, drug development for brain disorders has struggled to deliver effective small molecules as novel breakthrough classes of drugs. Discovery of effective chemical compounds for brain disorders has been greatly hampered by the fact that the few currently clinically used drugs were identified by serendipity, and these drugs’ mechanism of action is often poorly understood. Here, by leveraging drug repurposing as a means to quickly and safely evaluate the new pharmacological target NKCC1 and its implications in brain disorders in animal models and patients, we report an integrated strategy for the rational design and discovery of a novel, selective, and safe NKCC1 inhibitor, active in vivo. This compound has the potential to become a clinical drug candidate to treat several neurological conditions in patients. Eventually, this integrated drug-discovery strategy has the prospective to revive the appeal of drug-discovery programs in the challenging field of neuroscience.
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Affiliation(s)
- Annalisa Savardi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- Università degli Studi di Genova, Via Balbi, 5, 16126 Genoa, Italy
| | - Marco Borgogno
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Roberto Narducci
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Giuseppina La Sala
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Jose Antonio Ortega
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Maria Summa
- In Vivo Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Armirotti
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Rosalia Bertorelli
- In Vivo Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Contestabile
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Marco De Vivo
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- Corresponding author
| | - Laura Cancedda
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- Dulbecco Telethon Institute, Via Orus 2, 35129 Padova, Italy
- Corresponding author
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios. Transl Psychiatry 2020; 10:9. [PMID: 32066666 PMCID: PMC7026137 DOI: 10.1038/s41398-020-0692-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 11/23/2019] [Accepted: 12/08/2019] [Indexed: 12/11/2022] Open
Abstract
Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of γ-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (γ-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score ≥ 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.
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Autism Spectrum Disorder Interventions in Mainland China: a Systematic Review. REVIEW JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS 2019. [DOI: 10.1007/s40489-019-00191-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Jia F, Shan L, Wang B, Li H, Feng J, Xu Z, Saad K. Fluctuations in clinical symptoms with changes in serum 25(OH) vitamin D levels in autistic children: Three cases report. Nutr Neurosci 2019; 22:863-866. [PMID: 29629638 DOI: 10.1080/1028415x.2018.1458421] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by complicated interactions between genetic and environmental factors. Clinical trials, including case reports, case-control studies, and a double-blinded randomized clinical study, have suggested that high-dose vitamin D3 regimens may ameliorate the core symptoms of ASD. Vitamin D3 supplementation was effective in about three-quarters of children with ASD. To further investigate the relationship between vitamin D and ASD symptoms in vitamin D-responsive autistic children, changes in symptoms were assessed in three children with ASD who were given vitamin D3 supplementation followed by a long interruption. The core symptoms of ASD were remarkably improved during the vitamin D3 supplementation period when serum 25-hydroxyvitamin D [25(OH)]D levels reached over 40.0 ng/mL. However, symptoms reappeared after the supplementation was stopped, when serum 25(OH)D levels fell below 30.0 ng/mL but were again improved with re-administration of vitamin D3 after the interruption, when serum 25(OH)D levels exceeded 40.0 ng/mL. Overall, these results showed that the core symptoms of ASD fluctuated in severity with changes in serum 25(OH)D levels in children, indicating that maintaining a responsive 25(OH)D level is important for treating ASD. Maintaining a serum 25(OH)D level between 40.0 and 100.0 ng/ml may be optimal for producing therapeutic effects in vitamin D-responsive individuals with ASD.
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Affiliation(s)
- Feiyong Jia
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
- Institute of Pediatrics of First Hospital of Jilin University, Changchun 130021, People's Republic of China
- Neurological Research Center of First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Ling Shan
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Bing Wang
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Honghua Li
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Junyan Feng
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Zhida Xu
- Department of Psychiatry, University Medical Center Utrecht, Netherlands
| | - Khaled Saad
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
- Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
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Excitation/inhibition imbalance and impaired neurogenesis in neurodevelopmental and neurodegenerative disorders. Rev Neurosci 2019; 30:807-820. [DOI: 10.1515/revneuro-2019-0014] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 04/05/2019] [Indexed: 12/31/2022]
Abstract
AbstractThe excitation/inhibition (E/I) balance controls the synaptic inputs to prevent the inappropriate responses of neurons to input strength, and is required to restore the initial pattern of network activity. Various neurotransmitters affect synaptic plasticity within neural networks via the modulation of neuronal E/I balance in the developing and adult brain. Less is known about the role of E/I balance in the control of the development of the neural stem and progenitor cells in the course of neurogenesis and gliogenesis. Recent findings suggest that neural stem and progenitor cells appear to be the target for the action of GABA within the neurogenic or oligovascular niches. The same might be true for the role of neuropeptides (i.e. oxytocin) in neurogenic niches. This review covers current understanding of the role of E/I balance in the regulation of neuroplasticity associated with social behavior in normal brain, and in neurodevelopmental and neurodegenerative diseases. Further studies are required to decipher the GABA-mediated regulation of postnatal neurogenesis and synaptic integration of newly-born neurons as a potential target for the treatment of brain diseases.
