Plx 3397

[lookbehindyou]

Ihave a little problem. I was a former H user (10 years IV) and contracted HCV after year 5. 2 Years ago i treated with pegylated Interferon-alpha, Sovaldi and Ribavirin for 12 weeks and cleared the virus.

the problem is the following.
Treatment has blasted my brain immune system (consisting of cells called microglia). These cells are now going insane and produce ROS (reactive oxygen species) that attack the nerve tissue and lead to unbelievable memory loss. (i try to explain the magnitude of this memory loss. for example, i take my HiFi from my buddys room onto a table infront of my buddys room door, go to my room and forget what i did actually.) I forget what my parents names are. I forget my birthday date etc.


So, i take curcumin in a high dose to contain the damage the microglia cells are doing to the brain tissue. Curcumin inhibits TLR4, a receptor that is crucial for the activity of microglia. This is unfortunately not the solution. There is still no normal brain functioning and the next step will be this:


There's a drug in development called PLX3397 (Pexidartinib). This is an anti cancer drug. It inhibits the CSF1R (Colony Stimulating Factor 1 Receptor) that is crucial for the survival of microglia cells. The following link can describe the mode of action:

http://www.alzforum.org/news/research-news/microglial-magic-drug-wipes-them-out-new-set-appears



My question now, can this cure my condition? Is it a good approach?

thanks guys

 

[T. Calderone]

What has your physician recommended? I'm going to move this to Neuroscience and Pharmacology Discussion. Wish you luck!

 

[sekio]

Why do you have such a specific diagnosis for a rather vague symptom (memory loss)?

 

[lookbehindyou]

@Calderone
thank you, the physician supports my ideas:D

Why do you have such a specific diagnosis for a rather vague symptom (memory loss)?

The symptoms arose after the cessation of the IFN treatment 24 months ago. They included irritability, suicidal ideation, anxiety, muscle spasms, balance and movement problems, memory loss, cognitive impairment, blurred eyesight, insomnia, tinnitus and catatonia. The psychiatric symptoms didn't respond to lorazepam and NDRI as well as neuroleptics. The first partial resolvement of symptoms (the main relieve was being able to walk again for more than 10 minutes...) began with a low dose of natrexone (1-3mg).Partial symptom resolvement through naltrexone implicated that the cause of a broad band of the symptoms has to be CNS inflammation and i looked after more effective anti inflammatory agents. naltrexone has the downside of causing insomnia and dysphoria (the opposite of euphoria). I found DXM to be even more helpful ( 30mg q.i.d. ) and without the downside of dysphoria. The link here describes the anti inflammatory mechanisms of DXM
http://www.hindawi.com/journals/jir/2013/125643/
I had funny times on DXM, even on a low dose:D. Since long term intake of even low doses of DXM can cause brain lesions i again looked after alternatives. I found curcumin to be an anti inflammatory(brain) agent that also suppresses microglia activity via inhibition as well and I now take curcumin in a lipid emulsion formula for the bioavailability (48mg q.i.d. Curcuflex) and it really helps with the symptoms. Though it also is toxic in the long term, i will take it until i have better options.

 

[serotonin2A]

Any drug that is in development will not be useful for you because you need a medication that can be prescribed now. What about minocycline or nicergoline?

DXM, especially in low doses, doesn't cause brain lesions. You are extrapolating this based on findings with high doses of a different drug (PCP) in a different species (rats). There is no evidence DXM or even ketamine has this effect in monkeys, let alone humans. If they did damage pyramidal neurons in humans then FDA would have taken them off the market.

 

[Cotcha Yankinov]

^I second that DXM dose not cause Olney's Lesions. If taken at high doses there might be slight slight excitotoxicity as the glutamate rebounds on the comedown but other than that all I would be looking out for is intellectual deficits that may occur with long term abuse which might be due to long term inhibition of NMDA/plasticity and not due to actual neurotoxicity. But low dose is a different matter, take less than 100mg a day and you'll be fine.

Have you looked into memantine? It's a very neuroprotective NMDA antagonist.

