Inflammation is part of Gulf War Syndrome

Although mostly trying to avoid any politics-talk on this blog I am going to make some reference to it in this post set in the context of the Persian Gulf War otherwise known at the First Iraq War.

The recent publication of the Chilcot report describing the case for the UK's involvement in the 2003 Iraq War (the second Iraq War) has further lit up an already illuminating year in British politics, by perhaps adding fuel to the notion that 'finishing the job' might have been an important link between the two conflicts...

Operation Desert Storm - the combat phase of the First Gulf War (1991) - described by some as 'the most toxic war in history' left a mark not just on the region where it was fought and its people but also on many of the returning service personnel, some of whom came back in a pretty poor state of health. Their various symptoms known collectively as Gulf War Syndrome or Illness, are still the topic of discussions and debate to this day despite increasing evidence that they are 'real' symptoms (see here) and not just some psychosomatic manifestation of combat stress for example, as advocated by some quite prominent figures. The possible reasons for illness are varied (see here) but when one uses the words 'sarin' in the context of potential exposures for example you get a flavour for what might have been involved [1] and their potential contributions to health or rather ill-health.

The paper by Gerhard Johnson and colleagues [2] (open-access) adds further credence to the idea that Gulf War Illness (GWI) is indeed a real phenomenon and specifically: "that inflammation is a component of the pathobiology of GWI." Based on the examination of a relatively small number of veterans (85 out of 500 deployed veterans who were invited to participate), researchers undertook a "structured interview" that "assessed their health status, and blood samples were obtained." They managed to divide veterans up into GWI+ (n=57) and GWI- (n=28) groupings dependent on whether or not they reached the Fukuda criteria [3] for a "a chronic multisymptom condition" linked to deployment to the Gulf War.

Results: over 80 specific analytes were assayed for from the blood samples provided by participants. Many compounds had an immunological slant in terms of being cytokines or being other markers of immune system (specifically inflammatory) 'activation'. "The results of the current study provide evidence of alterations in a number of blood parameters that are readily measurable in routine clinical laboratories" was the headline as six specific compounds, all with inflammation in mind, were ripe for further independent study: plasma C-reactive protein (CRP), leptin, brain-derived neurotrophic factor (BDNF), and matrix metalloproteinase-9 (MMP-9)  = higher in the GWI+ group. Heart-type fatty acid binding protein (H-FABP) and matrix metalloproteinase-2 (MMP-2) = lower in the blood of GWI+ subjects. Alongside "the distributions of peripheral blood lymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI+ subjects" compared with GWI- participant data leading researchers to observe that "a model utilizing three readily measurable biomarkers [lymphocytes, monocytes, and C reactive protein]... appears to significantly augment the symptom-based case definition of GWI."

"The limitations of the study include small sample size, restricted geographic, ethnic, and sex composition of the study subjects, assay of blood parameters only once, some plasma protein assays, including cytokines, considered inevaluable due to a high percentage of assays below the level of detection, overlap of biomarker distributions within the normal range, absence of correction for multiple comparisons, a limited number of blood proteins found to be positively related to GWI+ status, and the absence of a confirmation cohort study." Apologies for just grafting a large chunk of text from the Johnson paper into this post, but when it comes to the limitations of their work, the authors do a pretty good job of cautioning against any over-hype and providing a roadmap to 'where next?'

And as part of that 'where next?' it appears that we might be talking quite soon about some findings if an associated ClinicalTrials.gov entry is anything to go by (see here) on the use of 'delayed-release prednisone' with this group. I say this without making any value judgements or providing anything that looks, sounds or smells like medical or clinical advice.

We wait and see.

And to close: "all is as the Force wills it" apparently...

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[1] Proctor SP. et al. Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology. 2006 Dec;27(6):931-9.

[2] Johnson GJ. et al. Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PLoS ONE 11(6): e0157855.

[3] Fukuda K. et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998 Sep 16;280(11):981-8.