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Mollajani R, Joghataei MT, Tehrani-Doost M. Bumetanide Therapeutic Effect in Children and Adolescents With Autism Spectrum Disorder: A Review Study. Basic Clin Neurosci 2019; 10:433-441. [PMID: 32284832 PMCID: PMC7149950 DOI: 10.32598/bcn.9.10.380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/10/2018] [Accepted: 10/17/2018] [Indexed: 11/23/2022] Open
Abstract
Introduction: Autism Spectrum Disorder (ASD) is characterized by several impairments in communications and social interactions, as well as restricted interests or stereotyped behaviors. Interventions applied for this disorder are based on multi-modal approaches, including pharmacotherapy. No definitive cure or medication has been introduced so far; therefore, researchers still investigate potential drugs for treating ASD. One of the new medications introduced for this purpose is bumetanide. The present article aimed to review the efficacy of this drug on the core symptoms of ASD and its potential side effects. Methods: We searched all papers reported on pharmacokinetics, pharmacodynamics, efficacy, and adverse effects of bumetanide on animal models and humans with ASD. The papers were extracted from the main databases of PubMed, Web of Science, and Scopus. Results: The findings revealed that cortical neurons have high Chloride ion (Cl−)i and excitatory actions of gamma-aminobutyric acid in the valproic acid animal model with ASD and mice with fragile X syndrome. Bumetanide, which has been introduced as a diuretic, is also a high-affinity-specific Na+−K+−Cl− cotransporter (NKCC1) antagonist that can reduce Cl− level. The results also indicate that bumetanide can attenuate behavioral features of autism in both animal and human models. Moreover, the studies showed that such medication could activate fusiform face area in individuals with ASD while viewing emotional faces. Also, recent findings suggest that a dose of 1 mg/d of this drug, taken twice daily, might be the best compromise between safety and efficacy. Conclusion: Recent studies provided some evidence that bumetanide can be a novel pharmacological agent in treating core symptoms of ASD. Future studies are required to confirm the efficacy of this medication in individuals with ASD.
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Affiliation(s)
- Raheleh Mollajani
- Cognitive Neuroscience Institute for Cognitive Science Studies, Tehran, Iran
| | - Mohamad Taghi Joghataei
- Department of Anatomy and Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Tehrani-Doost
- Research Center for Cognitive and Behavioral Sciences, Tehran university of Medial Sciences, Tehran, Iran
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Port RG, Oberman LM, Roberts TPL. Revisiting the excitation/inhibition imbalance hypothesis of ASD through a clinical lens. Br J Radiol 2019; 92:20180944. [PMID: 31124710 PMCID: PMC6732925 DOI: 10.1259/bjr.20180944] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 04/19/2019] [Accepted: 05/21/2019] [Indexed: 12/22/2022] Open
Abstract
Autism spectrum disorder (ASD) currently affects 1 in 59 children, although the aetiology of this disorder remains unknown. Faced with multiple seemingly disparate and noncontiguous neurobiological alterations, Rubenstein and Merzenich hypothesized that imbalances between excitatory and inhibitory neurosignaling (E/I imbalance) underlie ASD. Since this initial statement, there has been a major focus examining this exact topic spanning both clinical and preclinical realms. The purpose of this article is to review the clinical neuroimaging literature surrounding E/I imbalance as an aetiology of ASD. Evidence for E/I imbalance is presented from several complementary clinical techniques including magnetic resonance spectroscopy, magnetoencephalography and transcranial magnetic stimulation. Additionally, two GABAergic potential interventions for ASD, which explicitly attempt to remediate E/I imbalance, are reviewed. The current literature suggests E/I imbalance as a useful framework for discussing the neurobiological etiology of ASD in at least a subset of affected individuals. While not constituting a completely unifying aetiology, E/I imbalance may be relevant as one of several underlying neuropathophysiologies that differentially affect individuals with ASD. Such statements do not diminish the value of the E/I imbalance concept-instead they suggest a possible role for the characterization of E/I imbalance, as well as other underlying neuropathophysiologies, in the biologically-based subtyping of individuals with ASD for potential applications including clinical trial enrichment as well as treatment triage.
