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Bumetanide autism

Yehezkel Ben-Ari, Philippe Damier, Eric Lemonnier
The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE) in newborn babies and was associated with hearing loss (NEMO trial, Pressler et al., 2015). On the other hand, clinical and experimental observations suggest that the diuretic might provide novel therapy for many brain disorders including Autism Spectrum Disorders (ASD), schizophrenia, Rett syndrome, and Parkinson disease. Here, we discuss the differences between the pathophysiology of severe recurrent seizures in the neonates and neurological and psychiatric disorders stressing the uniqueness of severe seizures in newborn in comparison to other disorders...
2016: Frontiers in Cellular Neuroscience
Eric Lemonnier, Alain Lazartigues, Yehezkel Ben-Ari
Administration of the diuretic and NKCC1 chloride cotransporter antagonist bumetanide reduces the severity of autism spectrum disorders in children, and this effect is mediated by a reduction of the elevated intracellular chloride concentrations and a reinforcement of GABAergic inhibition (Lemonnier et al Transl Psychiatry. 2012;2:e202; Tyzio et al Science. 2014;343:675-679). Here, we report that this treatment also reduces the severity of symptoms in an adolescent with schizophrenia. Long-term treatment reduced hallucinations significantly, suggesting that this treatment may also be useful to treat schizophrenia...
March 2016: Clinical Neuropharmacology
Amteshwar Singh Jaggi, Aalamjeet Kaur, Anjana Bali, Nirmal Singh
Sodium potassium chloride co-transporter (NKCC) belongs to cation-dependent chloride co-transporter family, whose activation allows the entry of Na(+), K(+) and 2Cl(-) inside the cell. It acts in concert with K(+) Cl(-) co-transporter (KCC), which extrudes K(+) and Cl(-) ions from cell. NKCC1 is widely distributed throughout the body, while NKCC2 is exclusively present in kidney. Protein kinase A, protein kinase C, Ste20-related proline-alanine-rich kinase, oxidative stress responsive kinases, With No K=lysine kinase and protein phosphatase type 1 control the phosphorylation/dephosphorylation of key threonine residues of in regulatory domain of NKCC1...
2015: Current Neuropharmacology
Hong-Hua Li, Ling Shan, Lin Du, Fei-Yong Jia
Autism spectrum disorders (ASD) are a group of developmental dysfuntion of nervous system characterized by social interaction and communication disorders, restricted interests and repetitive stereotyped behaviors. The incidence of ASD has been increasing through the world. Some studies have shown that early reasonable individualized comprehensive intervention can obviously improve the prognosis of children with ASD. The etiology of ASD is unclear now, and behavioral and developmental intervention is the main therapy for ASD...
August 2015: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Lin Du, Ling Shan, Bing Wang, Honghua Li, Zhida Xu, Wouter G Staal, Feiyong Jia
OBJECTIVE: The purpose of this study was to investigate the therapeutic effects of combined bumetanide and applied behavior analysis (ABA) treatment in children with autism. METHODS: Sixty children diagnosed with autism according to the International Classification of Diseases, Tenth Revision (ICD-10) criteria (mean age of 4.5 years) were randomly divided into two groups: A single treatment group (n=28) and a combined treatment group (n=32). The combined treatment group received ABA training combined with oral bumetanide (0...
September 2015: Journal of Child and Adolescent Psychopharmacology
Hilgo Bruining, Laurien Passtoors, Natalia Goriounova, Floor Jansen, Britt Hakvoort, Maretha de Jonge, Simon-Shlomo Poil
The diuretic agent bumetanide has recently been put forward as a novel, promising treatment of behavioral symptoms in autism spectrum disorder (ASD) and related conditions. Bumetanide can decrease neuronal chloride concentrations and may thereby reinstate γ-aminobutyric acid (GABA)-ergic inhibition in patients with neurodevelopmental disorders. However, strategies to select appropriate candidates for bumetanide treatment are lacking. We hypothesized that a paradoxical response to GABA-enforcing agents such as benzodiazepines may predict the efficacy of bumetanide treatment in neurodevelopmental disorders...
August 2015: Pediatrics
Gregory L Holmes, Chengju Tian, Amanda E Hernan, Sean Flynn, Devon Camp, Jeremy Barry
There is a well-described association between infantile epilepsy and pervasive cognitive and behavioral deficits, including a high incidence of autism spectrum disorders. Despite the robustness of the relationship between early-life seizures and the development of autism, the pathophysiological mechanism by which this occurs has not been explored. As a result of increasing evidence that autism is a disorder of brain connectivity we hypothesized that early-life seizures would interrupt normal brain connectivity during brain maturation and result in an autistic phenotype...