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Johnson GJ, Slater BC, Leis LA, Rector TS, & Bach RR (2016). Blood Biomarkers of Chronic Inflammation in Gulf War Illness. PloS one, 11 (6) PMID: 27352030

Systemic low grade inflammation and bowel issues in autism?

The paper from Katarina Babinská and colleagues [1] (open-access here) presents an interesting, if preliminary take on two potentially important issues linked to at least some cases of autism: gastrointestinal (GI) issues and inflammation (see here and see here respectively).

Detailing the examination of plasma levels of a compound called high mobility group box 1 protein (HMGB1), a protein which has the apparent ability to 'bend DNA' and has some pretty potent immune effects [2] (one paper talked about HMGB1 as being a 'nuclear weapon in the immune arsenal'), authors reported results based on the examination of 31 people on the autism spectrum compared with 16 asymptomatic controls. As well as finding as a group, that those with autism presented with significantly higher levels of plasma HMGB1, they also reported that those with some of the highest levels of HMGB1 were more likely to present with GI issues. Ergo: "Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms."

Reiterating that this was a small study in terms of participant groups and that among control group participants were "10 siblings of the individuals with autism", these are interesting results. Whilst I might disagree with some of the terminology used by the authors in their paper such as the concept of 'low-functioning autism' and the term 'mental retardation' as a descriptor of the cognitive status of their participants with autism, I believe that there may be quite a bit more to do in this research area.

A quick trawl through some of the other literature where autism and HMGB1 are mentioned reveals that this is not the first time that elevations in HMGB1 have been reported. The paper from Emanuele and colleagues [3] for example, looking at a similarly small number of participants reported that: "HMGB1 levels may be affected in autistic disorder". Further: "Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder." I'm not overly sure that based on data from 22 adults with autism one can make such statements about a single biological parameter being linked to one of the core traits that makes up a diagnosis of autism, but certainly this paper adds to the Babinská data. The paper from Russo [4] on epidermal growth factor (EGF) and HMGB1 with autism in mind has been previously discussed on this blog (see here). In that entry, I also linked to a piece of research correlating HMGB1 to up-regulation of something like MMP-9 (which again has been discussed here before). Follow-up work from this author [5] has also been published.

What's more to say about HMBG1 and autism? Well, one might entertain the idea of adding HMBG1 to further research on markers of immune function in autism (see here) not forgetting the adhesion molecules too (see here). In light of the idea that there may be a link between the genetics of immune function and [some] autism (see here) one might also look at the gene producing HMBG1 and perhaps some of the other genetic/biological drivers controlling or moderating HMBG1 production.

Assuming that some people on the autism spectrum are in a state of "systemic low-grade inflammation" (accepting that this description probably covers most people with and without a diagnosis at some point in their lives) and that initial correlation noted with GI issues, one might also entertain the idea of looking at what happens to HMGB1 levels as and when bowel issues are 'treated'. I say this acknowledging that bowel issues and autism can mean quite a few things (see here and see here) and that science is not quite there yet in understanding how such bowel issues come about and what one might be able to do about them. Aside that is, from the Buie papers back in 2010 (see here and see here)...

Music: Dreaming of You by The Coral. You may not know their name, but you'll probably have heard the song before...

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[1] Babinská K. et al. Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism. Physiol Res. 2015 Feb 10;63 Suppl 4:S613-8.

[2] Bianchi ME. & Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev. 2007 Dec;220:35-46.

[3] Emanuele E. et al. Increased serum levels of high mobility group box 1 protein in patients with autistic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010 May 30;34(4):681-3.

[4] Russo AJ. Decreased Epidermal Growth Factor (EGF) Associated with HMGB1 and Increased Hyperactivity in Children with Autism. Biomark Insights. 2013 Apr 4;8:35-41.

[5] Russo AJ. Increased Epidermal Growth Factor Receptor (EGFR) Associated with Hepatocyte Growth Factor (HGF) and Symptom Severity in Children with Autism Spectrum Disorders (ASDs). J Cent Nerv Syst Dis. 2014 Sep 9;6:79-83.