So you believe your problems are due to your microglia being in a reactive state? I suppose there is a possibility of demyelination/lesions and this could be causing memory problems as well as the peripheral movement problems. Have you had a brain MRI to look at your white matter?

Hope you feel better soon

 

[lookbehindyou]

it's hard to write and thanks to a bug i now have to write everything again..


so, these drugs, especially the NMDA Antagonists look really promising. i will try to get my hands on them and i will again look into DXM (because it really helped! when i told that my doctor she smiled) I did a MRI 18 months ago unsuspicious. PLX 3397 was designated as breakthrough drug in late october, so i guess it will get approved in late 2016 / 2017. I get the crude substance (HCl salt) from a website for $10.000 / 37.000mg. They fed 290mg/kg PLX3397 to wild type mice for 21 days. That eradicated 99% of their microglia brain-wide. The H.E.D. is therefore 1.600mg/day. A treatment duration of 37 days @1000mg/day equals 37.000mg.

 

[Solipsis]

If ROS are the culprit, is this relevant:
http://www.bluelight.org/vb/threads/777119-how-good-is-idarevone
?

Or not because only big in Japan?

Also holy shit $10K seems like a lot of money for an unsure thing that I am assuming will not get covered by your healthcare insurance : p

But seriously sorry you got a bum deal.

 

[lookbehindyou]

my GI has a screw loose for happily prescribing me Interferon chemotherapy 2 months before drugs (harvoni) came out that have 'migraine' as most serious adverse event... anyway, well thank god we are not poor and can afford 10k though it's so much money and nobody can gurantee anything... i'll keep you updated.

 

[Cotcha Yankinov]

I think you should look into the aspect of the kynurenine pathway and the role quinolinic acid is probably playing, NMDA antagonists have proven protective in this regard. Because of possible shifts in tryptophan metabolism related to IDO you might be running low on serotonin which is very important for memory. Have you tried 5-HTP + ECGC (a decarboxylase inhibitor that will help your brain absorb more 5-HTP)? At this point I would definitely try 5-HTP... I would start low dose (50mg) and see if it has any side effects before proceeding to 100mg 3 times a day.

Assuming the TNFa inhibitors cross the BBB you should definitely look into those. A great portion of gliotransmitted glutamate is mediated through TNFa. I think there is extreme risk in eliminating all of your microglia, they are very important cells and are very involved in maintaining homeostasis. We should instead find a way to curb inflammation so that the activated microglia can return to their resting states.

Would this drug eliminate astrocytes as well??

I'm assuming you've looked into lipophilic anti oxidants such as vitamin E and tried NAC and ALA and such all together, if not I highly recommend it, along with daily vitamin C.

If your problem is amyloid plaques (which the microglia can produce) then things are trickier. Normally during REM sleep the plaques are cleared away but if for whatever reason if you're not getting good cerebrospinal fluid clearance of plaques during REM sleep (sleep apnea, poor sleep architecture, insomnia, poor vascularity of the brain) I really recommend exercise if you can manage to do any sort of cardio. Exercise increases expression of anti-inflammatory interleukins and it also increases neurogenesis as well as builds new serotonin cells which are very important for memory. In addition exercise increase angiogenesis or the generation of new blood vessels, which will help your brain function. Chronic deconditioning (lower blood pressure/brain blood perfusion) as well as bad vascularity can wreak havoc on the mind.

Memantine might be just what you need, and there isn't much harm in trying the tnf alpha inhibitors, while those currently unavailable I would definitely try 5-HTP and a mix of potent antioxidants consisting of vitamin E/C ALA, NAC, and curcumin. I should mention curcumin is probably therapeutic in treatment of IDO/kynurenine disorders.

 

[lookbehindyou]

i tried to write an answer 8 times. and everytime the site crashes my post.

