Ketogenic diet and the valproate mouse model of autism

A brief entry today and yet another blog post that starts with a quote (sorry)... "The offspring exposed to VPA [valproic acid] prenatally demonstrated a significant decrease in the number of play initiations/attacks and this was reversed with the KD [ketogenic diet]".

Gloucester Old Spot @ Wikipedia 

That finding reported in the paper by Ahn and colleagues [1] continues my interest in all-things related to prenatal VPA exposure and the reported effects on some offspring (see here). The added bonus of including some discussion about how the use of a ketogenic diet might reverse some of the effects of VPA exposure (in rats at least) is also worthwhile mentioning.

A couple of pointers perhaps...

• Rats, Sprague-Dawley mother rats, were given VPA or saline (as a control) during pregnancy and their pups (VPA-exposed vs. controls) were subjected to measures looking at "juvenile play behavior" and eventually "mitochondrial bioenergetic analysis" as a function of the use of a ketogenic or standard diet.
• Results: "Prenatal VPA exposure also disrupted the pattern of play responses". Not a great surprise there given everything else that has been linked to VPA exposure in-utero. But.. use of the ketogenic diet "was able to modify complex social behaviors and mitochondrial respiration". As noted previously, the reduction in play initiations made by the VPA exposed mice was to some degree rescued following use of the ketogenic diet.

Yes, I know that this was a study of rats, and whilst useful, rats are rats not humans. But I am nevertheless intrigued by the suggestion that something like a ketogenic diet - more typically indicated for some types of treatment resistant epilepsy - might to some degree, affect the behaviour and physiology of animals exposed to a traditional anticonvulsant like valproate during the nine months that made them. Does anyone else find that a little ironic? Also throw in mention of the words 'autism spectrum disorder' alongside that animal VPA exposure model alongside the ketogenic diet (see here) and I'm sure there's some more research to be done in this area.

Mode of action? I dunno. I will draw your attention to some interesting work on carnitine homoeostasis as a function of valproate administration [2] which might be relevant. Carnitine plays a role in mitochondrial function [3] and there is some suggestion that a ketogenic diet might help maintain carnitine levels in the presence of VPA [4]. Whether this applies to brain structures or neurochemistry potentially already affected by prenatal exposure to VPA is a question not yet asked or answered. Bearing in mind the gastrointestinal (GI) effects also noted in VPA exposure models (see here) I might also be inclined to 'look to the bowels' in terms of any potential effects from the ketogenic diet in that organ too.

Music to close and I was taken aback by the performance from Pumeza at the opening to the 2014 Commonwealth Games and her version of Freedom Come All Ye...

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[1] Ahn Y. et al. The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder. Dev Neurosci. 2014 Jul 8.

[2] Morand R. et al. Effect of short- and long-term treatment with valproate on carnitine homeostasis in humans. Ther Drug Monit. 2012 Aug;34(4):406-14.

[3] Zammit VA. et al. Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev. 2009 Nov 30;61(14):1353-62.

[4] Coppola G. et al. Plasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet. Brain Dev. 2006 Jul;28(6):358-65.

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Ahn Y, Narous M, Tobias R, Rho JM, & Mychasiuk R (2014). The Ketogenic Diet Modifies Social and Metabolic Alterations Identified in the Prenatal Valproic Acid Model of Autism Spectrum Disorder. Developmental neuroscience PMID: 25011527