Saturday, 8 February 2014

More bumetanide and autism discussion

For those with their ear to the autism research ground, the paper by Roman Tyzio and colleagues [1] must have sounded like a freight train coming given the volume of headlines that have been generated from this research (see here for example). Circling around the neurotransmitter, GABA (as in GABA dabba doo!), their findings based on two mouse models of autism, or rather autism and Fragile X syndrome - including the very interesting prenatal valproate (VPA) exposure model - suggested "hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations".

If that all that sounds like a different language to you, it basically boiled down to GABA doing the opposite of what it is normally supposed to do i.e. primarily act as an inhibitory neurotransmitter, potentially as a result of issues with chloride levels. The fact that the 'cuddle me' hormone, oxytocin is also a suggested trigger to facilitate that excitatory-to-inhibitory transition for GABA [2] in the early days adds to the intrigue. On it's own, this finding would probably have not generated as many media headlines as it did. But when combined with the suggestion that supplementation to mother rats with the diuretic drug bumetanide just before giving birth might help make that transition for GABA to fulfil it's inhibitory destiny ("it is your destiny") in offspring the research starts to take on a slightly different perspective. The Nature news write-up of the paper provides some additional reading on this issue (see here).

I've talked about bumetanide before on this blog (see here) as a consequence of the previous Lemonnier trial [3] which itself generated a fair few headlines at the time of publication. Since then, I've noted the odd mention on the drug in connection to the autism spectrum as per the case report from Grandgeorge and colleagues [4] and another paper from Lemonnier and colleagues [5] with a case of Fragile X syndrome in mind. The Grandgeorge results in particular, are worthy of inspection not least because of the focus on sensory issues and the link I make back to the very intense, intense world theory of autism [6] which has its roots in the VPA rodent model similar to the one used to test bumetanide in the Tyzio paper. I know we should be cautious of sweeping generalised models when it comes to autism (as per some chatter about the model) but lets not throw baby and bathwater out just yet. The scientific puritans out there might also be shaking their heads at the thought of case reports being mentioned here, but just remember the old adage about meeting one person with autism and all that.

There is obviously a degree of step-back caution to take from the Tyzio results insofar as rats being rats not humans. I believe the accompanying editorial from Zimmerman & Connors also raises a few potential issues which need to be resolved; not least how one ascertains who [humans] might be at risk for this process occurring and therefore when bumetanide might be indicated. Bear in mind too, that there are growing moves to look at reducing things like prenatal valproate exposure on the back of some regulatory statements recently being made (see here).

But I have to conclude that I do find the recent Tyzio report and the previous Lemonnier trial very interesting and look forward to seeing more research on this topic including safety studies, long-term follow-up and perhaps more data on who might be more likely to benefit from this research.

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[1] Tyzio R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science. 2014 Feb 7;343(6171):675-9.

[2] Tyzio R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science. 2006 Dec 15;314(5806):1788-92.

[3] Lemonnier E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012 Dec 11;2:e202. doi: 10.1038/tp.2012.124.

[4] Grandgeorge M. et al. The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. BMJ Case Rep. 2014 Jan 31;2014.

[5] Lemonnier E. et al. Treating Fragile X syndrome with the diuretic bumetanide: a case report. Acta Paediatr. 2013 Jun;102(6):e288-90. doi: 10.1111/apa.12235.

[6] Markram H. et al. The intense world syndrome--an alternative hypothesis for autism. Front Neurosci. 2007 Oct 15;1(1):77-96.

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ResearchBlogging.org Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, Khalilov I, Tsintsadze V, Brouchoud C, Chazal G, Lemonnier E, Lozovaya N, Burnashev N, & Ben-Ari Y (2014). Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science (New York, N.Y.), 343 (6171), 675-9 PMID: 24503856