CSF1R Receptor, Alzheimer's, Microglia and Inflammation.

[Remy]

Anyone know of any "natural'" CSF1R blockers??

@Tina, this research may interest you too!

It was originally thought that Alzheimer's disease disturbs the brain's immune response, but this latest study adds to evidence that inflammation in the brain can in fact drive the development of the disease.

The findings suggest that by reducing this inflammation, progression of the disease could be halted.

The team hope the discovery will lead to an effective new treatment for the disease, for which there is currently no cure.

The researchers at the University of Southampton used tissue samples from healthy brains and those with Alzheimer's, both of the same age. The researchers counted the numbers of a particular type of immune cell, known as microglia, in the samples and found that these were more numerous in the brains with Alzheimer's disease. In addition, the activity of the molecules regulating the numbers of microglia correlated with the severity of the disease.

The researchers then studied these same immune cells in mice which had been bred to develop features of Alzheimer's. They wanted to find out whether blocking the receptor responsible for regulating microglia, known as CSF1R, could improve cognitive skills. They gave the mice oral doses of an inhibitor that blocks CSF1R and found that it could prevent the rise in microglia numbers seen in untreated mice as the disease progressed. In addition, the inhibitor prevented the loss of communication points between the nerve cells in the brain associated with Alzheimer's, and the treated mice demonstrated fewer memory and behavioural problems compared with the untreated mice.

Importantly, the team found the healthy number of microglia needed to maintain normal immune function in the brain was maintained, suggesting the blocking of CSF1R only reduces excess microglia.

 

[Snow Leopard]

Specific CSF1R inhibitors cause severe fatigue, to the point that I spent some time trying to figure out how this could be (still don't know)...

http://www.sciencedirect.com/science/article/pii/S1532046410000535

 

[Remy]

Specific CSF1R inhibitors cause severe fatigue, to the point that I spent some time trying to figure out how this could be (still don't know)...

http://www.sciencedirect.com/science/article/pii/S1532046410000535

Hopefully there will be a work-around if these type of drugs come to market. It is a problem, that it is very difficult to only affect one thing, without causing a knock on cascade.

The agents developed to inhibit the structurally similar VEGFR2 tend to have relatively high potency for CSF1R and KIT and fatigue is a common, sometimes dose-limiting adverse effect of these drugs.

Although we have identified a strong association between these kinases and fatigue, it remains unclear whether one, two, or all three of these KTs mediates the fatigue.

If any of the three is differentially associated, there will be the opportunity in either development of new drugs or in administration of combinations of PKIs to decrease the associated fatigue by either selectively eliminating the offending KT affinity or by selecting two PKIs that when added together will maximize inhibition of the intended therapeutic KT, while reducing the inhibition of the unintended, fatigue-inducing target.

 

[Snow Leopard]

My initial hypothesis was indeed inhibition of VEGFR/PDGFR (and a few other kinases as well).
However aforementioned study used data from this interesting study which looked at the binding affinity of 38 inhibitors on 317 kinases!
http://www.nature.com/nbt/journal/v26/n1/full/nbt1358.html
The supplement table is open access:
http://www.nature.com/nbt/journal/v26/n1/suppinfo/nbt1358_S1.html

There is a related study here, which showed similar results:
http://www.nature.com/nbt/journal/v29/n11/full/nbt.1990.html?WT.ec_id=NBT-201111
Or: http://sci-hub.io/10.1038/nbt.1990

Of note, is:

The 'natural' inhibitors, eg Flavopiridol are far less specific and tend to have high affinity for multiple kinases, whereas some of the synthetic inhibitors have clearly been selected for their high specificity.
Manually looking at the chart at the inhibitors that had substantial differences in affinity for VEGFR or PDGFR vs CSF1R and the adverse reports in clinical trials showed the same pattern (it shouldn't really be a surprise, but I was a bit reluctant as it is unclear how inhibiting these receptors would cause fatigue - it is interesting in terms of induced human models of fatigue!) - that the association for fatigue was strongest for CSF1R and C-Kit as described in the aforementioned study.

Some drugs that have affinity for CSF1R but not VEGFR cause fatigue, eg Imatinib. http://www.ncbi.nlm.nih.gov/pubmed/23417029


GW2580, which was the inhibitor used by the researchers in the study you quoted has high affinity for CSF1R, but not VEGFR.
http://www.jneurosci.org/content/33/6/2481.full (2013)
http://brain.oxfordjournals.org/content/early/2016/01/07/brain.awv379 (2016)
There has been quite a bit of speculation about the benefits of this drug as a therapy for specific cancers for the last decade. This drug has not yet been tested in clinical trials in humans as a cancer therapy (not sure why, as it looks interesting!)

Aside from that, another drug that may be of interest is Masitinib.

Targeting CSF1R inhibits macrophage development (including microglia) and it is possible the adverse effects may be simply due to the resulting impairment of the immune system and increased rates of bacterial infection.

 

[loki]

there will be drug out in the future called PLX 3397 (Pexidartinib) it tagets CSF1R and kills off microglia in some days. then, when therapy is over the microglia grows back newly, insensitive, uncharged... maybe i will try it out anytime, but it's expensive as every new kid on the block