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Affiliation(s)
| | - Lindsay M Oberman
- Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland
| | - Timothy PL Roberts
- Department of Radiology, Lurie Family Foundations MEG Imaging Center, Children’s Hospital of Philadelphia, Pennsylvania
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Hong MP, Erickson CA. Investigational drugs in early-stage clinical trials for autism spectrum disorder. Expert Opin Investig Drugs 2019; 28:709-718. [PMID: 31352835 DOI: 10.1080/13543784.2019.1649656] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Introduction: Pharmacologic interventions in Autism Spectrum Disorder (ASD) have historically focused on symptom-based approaches. However, a treatment for the core social deficits has remained unidentified. While a definitive theory for the cause of ASD is not yet known, recent advances in our understanding of ASD pathophysiology have opened the door for research on new pharmaceutical methods to target core symptomology. Areas covered: Herein, we review the novel pharmacologic therapies undergoing early-stage clinical trials for the treatment of the social symptoms associated with ASD. Specifically, these strategies center on altering neurologic excitatory and inhibitory imbalance, neuropeptide abnormalities, immunologic dysfunction, and biochemical deficiencies in ASD. Expert opinion: Utilizing the growing field of knowledge regarding the pathological mechanisms and altered neurobiology of individuals with ASD has led to the development of many innovative pharmaceutical interventions. Clinical trials for neurobiologic and immunologic targets show promise in impacting the social behavior and processing deficits in ASD but need evaluation in larger clinical trials and continued biomarker development to more effectively and consistently assess pharmacologic effects. Additionally, evaluating patient-specific drug responsivity and integrating behavioral intervention in conjunction with pharmacologic treatment is crucial to developing a successful approach to ASD treatment.
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Affiliation(s)
- Michael P Hong
- a Division of Psychiatry, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.,b College of Medicine, University of Cincinnati , Cincinnati , Oh , USA
| | - Craig A Erickson
- a Division of Psychiatry, Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.,b College of Medicine, University of Cincinnati , Cincinnati , Oh , USA
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Sanfeliu A, Hokamp K, Gill M, Tropea D. Transcriptomic Analysis of Mecp2 Mutant Mice Reveals Differentially Expressed Genes and Altered Mechanisms in Both Blood and Brain. Front Psychiatry 2019; 10:278. [PMID: 31110484 PMCID: PMC6501143 DOI: 10.3389/fpsyt.2019.00278] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 04/11/2019] [Indexed: 12/11/2022] Open
Abstract
Rett syndrome is a rare neuropsychiatric disorder with a wide symptomatology including impaired communication and movement, cardio-respiratory abnormalities, and seizures. The clinical presentation is typically associated to mutations in the gene coding for the methyl-CpG-binding protein 2 (MECP2), which is a transcription factor. The gene is ubiquitously present in all the cells of the organism with a peak of expression in neurons. For this reason, most of the studies in Rett models have been performed in brain. However, some of the symptoms of Rett are linked to the peripheral expression of MECP2, suggesting that the effects of the mutations affect gene expression levels in tissues other than the brain. We used RNA sequencing in Mecp2 mutant mice and matched controls, to identify common genes and pathways differentially regulated across different tissues. We performed our study in brain and peripheral blood, and we identified differentially expressed genes (DEGs) and pathways in each tissue. Then, we compared the genes and mechanisms identified in each preparation. We found that some genes and molecular pathways that are differentially expressed in brain are also differentially expressed in blood of Mecp2 mutant mice at a symptomatic-but not presymptomatic-stage. This is the case for the gene Ube2v1, linked to ubiquitination system, and Serpin1, involved in complement and coagulation cascades. Analysis of biological functions in the brain shows the enrichment of mechanisms correlated to circadian rhythms, while in the blood are enriched the mechanisms of response to stimulus-including immune response. Some mechanisms are enriched in both preparations, such as lipid metabolism and response to stress. These results suggest that analysis of peripheral blood can reveal ubiquitous altered molecular mechanisms of Rett and have applications in diagnosis and treatments' assessments.
