Sunday, 21 April 2013

All eyes on minocycline

Minocycline, the tetracycline antibiotic, is probably not something that most people would traditionally link with autism or conditions presenting with autism-like behaviours. Indeed, the suggestion that antibiotics or antimicrobials if you prefer, may be able to modify either the behaviour or linked biochemistry of the autism spectrum disorders (ASDs) or even influence the onset and expression of ASD is quite frankly a little bit unusual.
Minocycline (for chemists) @ Wikipedia  

But unusual is what often crops up on this blog. And how if one assumes that autism, sorry the autisms, are not just conditions solely pertaining to the grey-pinkish matter floating inside our skull, one starts to see how behaviour and physiology might provide some interesting perspectives. Say for example, when one starts to look at the gut microbiome...

On today's post I'm considering a few reports which recently cropped up on the research radar including the results of placebo-controlled trial of minocycline for Fragile X syndrome (FXS) published by Mary Jacena Leigh and colleagues* (open-access), a small open-trial of minocycline reported by Carlos Pardo and colleagues** (open-access) and although not autism-related, the results of a study by Parvin Ataie-Kachoie and colleagues*** (open-access) on what happened to an ovarian cancer cell line when minocycline was added, specifically with the cytokine IL-6 in mind. A bit of a mixed bag of studies by all accounts but with some potential common threads.

The Leigh study has already been covered by some media (see here) so no grand description needed from me. Suffice to say that there is a suggestion from this MIND Institute study, that minocycline might have some modest positive impact on various aspects of behaviour in paediatric cases of FXS with the requirement for further research. As per some previous chatter on this blog, this is not necessarily new news for FXS as per studies like the one by Paribello and colleagues**** (open-access). Interestingly, the Paribello results also mention something called matrix metalloproteinase-9 (MMP-9) as a particular target of minocycline which has also been discussed on this blog (see here). So, potentially (potentially!) there may be some merit in looking at minocycline for cases of FXS; although as per my blog caveat, I'm not recommending anything.

Moving on. The Pardo study (see here for the trial record), whilst small in participant numbers, looked more directly at the use of minocycline - and vitamin B6 - with ten children diagnosed with an ASD. The focus was on autism with a regressive aetiology linked to presentation, and alongside various behavioural measures, there was also analyses of various biological fluids for "markers of neuroinflammation". The study was open and unblinded so not exactly the same calibre as the Leigh trial.

The main result of the trial, er... no clinical improvements following minocycline use, even after six months of use. Indeed not only were no significant changes to behaviour reported but a variety of respiratory and gastrointestinal (GI) side-effects correlated with minocycline use. The efficacy and safety profile was not particularly great based on these study results allowing for the lack of any control group and the dosage used.

There were however, a few reported changes to some of the biochemistry under investigation, specifically with brain derived neurotrophic factor (BDNF) and hepatocyte growth factor (HGF) in mind but not in the more classically related parameters such as that MMP-9 connection. This lack of effect of minocycline on MMP-9 is slightly unusual but potentially revealing. Certainly the review by Siller & Broadie***** (open-access) hints that MMP inhibition might be a key part of the effects of minocycline in FXS. It's possible a few scenarios might pertain with regards to the biological/genetic differences between autism and FXS. One might even speculate that there is some involvement for the TIMPs (tissue inhibitors of metalloproteinases) in that non MMP inhibitory effect noted from minocycline in autism, but much more work is perhaps needed.

Indeed the authors very overtly noted that "minocycline exerted biological effects that were not translated into behavioral or neurological changes" which certainly questions the link between some of the biochemistry that was seemingly affected and presented symptoms assuming there wasn't more subtle behavioural changes.

Finally, there is the Ataie-Kachoie study on minocycline application to ovarian cancer cell lines. I'll freely admit that I know even less about cancer cell lines than I do about autism so please excuse any widely inaccurate statements that I might make. The long-and-short of it was that in the lab, minocycline seems to have an interesting effect on "the IL-6 signaling pathway" at least in ovarian cancer cells such that minocycline might reduce IL-6 or at least prevent increases after certain events. As part of my learning jounrney through this paper I did not know that IL-6 was for example being linked to cancer metastasis as discussed by Tawara and colleagues****** for example. Seemingly this metastasis might correlate with those MMPs (particularly MMP-2 and MMP-9).

I know I'm moving further and further away from my autism and FXS purpose with the Ataie-Kachoie data, but there may be some lessons to be learned. That for example minocycline might affect cases of FXS by means of impacting on MMP-9 is already under discussion. The added suggestion that minocycline might also be working on cytokines like IL-6 in an anti-inflammatory fashion is certainly another source of discussion. Indeed, I note from the Pardo autism study, that in Table 3 showing the pre- and post-treatment effects on biochemistry, the value reduction for serum IL-6 just managed to escape that magical significance point coming in at p=0.08. The change in another interesting cytokine, TNF-alpha, was even closer (p=0.074).

This has been a post comparing apples and pears to a large extent and reiterating my earlier caveat, I am by no means advocating minocycline for anything other than it's intended use with appropriate medical physician support and supervision. Outside of the discussions already included, what this post does serve to show is that (a) the actions of medicines are not necessarily restricted to what's printed on the patient information leaflet, and (b) some of those 'extra' actions might yet hold some promise for some presenting with autism or autism-like behaviours across the autisms and indeed other conditions.

To close, while recently watching the excellent film 'The Sting' I was again entranced by the piano genius of Scott Joplin's 'The Entertainer'.


* Leigh MJ. et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with Fragile X Syndrome. J Dev Behav Pediatr. 2013; 34: 147–155.

** Pardo CA. et al. A pilot open-label trial of minocycline in patients with autism and regressive features. Journal of Neurodevelopmental Disorders 2013: 5: 9.

*** Ataie-Kachoie P. et al. Minocycline suppresses Interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: In Vitro and In Vivo studies. PLoS ONE. 2013; 8: e60817.

**** Paribello C. et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010; 10: 91.

***** Siller SS. & Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for Fragile X Syndrome. Neural Plasticity. 2012; 124548.

****** Tawara K. et al. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Management & Research. 2011; 3: 177-189.

---------- Leigh, M., Nguyen, D., Mu, Y., Winarni, T., Schneider, A., Chechi, T., Polussa, J., Doucet, P., Tassone, F., Rivera, S., Hessl, D., & Hagerman, R. (2013). A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome Journal of Developmental & Behavioral Pediatrics, 34 (3), 147-155 DOI: 10.1097/DBP.0b013e318287cd17