May 2015: Neurobiology of Disease
Maria D Donovan, Fionn E O'Brien, Geraldine B Boylan, John F Cryan, Brendan T Griffin
OBJECTIVES: Recent data highlight the potential of bumetanide as a treatment for neonatal seizures and autism, as it facilitates the excitatory to inhibitory switch in gamma-aminobutyric acid signalling. This study examines the extent of blood-brain barrier (BBB) permeation of bumetanide, a key determinant of the efficacy of centrally acting drugs. Furthermore, the impact of efflux transporter organic anion transporter 3 (oat3) inhibition on bumetanide pharmacokinetics was investigated...
April 2015: Journal of Pharmacy and Pharmacology
Kathrin Töllner, Claudia Brandt, Kerstin Römermann, Wolfgang Löscher
Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too...
January 5, 2015: European Journal of Pharmacology
Sanaz Eftekhari, Amene Shahrokhi, Vera Tsintsadze, Romain Nardou, Corinne Brouchoud, Magali Conesa, Nail Burnashev, Diana C Ferrari, Yehezkel Ben-Ari
Bambini-Junior et al. questioned whether our treatment in two rodent models of autism has a long-lasting effect into adulthood. In response, we show that bumetanide treatment around delivery attenuates autistic behavioral features in adult offspring. Therefore, the polarity of γ-aminobutyric acid (GABA) actions during delivery exerts long-lasting priming actions after birth.
October 10, 2014: Science
Victorio Bambini-Junior, Gustavo Della Flora Nunes, Tomasz Schneider, Carmem Gottfried
Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored the impaired oxytocin-mediated γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery in animal models of autism, ameliorating some autistic-like characteristics in the offspring. However, standard practices in the study of these models, such as the use of sex-dimorphic or males-only analyses and implementation of tests measuring social behavior, are lacking to definitely associate their findings to autism.
October 10, 2014: Science
Giada Cellot, Enrico Cherubini
γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation-chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors...
2014: Frontiers in Pediatrics
Roman Tyzio, Romain Nardou, Diana C Ferrari, Timur Tsintsadze, Amene Shahrokhi, Sanaz Eftekhari, Ilgam Khalilov, Vera Tsintsadze, Corinne Brouchoud, Genevieve Chazal, Eric Lemonnier, Natalia Lozovaya, Nail Burnashev, Yehezkel Ben-Ari
We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes...
February 7, 2014: Science
Marine Grandgeorge, Eric Lemonnier, Céline Degrez, Nelle Jallot
Sensory behaviours were not considered as core features of autism spectrum disorders until recently. However, they constitute an important part of the observed symptoms that result in social maladjustment and are currently quite difficult to treat. One promising strategy for the treatment of these behaviours is the use of bumetanide, which was previously shown to reduce the severity of autism spectrum disorders. In this study, we proposed to evaluate sensory behaviours using Dunn's Sensory Profile after 18 months of bumetanide treatment in a 10-year-old girl with Asperger syndrome...
2014: BMJ Case Reports
Nouchine Hadjikhani, Nicole R Zürcher, Ophelie Rogier, Torsten Ruest, Loyse Hippolyte, Yehezkel Ben-Ari, Eric Lemonnier
Clinical observations have shown that GABA-acting benzodiazepines exert paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl-)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer antagonist bumetanide, that decreases (Cl-)i and reinforces GABAergic inhibition, reduces the severity of autism symptoms. Here, we report results from an open-label trial pilot study in which we used functional magnetic resonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism...
February 2015: Autism: the International Journal of Research and Practice
Eric Lemonnier, Gaëlle Robin, Céline Degrez, Roman Tyzio, Marine Grandgeorge, Yehezkel Ben-Ari
UNLABELLED: We report that daily administration of the diuretic NKCC1 chloride co-transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX. CONCLUSION: This single case report showed an improvement of the scores of each test used after 3 months of treatment...
June 2013: Acta Paediatrica
Jean-Yves Nau
No abstract text is available yet for this article.
December 19, 2012: Revue Médicale Suisse
E Lemonnier, C Degrez, M Phelep, R Tyzio, F Josse, M Grandgeorge, N Hadjikhani, Y Ben-Ari
Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study,(1) we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition...
2012: Translational Psychiatry
Eric Lemonnier, Yehezkel Ben-Ari
UNLABELLED: The inhibitory transmitter GABA has been suggested to play an important role in infantile autistic syndrome (IAS), and extensive investigations suggest that excitatory actions of GABA in neurological disorders are because of a persistent increase of [Cl(-) ](I) . AIMS:   To test the effects of the chloride co-transporter NKCC1 diuretic compound Bumetanide that reduces [Cl(-) ](I) on IAS. METHODS:   Bumetanide was administered daily (1mg daily) during a 3-month period and clinical and biological tests made...
December 2010: Acta Paediatrica
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