If you're used to reading about autism research on this blog, you might be wondering why on earth I've posted about this study. Well, with that pinch of salt at the ready, the Ding study got some of the grey-pinkish matter thinking...
- So, homocysteine and autism. I hope I'm not inflating the collected literature on this topic too much but elevations of Hcy certainly do seem to be quite consistently reported [2] (open-access here) and importantly, spanning various geographies of autism [3] (open-access here).
- Homocysteine in relation to the MMPs is something new to me but there is quite a body of peer-reviewed work suggesting that Hcy does seem to have an effect on the MMPs, particularly MMP-9 [4] in terms of enhancing MMP-9 production via the ERK (extracellular signal-regulated kinase) pathway. To quote from the Lee paper [4] "MMP-9 expression was concentration- and time-dependently increased by Hcy". MMP-9 is still something which needs exploring when it comes to autism but at least one study has hinted that amniotic fluid levels of MMP-9 when elevated might tie into some elevated risk of subsequent offspring autism [5] (see a previous post on this trial). I might add that MMP-9 levels have also been talked about with ADHD (attention deficit hyperactivity disorder) in mind too (see here).
- Then to the next stage of the speculations... MMP-9 and it's possible relationship with intestinal permeability AKA leaky gut. It seems that MMP-9 might have the ability to affect permeability [6] at least in the laboratory. To quote from Munjal and colleagues: "Hcy instigated HIMEC [human intestinal microvascular endothelial cell] monolayer permeability through activation of MMP-9". Further: "this increased permeability was alleviated by inhibition of MMP-9 activity". Leaky gut and autism y'say? Well, let's just say that there is peer-reviewed science suggesting this phenomenon to be present in at least some cases of autism (see here and see here).
OK, I know there's been speculation a-plenty in this post and by saying all of this I am by no means try to pin everything on homocysteine, MMP-9 or anything else when it comes to autism. I would never be that silly. I would however suggest that there is a study or two to be done based on these speculations, asking questions about whether MMP-9 is truly elevated in some cases of autism, and whether homocysteine levels or gut permeability measures may show some connection to one and another and MMP-9. That also the Ding paper focused on an animal model of acquired colitis, an inflammatory bowel disease, also offers another potential differentiating factor if one is to assume that autism is not protective of any other condition, including those of the inflammatory bowel disease grouping (see here and see here). I could go on further and bring GABA receptors and how use of something like "The GABA-A receptor agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation" [7] (open-access here) but that's perhaps another topic for another day, alongside minocycline [8] or even melatonin [9].
I'm quite finished now. Apart, that is, from telling you that You Give Love a Bad Name... (the Bon Jovi song that is, not necessarily you personally).
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[1] Ding H. et al. Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. Gastroenterol Rep (Oxf). 2014 Apr 27.
[2] Kałużna-Czaplińska J. et al. A focus on homocysteine in autism. Acta Biochim Pol. 2013;60(2):137-42.
[3] Tu WJ. et al. Serum homocysteine concentrations in Chinese children with autism. Clin Chem Lab Med. 2013 Feb;51(2):e19-22.
[4] Lee SJ. et al. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):89-94.
[5] Abdallah MW. et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. 2012 Dec;5(6):428-33.
[6] Munjal C. et al. Matrix metalloproteinase-9 in homocysteine-induced intestinal microvascular endothelial paracellular and transcellular permeability. J Cell Biochem. 2012 Apr;113(4):1159-69.
[7] Tyagi N. et al. Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway. J Cell Physiol. 2009 Jul;220(1):257-66.
[8] Dziembowska M. et al. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A. 2013 Aug;161A(8):1897-903.
[9] Rudra DS. et al. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res. 2013 May;54(4):398-405.
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Ding H, Mei Q, Gan HZ, Cao LY, Liu XC, & Xu JM (2014). Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism. Gastroenterology report PMID: 24787389
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