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Affiliation(s)
- Albert Sanfeliu
- Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland
| | - Karsten Hokamp
- Department of Genetics, School of Genetics and Microbiology, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
| | - Michael Gill
- Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland
| | - Daniela Tropea
- Neuropsychiatric Genetics, Department of Psychiatry, School of Medicine, Trinity Translational Medicine Institute, St James Hospital, Dublin, Ireland
- Department of Psychiatry, School of Medicine, Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland
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Kharod SC, Kang SK, Kadam SD. Off-Label Use of Bumetanide for Brain Disorders: An Overview. Front Neurosci 2019; 13:310. [PMID: 31068771 PMCID: PMC6491514 DOI: 10.3389/fnins.2019.00310] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/19/2019] [Indexed: 01/17/2023] Open
Abstract
Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl− gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl− importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl− levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.
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Affiliation(s)
- Shivani C Kharod
- Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States
| | - Seok Kyu Kang
- Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States
| | - Shilpa D Kadam
- Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States.,Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Sapey-Triomphe LA, Lamberton F, Sonié S, Mattout J, Schmitz C. Tactile hypersensitivity and GABA concentration in the sensorimotor cortex of adults with autism. Autism Res 2019; 12:562-575. [PMID: 30632707 DOI: 10.1002/aur.2073] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 12/12/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022]
Abstract
Sensory hypersensitivity is frequently encountered in autism spectrum disorder (ASD). Gamma-aminobutyric acid (GABA) has been hypothesized to play a role in tactile hypersensitivity. The aim of the present study was twofold. First, as a study showed that children with ASD have decreased GABA concentrations in the sensorimotor cortex, we aimed at determining whether the GABA reduction remained in adults with ASD. For this purpose, we used magnetic resonance spectroscopy to measure GABA concentration in the sensorimotor cortex of neurotypical adults (n = 19) and ASD adults (n = 18). Second, we aimed at characterizing correlations between GABA concentration and tactile hypersensitivity in ASD. GABA concentration in the sensorimotor cortex of adults with ASD was lower than in neurotypical adults (decrease by 17%). Interestingly, GABA concentrations were positively correlated with self-reported tactile hypersensitivity in adults with ASD (r = 0.50, P = 0.01), but not in neurotypical adults. In addition, GABA concentrations were negatively correlated with the intra-individual variation during threshold measurement, both in neurotypical adults (r = -0.47, P = 0.04) and in adults with ASD (r = -0.59, P = 0.01). In other words, in both groups, the higher the GABA level, the more precise the tactile sensation. These results highlight the key role of GABA in tactile sensitivity, and suggest that atypical GABA modulation contributes to tactile hypersensitivity in ASD. We discuss the hypothesis that hypersensitivity in ASD could be due to suboptimal predictions about sensations. Autism Research 2019, 12: 562-575. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often experience tactile hypersensitivity. Here, our goal was to highlight a link between tactile hypersensitivity and the concentration of gamma-aminobutyric acid (GABA) (an inhibitory neurotransmitter) in the brain of adults with ASD. Indeed, self-reported hypersensitivity correlated with reduced GABA levels in brain areas processing touch. Our study suggests that this neurotransmitter may play a key role in tactile hypersensitivity in autism.
