The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects

Centre de Resssources autisme de Bretagne, CHRU Brest Hopital Bohars, Bohars, France.
Acta Paediatrica (Impact Factor: 1.67). 12/2010; 99(12):1885-8. DOI: 10.1111/j.1651-2227.2010.01933.x
Source: PubMed

ABSTRACT 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) .
  To test the effects of the chloride co-transporter NKCC1 diuretic compound Bumetanide that reduces [Cl(-) ](I) on IAS.
  Bumetanide was administered daily (1mg daily) during a 3-month period and clinical and biological tests made. We used 5 standard IAS severity tests - Childhood Autism Rating Scale, Aberrant Behaviour Checklist, Clinical Global Impressions; Repetitive and Restrictive Behaviour and the Regulation Disorder Evaluation Grid.
 We report a significant improvement in IAS with no side effects.
 Bumetanide decreases autistic behaviour with no side effects suggesting that diuretic agents may exert beneficial effects on IAS and that alterations of the actions of GABA may be efficient in IAS treatment calling for large scale randomized trials.

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Available from: Eric Lemonnier, Sep 28, 2015
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    • "Bumetanide may not only reverse GABA action from the depolarizing to the hyperpolarizing direction, but it may also reduce cell excitability by an ephaptic type of mechanism involving regulation of the cell volume and the extracellular space (122). Animal data validate previous findings by the same group, showing amelioration of autistic symptoms in children treated for 3 months with bumetanide (123, 124). Although these studies should be expanded to larger multicenter trials with more restricted inclusion and exclusion criteria and more extended investigations on the dose/response action of the diuretic as well as persistence of action after drug’s withdrawal, the significant improvement of the autistic behavior associated with a statistically significant amelioration of childhood autism rating scale (CARS) and clinical global impressions (CGI) scores in the absence of clear side effects make this diuretic a very promising drug to cure ASDs. "
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    ABSTRACT: 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. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders.
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    ABSTRACT: Brain slices incubated with glucose have provided most of our knowledge on cellular, synaptic, and network driven mechanisms. It has been recently suggested that γ-aminobutyric acid (GABA) excites neonatal neurons in conventional glucose-perfused slices but not when ketone bodies metabolites, pyruvate, and/or lactate are added, suggesting that the excitatory actions of GABA are due to energy deprivation when glucose is the sole energy source. In this article, we review the vast number of studies that show that slices are not energy deprived in glucose-containing medium, and that addition of other energy substrates at physiologic concentrations does not alter the excitatory actions of GABA on neonatal neurons. In contrast, lactate, like other weak acids, can produce an intracellular acidification that will cause a reduction of intracellular chloride and a shift of GABA actions. The effects of high concentrations of lactate, and particularly of pyruvate (4-5 mm), as used are relevant primarily to pathologic conditions; these concentrations not being found in the brain in normal "control" conditions. Slices in glucose-containing medium may not be ideal, but additional energy substrates neither correspond to physiologic conditions nor alter GABA actions. In keeping with extensive observations in a wide range of animal species and brain structures, GABA depolarizes immature neurons and the reduction of the intracellular concentration of chloride ([Cl-]i) is a basic property of brain maturation that has been preserved throughout evolution. In addition, this developmental sequence has important clinical implications, notably concerning the higher incidence of seizures early in life and their long-lasting deleterious sequels. Immature neurons have difficulties exporting chloride that accumulates during seizures, leading to permanent increase of [Cl-]i that converts the inhibitory actions of GABA to excitatory and hampers the efficacy of GABA-acting antiepileptic drugs.
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