Bumetanide Treatment for Psychiatric Disorders and the Modulation of Central Nitric Oxide Metabolism
Lemonnier et al1 reported a case study of the effectiveness of the diuretic and NKCC1 chloride cotransporter antagonist bumetanide in ameliorating symptoms in an adolescent with schizophrenia. This finding replicates the therapeutic potential of bumetanide in other clinical populations, such as autism spectrum disorders (ASDs). Du et al2 conducted a pilot study to investigate the potential therapeutic effect of a combined treatment program of oral bumetanide and applied behavior analysis (ABA) for children with autism. Autism symptoms were evaluated by the Autism Behavior Checklist (ABC), the Childhood Autism Rating Scale, and the Clinical Global Impressions (CGI) before and 3 months after treatment initiation. While both treatment modalities yielded improvement on autistic symptoms, total scores on the ABC and the CGI were statistically significantly lower in the combined treatment group versus ABA training alone, leading Du et al2 to conclude that a combined treatment with bumetanide may improve autistic symptoms greater than ABA training alone. Most recently, Lemonnier et al3 published a phase 2B study assessing both the safety effects and the dose-response relationship of bumetanide on autistic symptoms in 88 pediatric patients with ASD. Significant clinical improvement on the Childhood Autism Rating Scale and CGI, as well the Social Responsiveness Scale, was reported. These studies afford the conclusion that pharmacologic doses of bumetanide may provide therapeutic benefit in neuropsychiatric disorders, presumably through its known role as a specific Na-K-2Cl cotransporter inhibitor and restorer of GABAergic inhibition. However, in light of recent epidemiological findings regarding environmental contributors to neurodevelopmental disorder etiology, this letter suggests yet another important mechanism underlying the therapeutic benefit of bumetanide.
It has been suggested that chronic environmental exposure to the agricultural and combustion pollutant, nitrous oxide (N2O) may contribute to the rising prevalence of neurodevelopmental disorders, including ASD and schizophrenia.4–6 Among the many mechanisms explored by a review on the subject, including central dynorphinergic release and activation of the κ opioid receptor (an opioid family implicated in social aversion and behavioral stereotypy), N-methyl-D-aspartate receptor antagonism, and clinically significant effects on gastrointestinal, ophthalmic, and auditory functioning, N2O has been shown to disrupt the α7 nicotinic acetylcholine receptor, a receptor coupled to neuronal nitric oxide synthase (nNOS) metabolism. Central uncoupling of NO metabolism via N2O exposure may lead to compensatory reprogramming, including enhanced peripheral oxidative stress mechanisms, as shown in N2O-exposed rats,7 to perhaps reestablish faulty central nNOS mechanics.4 Consistent with this notion, animal studies have shown altered social behavior and increased aggression in nNOS-KO mice,8 whereas Quock et al9 noted that N2O exposure generally resulted in an inverted U-shaped dose-response curve among treated rats in a social interaction test. These studies support the hypothesis that exposure to low-dose environmental N2O may contribute to social deficit behaviors in ASD through a redox-mediated modulation of central NO signaling.
The link between nNOS and Na+ cotransporters has come under scrutiny, particularly under conditions of mild or moderate oxygen deprivation. The Na+-K+-2Cl− cotransporter has been shown to be integral in the oxygen-sensing response of nNOS, as inhibition of the transporter by bumetanide curtailed the nNOS-mediated increase in NO and the arteriole dilation.10 The disturbed NO metabolism that occurs from N2O exposure may increase superoxide levels,4,7 which have been shown to augment Na-K-2Cl cotransporter activity in the thick ascending limb.11 These data argue for the possibility that N2O-induced nNOS disruption may lead to a redox-mediated compensatory up-regulation in Na+ cotransporters. If so, it would be relevant to understand whether, under therapeutic intake, chronic bumetanide-mediated inhibition of the Na+-K+-2Cl− cotransporter yields compensatory increases in nNOS, likely reversing behavioral and social impairments that have been noted in nNOS−/− mice.