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Affiliation(s)
- Laurie-Anne Sapey-Triomphe
- Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, INSERM UMRS 1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Université de Lyon, F-69000, Lyon, France.,Laboratory of Experimental Psychology, Department of Brain and Cognition, KU Leuven, Leuven, Belgium
| | - Franck Lamberton
- SFR East Lyon Health, CNRS UMS 3453, INSERM US7, Lyon 1 University, Lyon, France.,CERMEP, Imagerie du Vivant, Lyon, France
| | - Sandrine Sonié
- Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, INSERM UMRS 1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Université de Lyon, F-69000, Lyon, France.,Centre de Ressource Autisme Rhône-Alpes, Centre Hospitalier Le Vinatier, Bron, France.,Hôpital Saint-Jean-de-Dieu, Lyon, France
| | - Jérémie Mattout
- Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, INSERM UMRS 1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Université de Lyon, F-69000, Lyon, France
| | - Christina Schmitz
- Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, INSERM UMRS 1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, Université de Lyon, F-69000, Lyon, France
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James BJ, Gales MA, Gales BJ. Bumetanide for Autism Spectrum Disorder in Children: A Review of Randomized Controlled Trials. Ann Pharmacother 2018; 53:537-544. [PMID: 30501497 DOI: 10.1177/1060028018817304] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
OBJECTIVE To evaluate clinical trials using bumetanide in autism spectrum disorder (ASD) treatment. DATA SOURCES PubMed and Ovid MEDLINE (1946 to October 2018) were searched using terms bumetanide and autism. Bibliographies were reviewed for other relevant trials. STUDY SELECTION AND DATA EXTRACTION English language, randomized, controlled, clinical trials in humans were evaluated. Three trials met all inclusion criteria. DATA SYNTHESIS Oral bumetanide was studied in 208 patients, 2 to 18 years old, with ASD. Trials evaluated bumetanide's impact on core behavioral features using several different autism assessment scales. All trials used the Childhood Autism Rating Scale to assess improvement at 90 days, with one trial finding statistical significance. The Clinical Global Impressions Scale identified statistically significant improvements in 2 of the 3 trials. The Autism Behavioral Checklist and Social Responsiveness Scales identified statistical benefit in the 2 trials utilizing those outcomes. Behaviors most improved by bumetanide included social communication, interactions, and restricted interest. No dose-effect correlation was identified in the dose-ranging trial. Adverse effects, including hypokalemia and polyuria, occurred more often with higher doses and resulted in withdrawal rates of 17% to 43%. Bumetanide 0.5 mg twice daily was the most studied and best tolerated dose. Limitations included unclear clinical success definitions and evaluation methodology variability. Relevance to Patient Care and Clinical Practice: No effective treatment options for core ASD symptoms have been approved. This review presents preliminary safety and efficacy data for bumetanide in ASD. CONCLUSIONS Low-dose oral bumetanide may be useful in patients with moderate to severe ASD when behavioral therapies are not available.
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Affiliation(s)
- B Jordan James
- 1 Southwestern Oklahoma State University College of Pharmacy, Weatherford, OK, USA
| | - Mark A Gales
- 1 Southwestern Oklahoma State University College of Pharmacy, Weatherford, OK, USA.,2 INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA.,3 Great Plains Family Medicine Residency Program, Oklahoma City, OK, USA
| | - Barry J Gales
- 1 Southwestern Oklahoma State University College of Pharmacy, Weatherford, OK, USA.,2 INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA.,3 Great Plains Family Medicine Residency Program, Oklahoma City, OK, USA
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Wang B, Li HH, Yue XJ, Jia FY, DU L. [A review on the role of γ-aminobutyric acid signaling pathway in autism spectrum disorder]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2018; 20:974-978. [PMID: 30477634 PMCID: PMC7389027 DOI: 10.7499/j.issn.1008-8830.2018.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/28/2018] [Indexed: 06/09/2023]
Abstract
The etiology and pathogenesis of autism spectrum disorder (ASD) are not yet clear. Studies have shown that there are many neurotransmitter abnormalities in children with ASD, mainly involving in glutamate, γ-aminobutyric acid (GABA), dopamine, 5-HT and oxytocin. The imbalance of excitatory glutamatergic neurotransmitters and inhibitory GABAergic neurotransmitters is closely related to the pathogenesis of ASD. Both animal model studies and clinical studies on ASD suggest that GABA signaling pathway may play an important role in the pathogenesis of ASD. This article reviews the research on the association between GABA signaling pathway and the pathogenesis of ASD to further explore the pathogenesis of ASD and provide theoretical basis for the treatment of ASD.
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Affiliation(s)
- Bing Wang
- Department of Developmental and Behaviorial Pediatrics, First Hospital of Jilin University, Changchun 130021, China.