About PLX 3397 and astrocytes:

[...]However, robust increases in the astrocytic markers glial fibrillary acidic protein (GFAP) and S100 were found. GFAP mRNA levels were also increased with 7 days of PLX3397 treatment, as measured via real-time PCR (Figure S3C). To further investigate these changes in astrocytic markers, we performed immunofluorescent stains for GFAP at all treatment time points. GFAP cell counts showed no differences with treatment, despite the measured increases in mRNA and protein (Figures S3D–S3G). Likewise, S100 cell counts also revealed no differences (Figure S3G). No changes in signal intensity with either GFAP or S100 were measured; likewise, morphological analyses revealed no changes in astrocyte cell body volumes, process lengths, or diameters (Figures S3H–S3P). Thus, depletion of microglia results in increased mRNA and protein for astrocytic markers, but no changes in cell numbers or morphology.[...]


About PLX3397 and microglial repopulation:

Rapid Restoration of CNS Microglia after Drug Removal
Eighteen-month-old wild-type mice were treated with PLX3397 for 28 days to eliminate microglia, first to show that microglia are still dependent upon CSF1R signaling in the aged brain, and second, to explore microglial homeostasis in the aged brain. At this point, all mice were switched to vehicle chow and then sacrificed 0, 3, 7, 14, and 21 days later to assess any microglial repopulation (n = 4 per group; Figure 4A). Remarkably, within 3 days IBA1+ cells appear throughout the brain with very different morphologies to resident microglia in control brains (Figures 4B and 4D). They are much larger, with only short stubby processes. By 7 days of recovery, the total number of microglia exceeds that of control mice, and their morphologies lie between that of the cells seen at 3 days and untreated microglia (Figures 4B 4H). By 14 days of recovery, the microglia numbers stabilize to untreated levels, and the repopulating microglia resemble normal ramified microglia. Thus, repopulation of the microglia-depleted brain occurs through rapid increases in cell numbers and differentiation into microglial morphologies. The cells seen at the 3-day recovery time point are unique: they are much larger than resident ramified microglia (Figure 4I) and appear throughout the CNS, rather than in discrete locations (Figure S5). Curiously, we also found that these cells express several markers not seen in microglia in control brains, nor in surviving microglia while being treated (Figure 4K). They are very strongly positive for the lectin IB4, as well as CD45. Many of these cells are Ki67+, a marker of cell proliferation, and CD34+, a marker of hematopoietic stem
cells (HSCs), whereas _10% of these cells also show c-Kit staining, another HSC marker. The majority of cells are also nestin+, a neuroectodermal development marker, a surprising finding given the myeloid lineage of microglia. However, at day 7, IBA1+ cells assume a more typical microglia morphology; have repopulated the entire CNS; and are CD45, IB4, CD34, c-Kit, nestin, and Ki67 negative. By 14 days, cells are morphologically indistinguishable from resident microglia in control brains and have comparable numbers (Figure 4H). Thus, the adult CNS has a highly plastic and dynamic microglial population that can be entirely repopulated after microglial elimination, even in the aged brain. [...]

What TNF-a inhibitors do you mean? DXM? I will 100% look into 5HTP plus the booster and see what it does.

 

[lookbehindyou]

pictures in another post because the site eats them.

 

[Cotcha Yankinov]

while you're making a post I suggest constantly copying and pasting the text into a word editor, that way you don't lose all that you've written.

Please do look into the 5-HTP, but please note that there are sometimes rare side effects such as anxiousness and such. But it is most definitely worth trying, the tryptophan metabolism shifts/kynurenine pathway problems are known to cause serotonin deficiency and excitotoxicity at the same time (through NMDA). It is theorized to be a big player in neurodegenerative disease. I would consider stopping DXM on the days that you try 5-HTP however, DXM is a mild serotonin reuptake inhibitor.

https://en.m.wikipedia.org/wiki/TNF_inhibitor

They are used for demyelination diseases and these diseases involve the microglia so these drugs must have some effect on microglia even if it is very indirect.

The increases in GFAP could be a reactive astrogliosis response to all of the microglial cell death but it doesn't make sense why we aren't seeing increased numbers of astrocytes and hypertrophied end feet. But if this drug doesn't touch astrocytes that's very good, astrocytes are essential. Still a very dangerous drug. Exhaust your options first I think.