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Babinská K, Bucová M, Ďurmanová V, Lakatošová S, Jánošíková D, Bakoš J, Hlavatá A, & Ostatníková D (2015). Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism. Physiological research / Academia Scientiarum Bohemoslovaca, 63 Suppl 4 PMID: 25669692

Minocycline for schizophrenia?

"Minocycline may improve the psychopathology of schizophrenia, especially the negative symptoms, and seems to be well tolerated".

A Bachelors Drawer (apparently) @ Wikipedia 

That was the finding from the systematic review and meta-analysis undertaken by Oya and colleagues [1] looking at the collected literature on the use of "minocycline augmentation therapy in patients with schizophrenia receiving antipsychotic agents". Augmentation therapy by the way, refers to the addition of minocycline to existing pharmacotherapy for schizophrenia.

I wasn't all that surprised to read the Oya paper given that for some time now, there have been scientific rumblings about how antibiotics might do quite a bit more than just 'killing bacteria' [2]. "Scientists shocked" was how one media report has previously talked about this area of research; which conjures up all-manner of visions of stunned science-types walking around with lab coats on and mouths and eyes wide open in amazement.

The reports that minocycline might act on the negative symptoms of schizophrenia (see here) is also quite an important detail, because these are often the symptoms which affect daily living skills, potentially manifesting as "losing interest and motivation in life and activities, including relationships and sex... [and a] lack of concentration, not wanting to leave the house and changes in sleeping patterns". These are also the symptoms which tend to respond less well to traditional management strategies like medication.

The final question(s) are how and why does minocycline affect cases of schizophrenia? The paper from Zhang and Zhao [3] (open-access) provides quite a good overview of the various hypotheses put forward. Unsurprisingly, some effect on inflammation figures quite strongly in the suggestions put forward. I could go on and on and on about the various research in this area (see here for example) but won't on this occasion. Instead, I'll direct you to a previous post I wrote on minocycline and Fragile X syndrome (see here) which mentions some effect from minocycline on matrix metalloproteinase-9 (MMP-9). I'd like to think that this is a potentially important point because of the tie-in with something like homocysteine (see here), the big H, which has also been mentioned with schizophrenia in mind (see here). Just speculatin' of course.

Music to close. Frank Sinatra and something about a lot of coffee in Brazil?

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[1] Oya K. et al. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2014 Aug 4.

[2] Levkovitz Y. et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010 Feb;71(2):138-49.

[3] Zhang L. & Zhao J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014 Jun 17;10:1103-11.

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Oya K, Kishi T, & Iwata N (2014). Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Human psychopharmacology PMID: 25087702

Homocysteine, gut permeability and MMP-9?

A speculative post this one, on the paper by Hao Ding and colleagues [1] (open-access here) looking at how, in a rodent model of colitis, homocysteine (the big 'H') might play some part in aggravating "inflammatory damage" potentially through promotion of some of the matrix metalloproteinases, MMP-2 and MMP-9. The words: "Hcy [homocysteine] can increase intestinal permeability" added to the interest.

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

MMP-9 and symptom severity of ADHD

"The statistical regression analysis revealed a correlation between increased serum MMP-9 levels and severity of symptoms in the ADHD". That was the sentence that caught my eye taken from the paper by Halina Kadziela-Olech and colleagues [1] (open-access here) looking at serum matrix metalloproteinase-9 (MMP-9) levels in children with hyperkinetic disorder (HKD) [2] "a severe form of a syndrome which is referred to in DSM-IV... and the American literature as attention deficit hyperactivity disorder (ADHD)".

Hamlet @ Wikipedia 

MMP-9 is something that has already been talked about on this blog with autism in mind (see here) but basically refers to a protease which is involved in degrading proteins of the extracellular matrix [3] and other duties. As Kadziela-Olech et al  point out, there is some preliminary interest in MMP-9 with reference to "neuropsychiatric disorders" particularly with schizophrenia in mind [4]. Interestingly also is that quite a bit of the conversation about MMP-9 and its potential effects have focused on the blood-brain barrier [5] under certain circumstances, which is something that I've always been more than a little interested in (see here) particularly transport across this important barrier.