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Olde Engberink AHO, Meijer JH, Michel S. Chloride cotransporter KCC2 is essential for GABAergic inhibition in the SCN. Neuropharmacology 2018; 138:80-86. [PMID: 29782876 DOI: 10.1016/j.neuropharm.2018.05.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 04/26/2018] [Accepted: 05/17/2018] [Indexed: 12/31/2022]
Abstract
One of the principal neurotransmitters of the central nervous system is GABA. In the adult brain, GABA is predominantly inhibitory, but there is growing evidence indicating that GABA can shift to excitatory action depending on environmental conditions. In the mammalian central circadian clock of the suprachiasmatic nucleus (SCN) GABAergic activity shifts from inhibition to excitation when animals are exposed to long day photoperiod. The polarity of the GABAergic response (inhibitory versus excitatory) depends on the GABA equilibrium potential determined by the intracellular Cl- concentration ([Cl-]i). Chloride homeostasis can be regulated by Cl- cotransporters like NKCC1 and KCC2 in the membrane, but the mechanisms for maintaining [Cl-]i are still under debate. This study investigates the role of KCC2 on GABA-induced Ca2+ transients in SCN neurons from mice exposed to different photoperiods. We show for the first time that blocking KCC2 with the newly developed blocker ML077 can cause a shift in the polarity of the GABAergic response. This will increase the amount of excitatory responses in SCN neurons and thus cause a shift in excitatory/inhibitory ratio. These results indicate that KCC2 is an essential component in regulating [Cl-]i and the equilibrium potential of Cl- and thereby determining the sign of the GABAergic response. Moreover, our data suggest a role for the Cl- cotransporters in the switch from inhibition to excitation observed under long day photoperiod.
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Affiliation(s)
- A H O Olde Engberink
- Department of Cellular and Chemical Biology, Laboratory for Neurophysiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands
| | - J H Meijer
- Department of Cellular and Chemical Biology, Laboratory for Neurophysiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands
| | - S Michel
- Department of Cellular and Chemical Biology, Laboratory for Neurophysiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, the Netherlands.
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Katsarou A, Moshé SL, Galanopoulou AS. INTERNEURONOPATHIES AND THEIR ROLE IN EARLY LIFE EPILEPSIES AND NEURODEVELOPMENTAL DISORDERS. Epilepsia Open 2017; 2:284-306. [PMID: 29062978 PMCID: PMC5650248 DOI: 10.1002/epi4.12062] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2017] [Indexed: 12/22/2022] Open
Abstract
GABAergic interneurons control the neural circuitry and network activity in the brain. The advances in genetics have identified genes that control the development, maturation and integration of GABAergic interneurons and implicated them in the pathogenesis of epileptic encephalopathies or neurodevelopmental disorders. For example, mutations of the Aristaless-Related homeobox X-linked gene (ARX) may result in defective GABAergic interneuronal migration in infants with epileptic encephalopathies like West syndrome (WS), Ohtahara syndrome or X-linked lissencephaly with abnormal genitalia (XLAG). The concept of "interneuronopathy", i.e. impaired development, migration or function of interneurons, has emerged as a possible etiopathogenic mechanism for epileptic encephalopathies. Treatments that enhance GABA levels, may help seizure control but do not necessarily show disease modifying effect. On the other hand, interneuronopathies can be seen in other conditions in which epilepsy may not be the primary manifestation, such as autism. In this review, we plan to outline briefly the current state of knowledge on the origin, development, and migration and integration of GABAergic interneurons, present neurodevelopmental conditions, with or without epilepsy, that have been associated with interneuronopathies and discuss the evidence linking certain types of interneuronal dysfunction with epilepsy and/or cognitive or behavioral deficits.
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Affiliation(s)
- Anna‐Maria Katsarou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Solomon L. Moshé
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Department of PediatricsAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Aristea S. Galanopoulou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
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Ben-Ari Y. NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. Trends Neurosci 2017; 40:536-554. [PMID: 28818303 DOI: 10.1016/j.tins.2017.07.001] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/03/2017] [Accepted: 07/10/2017] [Indexed: 12/23/2022]
Abstract
In physiological conditions, adult neurons have low intracellular Cl- [(Cl-)I] levels underlying the γ-aminobutyric acid (GABA)ergic inhibitory drive. In contrast, neurons have high (Cl-)I levels and excitatory GABA actions in a wide range of pathological conditions including spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, autism, Rett and Down syndrome, various types of epilepsies, and other genetic or environmental insults. The diuretic highly specific NKCC1 chloride importer antagonist bumetanide (PubChem CID: 2461) efficiently restores low (Cl-)I levels and attenuates many disorders in experimental conditions and in some clinical trials. Here, I review the mechanisms of action, therapeutic effects, promises, and pitfalls of bumetanide.
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Affiliation(s)
- Yehezkel Ben-Ari
- New INMED, Aix-Marseille University, Campus Scientifique de Luminy, Marseilles, France.
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50
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Bumetanide Treatment for Psychiatric Disorders and the Modulation of Central Nitric Oxide Metabolism. Clin Neuropharmacol 2017; 40:192-193. [PMID: 28704252 DOI: 10.1097/wnf.0000000000000228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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