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Read with caution!

This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk.

A quick post on two slightly-related topics: indometacin and inflammation in prion disease.

Manueldis 1998, who I’ve mentioned previously in the dapsone post, also tested indometacin, another anti-inflammatory drug.  Manueldis found a very small (probably about 5%, judging by Fig 1) delay in symptom onset in rats treated with indometacin, but no significant delay in death.

As far as I can tell, Manueldis was the only one to test indometacin in an animal model, but Veerhuis 2002 tested it in a cell culture model.  Microglia are activated in prion disease, and secrete “neurotoxic agents” and IL-1 and IL-6 in response to contact with neurotoxic fragments of PrP.  This study examined how microglia respond to PrP synthetic fragments (release of TNF-Alpha, IL-1, PGE(2)) and whether indometacin would inhibit microglial activation and reduce toxicity.  It didn’t.

There has been a lot of other work on inflammation in prion diseases over the years, more than I can wrap my head around.  The topic has gotten a lot of press just recently with Crespo 2012‘s claim that inflammation is a central part of the neurodegeneration process in prion disease, capable of creating a “self-maintained disease state”.  This paper is pure computational biology, a network analysis of genes that are differentially expressed during prion infection.  It should hardly be surprising that inflammation-related genes are differentially expressed during a disease that leads to inflammation, but the authors’ claim is stronger than that: they argue that a few core genes involved in inflammation lie at the center of this network, regulating each other to keep disease going:

What we consider remarkable and constitutes our main finding is the key role that neuroinflammation plays in the specific case of prion disease, connecting different functional modules and constituting a switch that allows the network to reach a self-maintained disease state, once triggering factors (protein deposition and the formation of amyloid plaques) initiate the process.

I’m not sufficiently well-read on the inflammation-and-prions literature to have a very strong opinion on this, but I feel that the conclusion is worded a bit more strongly than the evidence merits.   Inflammation is certainly a feature of prion disease, and it could well be one contributor to disease pathology.  Still, the conclusion that inflammation leads to a “self-maintained disease state” seems to go a bit far.  I’m open to being proven wrong – the authors state they plan to test their hypothesis by looking at whether mice with one of these core genes knocked out have a different reaction to prion infection.  But considering the evidence we have now, the role of inflammation seems much more marginal and/or downstream.  There is better evidence for the possibility of anti-inflammatories as Alzheimer’s therapeutics, and that has inspired a number of studies of anti-inflammatory drugs in scrapie mice–ibuprofen, dapsone and indometacin– none of which have been extremely successful.  Statin fanatics like Dr. Agus will point out that statins also reduce inflammation in the long term.   Arguably this could be another possible explanation for the consistent finding of a small but significant delay in prion disease onset in mice treated with statins.  But remember that statin treatment didn’t reduce PrPSc accumulation, it just allowed the mice to tolerate greater neurological insult before succumbing to symptoms and death.  Overall, I could be more easily convinced that inflammation has some role in the presentation of symptoms and less easily convinced that it lies at the core of the disease process.