Anyhow, back to the paper in question:

• Analysis was conducted on 37 boys with HKD/ADHD all properly assessed, as were cognitive functions (via the WISC-R). Blood samples were donated and MMP-9 activity assessed by ELISA (see here).
• Results: bearing in mind there was no asymptomatic control group, it's pretty pointless for me to talk about the serum levels of detected MMP-9 in cases overall. Of more relevance were the various associations made between levels of MMP-9 and presented symptoms: "The MMP-9 levels were significantly associated with symptoms severity of HKD and of ADHD".
• In particular, MMP-9 levels seemed to correlate best with the impulsivity symptom domain when it came to HKD.

In the paper discussion, the authors do go through some of the possible ways that MMP-9 might relate to ADHD/HKD. Part of those discussions focus on blood-brain barrier (BBB) permeability and whether some of the reported risk factors for ADHD may affect MMP-9 expression onwards to a sort of 'leaky' BBB (sounds very familiar). I note also mention of minocycline as a MMP-9 inhibitor (see here) which may very well tie back into some of the research work being done with autism / Fragile X syndrome in mind, particularly given the overlap being reported between diagnoses like autism and ADHD. Some light reading around the topic of MMP-9 also reveals that there may be lots of other functions/relationships to had for this protease. With my cherry-picking hat on, I note the paper by Rodrigues and colleagues [6] talking about inflammation and in particular: "MMP-9 expression in the colon causes alterations in the fecal microbiome" given my interest in all-things gut microbiomics.

Ultimately however, quite a bit more work needs to be done in this area before anyone gets too carried away. Bearing in mind the Kadziela-Olech study was a snapshot study and as I said, without relevant control groups, there are some limitations on what can be said about the findings. Looking also at the plots correlating behavioural presentation and MMP-9 levels it's quite obvious that the relationship between the two variables is not altogether straight-forward despite what the statistics might suggest.

But don't let that deflect from their findings and the need for more research in this area...

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[1] Kadziela-Olech H. et al. Serum matrix metalloproteinase-9 levels and severity of symptoms in boys with attention deficit hyperactivity disorder ADHD/hyperkinetic disorder HKD. Eur Child Adolesc Psychiatry. 2014 Mar 17.

[2] Cameron M. & Hill P. Hyperkinetic Disorder: Assessment and Treatment. Adv Psychiatr Treat. 1996; 2: 94-102.

[3] Birkedal-Hansen H. et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993;4(2):197-250

[4] Yamamori H. et al. Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine. Neurosci Lett. 2013 Nov 27;556:37-41.

[5] Li YJ. et al. Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels. J Neuroinflammation. 2013 Jul 5;10:80.

[6] Rodrigues DM. et al. Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis. BMC Microbiol. 2012 Jun 13;12:105.

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Kadziela-Olech H, Cichocki P, Chwiesko J, Konstantynowicz J, & Braszko JJ (2014). Serum matrix metalloproteinase-9 levels and severity of symptoms in boys with attention deficit hyperactivity disorder ADHD/hyperkinetic disorder HKD. European child & adolescent psychiatry PMID: 24633733

Matrix metalloproteinases and autism

Peptidases. The enzymes that split apart peptide bonds, have always been of some interest to me. Not only resulting from my continued interest in peptides as being one potential suggestion why a gluten- and/or casein-free diet might affect symptom presentation in some cases of autism but also because of their relationship to the building blocks of functional life, the amino acids, which are really starting to make some waves in autism research.

Just split @ Wikipedia  

With all this in mind, it was perhaps inevitable that I would arrive at a post on a specific class of peptidases, the matrix metalloproteinases (MMPs) and some very preliminary suggestions of potential involvement in cases of autism and beyond. Please note that not all peptidases work on the same types of peptides, just in case you wondered.

It was the paper by Abdallah and colleagues* which spurred me into writing this post, and their suggestion that analysis of amniotic fluid samples indicated that levels of MMP-9 were elevated in cases later diagnosed with an autism spectrum disorder (ASD). The fact that they also mentioned BDNF was a bonus interest.

