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I'll state from the outset that the Angelidou paper is a talky-talky review paper and as per quite a few review papers, there is a healthy sprinkling of speculation also included. In this case it is the suggestion that a premature birth combined with a specific pattern of 'susceptibility' genes might predispose an infant via various triggers to mast cell activation (see my previous post on this topic) onwards to brain inflammation and autism.
I've already covered autism and SEN and prematurity in previous posts (see here for example), so won't dwell too much on that for now aside from directing you to another relevant paper in this area by Leavey and colleagues** recently published, quote confirming "the role of shortened gestation in ASD risk". As to the susceptibility genes side of things, well once again the ENCODE project really suggests that we should be looking a little further and a little wider when it comes to all things genetics but I'm going to leave that for now.
One specific part of the paper by Angelidou was however of particular interest to me: neurotensin (NT) and the evidence base with relation to autism. A quick description first: neurotensin is a peptide found in various tissues including brain and gastrointestinal (GI) tract. Originally categorised as a hypotensive (lowering blood pressure) by Carraway & Leeman*** it appears that this peptide has quite a few potential functions and relations as per the work on its neuromodulatory action on dopamine release (see this paper by Fawaz and colleagues**** open-access) and the lessons which could be learned for various pharmacotherapies such as the neuroleptics which may be of relevance to quite a few conditions. Other, seemingly quite diverse areas, also seem to have been linked to neurotensin chemistry including alcohol metabolism and some cancers. Indeed some pretty strong evidence of involvement for neurotensin and diseases associated with premature death was recently published.
With autism in mind, the current science base for neurotensin is a little bit limited. There are however some key papers to point out:
- The mast cell activation theme runs through a lot of the research starting with this paper by Angelidou (again!) and colleagues***** (open-access). Out of several peptides that are potentially able to stimulate mast cells (including beta-endorphin), the authors reported that only levels of neurotensin were found to be significantly elevated in their cohort of children with autism compared with controls. Having said that, with participant group numbers of n=19 (autism) and n=16 (controls), there was a very preliminary air to this data.
- Next on the list is this paper by Zhang and colleagues****** (open-access) again with some familiar names on the authorship list. This paper extends the previous findings of elevated neurotensin levels in cases of autism to suggest that such elevations might also have the propensity to influence the "release of extracellular mitochondrial DNA (mtDNA) that could act as "autoimmune" trigger". In case you want to read more about mitochondrial DNA and 'anti-mitochondrial antibody Type 2' take a look at these pages (here and here). I'll probably do a super-post on autism and mitochondria at some point given this and the growing literature in this area.
- And continuing the story, this paper by Asadi and Theoharides******* (open-access). Not too much more to say here aside from some indication "that stress and infection-mimicking extracellular mitochondrial components augment allergic inflammation that may be involved in the early pathogenesis of ASDs".
- Finally, Ghanizadeh******* (open-access), who seems to have a whole stream of ideas relating to autism and related conditions (see here), offers a brief but interesting opinion piece about how targeting neurotensin levels in cases of autism might have some interesting therapeutic advantages, bringing into play everyone's favourite excitatory amino acid and neurotransmitter, glutamate (and its receptors and signalling), alongside the calming effects of GABA.
There's not too much more to add at the moment to this body of work on neurotensin and autism. I've not for example talked about the neurotensin receptors (see here) nor the genetics of neurotensin (see here) despite there probably being some important connections to be made. Complementary to the mast cell activation investigations in cases of autism, there does appear to be some good reasoning to continue research in this area.
* Angelidou A. et al. Perinatal stress, brain inflammation and risk of autism-review and proposal. BMC Pediatrics. 2012; 12: 89.
** Leavey A. et al. Gestational age at birth and risk of autism spectrum disorders in Alberta, Canada. The Journal of Pediatrics. September 2012.
*** Carraway R. & Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. Journal of Biological Chemistry. 1973; 248: 6854-6861.
**** Fawaz CS. et al. Presynaptic action of neurotensin on dopamine release through inhibition of D2 receptor function. BMC Neuroscience. 2009; 10: 96.
***** Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. Journal of Neuroinflammation. 2010; 7: 48.
****** Zhang B. et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. Journal of Neuroinflammation. 2010; 7: 80.
******* Ghanizadeh A. Targeting neurotensin as a potential novel approach for the treatment of autism. Journal of Neuroinflammation. 2010; 7: 58.
Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S, & Theoharides TC (2012). Perinatal stress, brain inflammation and risk of autism-Review and proposal. BMC pediatrics, 12 (1) PMID: 22747567