Wednesday, 10 September 2014

Donepezil and D-cycloserine rescue behaviours in VPA exposed animals

In a post not-so-long-ago I talked about an interesting piece of research by Ahn and colleagues [1] suggesting that a ketogenic diet might yet hold some promise to "modify complex social behaviors and mitochondrial respiration" affected in the "prenatal valproic acid (VPA) rodent model of ASD [autism spectrum disorder]". The idea being that exposure to valproic acid (valproate) during the nine months that made us might carry some heightened risk for adverse effects on offspring development (see here) and a dietary change might rescue some functions.
"Daisy, Daisy, give me your answer do"

Well, the floodgates have well and truly opened when it comes to looking at various pharmacological agents that 'might' also rescue abilities thought to be affected by prenatal valproate exposure as today I discuss two papers.

First up is the paper by Wellmann and colleagues [2] which reported that: "D-cycloserine normalized the VPA-induced increase in play fighting in males and also increased social motivation in females". Second is the paper by Kim and colleagues [3] (open-access here) who observed: "Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring".

Aside from reiterating that these were studies of rodents and not humans, I was slightly taken aback by the reported findings. Cycloserine is normally packaged as an antibiotic but, as with many medicines these days, the pharmacological effects of the compound seem to extend far beyond the intended (antimicrobial) action [4]. I've talked about D-cycloserine before on this blog (see here) and some rather interesting research linking administration to several conditions. With autism in mind, I'll bring to your attention the paper by Urbano and colleagues [5] as one example of how far and wide this pharmaceutic is venturing. As to mode of action, well, I'd be clutching at straws if I was to hazard any guess. I might suggest that something around glutamate metabolism might be something to look at [6] which coincides with one of the proposed actions of D-cycloserine [7].

Donepezil (Aricept®) falls under the category of acting as a reversible acetylcholinesterase inhibitor (AChEI). More usually indicated for dementia and particularly Alzheimer's disease [8] Kim et al describe how "prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring". You can, therefore, perhaps see the logic in using donepezil as an AChEI particularly when one takes into account how other AChE inhibitors have been studied with autistic behaviours in mind [9]. Indeed, this is not the first time that donepezil has specifically been talked about in relation to autism, mouse models of autism, as per the findings from Karvat & Kimchi [10] and their discussions based on the BTBR 'dangermouse' where: "i.p. [intraperitonealinjection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner". And there is the promise of more to come with this medicine.

Reiterating that the Wellmann and Kim results (and the Ahn results) are based on studies of rodents not people, these are an interesting datasets crying out for further replication and study. Scientific glimmers are appearing which provide further data on what biological functions might be affected by prenatal valproate exposure and importantly, what might be done to [safely] rescue certain functions. But we're not there yet... and I haven't even mentioned epigenetics [11] ...

An unusual song from Ween to close... Push th' Little Daisies. Having said that, Ween are/were an unusual band...


[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] Wellmann KA. et al. D-Cycloserine Ameliorates Social Alterations That Result From Prenatal Exposure To Valproic Acid. Brain Res Bull. 2014 Aug 14. pii: S0361-9230(14)00120-8.

[3] Kim JW. et al. Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism. PLoS One. 2014 Aug 18;9(8):e104927.

[4] Rodrigues H. et al. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis. PLoS One. 2014 Jul 3;9(7):e93519.

[5] Urbano M. et al. A trial of D-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol. 2014 May-Jun;37(3):69-72.

[6] Bristot Silvestrin R. et al. Animal model of autism induced by prenatal exposure to valproate: altered glutamate metabolism in the hippocampus. Brain Res. 2013 Feb 7;1495:52-60.

[7] Hashimoto K. Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets. 2014 Sep;18(9):1049-63.

[8] McGleenon BM. et al. Acetylcholinesterase inhibitors in Alzheimer’s disease. British Journal of Clinical Pharmacology. 1999; 48: 471-480.

[9] Ghaleiha A. et al. Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2013 Oct 15;28(7):677-685.

[10] Karvat G & Kimchi T. Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism. Neuropsychopharmacology. 2014 Mar;39(4):831-40.

[11] Tordjman S. et al. Gene × Environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014 Aug 4;5:53.

---------- Wellmann KA, Varlinskaya EI, & Mooney SM (2014). D-Cycloserine Ameliorates Social Alterations That Result From Prenatal Exposure To Valproic Acid. Brain research bulletin PMID: 25130667 Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, Choi CS, Kim KC, Gonzales EL, You JS, Choi DH, Lee J, Han SH, Yang SM, Cheong JH, Shin CY, & Bahn GH (2014). Subchronic Treatment of Donepezil Rescues Impaired Social, Hyperactive, and Stereotypic Behavior in Valproic Acid-Induced Animal Model of Autism. PloS one, 9 (8) PMID: 25133713