Perhaps I should back up a little and provide a quick overview of the MMPs. So with my Twitter limit: zinc-dependent, embryonic development, removal of extracellular matrix, immune function and inflammation, synaptic plasticity**, etc. There are a number of very good review articles on the MMPs including this one by Birkedal-Hansen and colleagues*** (open-access).

The specific MMP discussed by Abdallah et al, MMP-9, has been the topic of quite a lot of research interest over the years. The degradation of collagen is an obvious starting point for all the MMPs, hence a link with connective tissue disorders such as rheumatoid arthritis**** (open-access). It is however with the brain and various neuropsychiatric conditions in mind, that I find myself drawn to the potential effects of MMP-9.

Domenici and colleagues***** (open-access) for example, reported on the possibility that elevated plasma MMP-9 levels may (alongside other compounds) be a biomarker for depression in their cohort. Indeed the genetics of MMP-9 have been similarly linked to bipolar and related disorders. There remains however the chicken-and-egg situation of which came first, MMP-9 or symptoms, not really answered by studies such as this one by Rybakowski and colleagues****** relying on MMP-9 levels to predict staging of bipolar disorder.

Outside of the Abdallah study, there is not presently a great wealth of research done on the MMPs with autism in mind. Accepting the fact that Abdallah was looking in amniotic fluids samples and therefore not functional levels per se, I did turn up this paper by Siller and Broadie******* (open-access) looking at MMPs in Fragile X syndrome (FXS). Regular readers might remember a few papers discussed on this blog in recent times with FXS as the target condition (see here and here) presenting with autistic features. Siller and Broadie asked whether administration of the antibiotic minocycline might actually serve to inhibit MMP (activity or formation?). The answer: it might as per other work in this area but please note that this is not to be construed as medical advice.

I was likewise interested to read the paper by Jang and colleagues******** on how everyone's favourite sleeping aid, melatonin, might also have some important effects on MMP-9 levels, at least in a rat model of stroke. That and the possibility(!) that this relationship might also involve blood-brain barrier (BBB) disruption really got the grey matter working. Once again a pharmacological effect that you won't see on the drug packaging insert.

We have yet to see all there potentially is about MMPs with autism in mind. With all the current interest in excitotoxicity in cases of autism linked to things like glutamate and compounded by the whole microglia story, I'm sure it is a topic that will gain in research popularity and perhaps even open up new avenues for intervention********* for specific people and/or groups should perturbed levels be found and replicated. Given also the possibility of a viral link to elevations in MMP9********** one has to assume that environment may also play a hand in some presentations and potentially tie into those models of maternal infection as being a risk factor for offspring autism?

To finish, the King at his best...

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* Abdallah MW. et al. Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study. Autism Res. September 2012.

** Huntley GW. Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nature Reviews Neuroscience. 2012; 13: 743-757.

*** Birkedal-Hansen H. et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med. 1993 ;4: 197-250.

**** Distler JHW. et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. PNAS. 2005; 102: 2892-2897.

***** Domenici E. et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One. 2010; 5: e9166.

****** Rybakowski JK. et al. Increased serum matrix metalloproteinase-9 (MMP-9) levels in young patients during bipolar depression. J Affect Disord. August 2012.

******* Siller SS. & Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for fragile X syndrome. Neural Plast. 2012: 124548

******** Jang JW. et al. Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model. J Neurol Sci. 2012. pii: S0022-510X(12)00524-2

********* Leonardo CC. & Pennypacker KR. Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation. 2009; 6: 13.

********** Kolb SA. et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulation of MMP-9 and TIMP-1 in cerebrospinal fluid. J Neuroimmunol. 1998; 84: 143-150.

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Abdallah MW, Pearce BD, Larsen N, Greaves-Lord K, Nørgaard-Pedersen B, Hougaard DM, Mortensen EL, & Grove J (2012). Amniotic Fluid MMP-9 and Neurotrophins in Autism Spectrum Disorders: An Exploratory Study. Autism research : official journal of the International Society for Autism Research PMID: 23008271