Since microglia are the main problem in multiple sclerosis I believe the literature regarding MS is very relevant here, I'll have to search for a recent review on MS "neuroinflammation" treatments but I suggest you do the same. I do seem to remember there are drugs out there that have dangerous hospital administration procedures but they are immunosuppressants. There are also probably various things you can antagonize that might result in breaking out of the positive feedback loop of inflammation.

Does prednisone help control the microglia?

I think we should look into the drugs used in MS and what they can do for neuroinflammation.

Best of luck, I hope you feel better soon.

 

[lookbehindyou]

Thank you for being so informative, i have to get a coffee


In MS, patients often recieve Interferon-beta. I heared once that it enhances the permability of the blood brain barrier which keeps out leukocytes, another time i heared it induces inhibition of t cell activation. It also has antiviral properties. All this contributes to the therapeutic effect in RRMS and i believe it also is a great cash cow. Since IFN-beta also activates the microglia, and the microglia itself can act neuroprotective, there should also lie a mechanism.
Then there's natalizumab. It keeps the white blood cells away from attacking nerve tissue. I do not have information about how the other agents modulate microglia but i can say that there's a number of MS patients that significantly profit from a low dose naltrexone, which is an TLR4 inhibitor. And TLR4 is a microglial receptor. By switching off microglia, ROS is automatically turned off too.
As is wrote i tested NTX by myself and it really impacted my ability to move and to think to the positive. I think there's a great number of long known chemical substances (like NTX) that don't get the attention they deserve. Nobody will do a big random double blind placebo controlled trial with substances which patent expired since 20 years to bring a drug on the market that sells for the price of bread. These trials cost millions and the pharma companies are not dumb.8)


//ps
prednisone has definitely an impact on the microglia, as i see in these two abstracts:


http://www.ncbi.nlm.nih.gov/pubmed/11708428
Subacute exposure to PDN induced anxiety and reactivity of microglia. The relevance of these features for patients using PDN remains to be elucidated.


http://www.ncbi.nlm.nih.gov/pubmed/12425433
These results suggest that chronic exposure to PDN produces learning and memory impairment, reduces neural viability, and increases glial reactivity in cerebral regions with these cognitive functions.


These TNF Inhibitors are really interesting, i know some of them but i have to work myself through it.
On monday i get a bottle of 5HTP to see how it works. I'll get back on DXM with and without 5HTP to see any differences. I was a DirectX c++ computer programmer and musician before treatment but lost the ability to think in structures and focus on different problems which is crucial in programming. Though it is a good marker for head performance and i'll see if there's a difference. i have to thank you for your understanding of this matter.95% of Doctors treat symptoms, not causes. You know way more than i about the subject :D thanks!

 

[Cotcha Yankinov]

I thought you might find it interesting that musicians tend to have larger corpus callosums and that learning music increases the size and connectivity of the corpus callosum. Most of the microglia are stored in the corpus callosum, it is known as the "fountain of microglia", it's theorized to be a good pathway for microglia to reach the rest of the brain. I wouldn't be surprised if increased brain activity (excitotoxicity?) in the corpus callosum has increase your risk of microglial activation. Have you ever considered something such as sodium valproate? I am very interested in this drug myself, I will have to learn more about what it might have to offer you sometime but it is a very interesting drug. Very neuroprotective.

I think there is a chance that calming your neurons might help the glial cells calm down as well. Especially if there is excitotoxicity I would say this is true, your glial cells could be reacting to excitotoxicity and something like sodium valproate could help with this, but valproate might help in other ways outside of this too. The GSK-3 interactions are far reaching but valproate has many neurotrophic effects to offer.

I absolutely agree with what you have to say about the pharma, I think there are many drugs that could be repurposed for different diseases but there just isn't money in it.

There have been multiple studies that highlight the importance of serotonin in regulating the immune system, I think it might be relevant to understand what the connections are and if you need more or less serotonin and of what kind. I seem to recall a study called "a dialogue between the immune system and brain spoken in the language of serotonin". There are many different kinds of receptors on different cells, dumb question but are there serotonin receptors interacting with microglia in some way? Even if indirect.

Your disease state might have been set off by IFN but there might be more than one way to shut down the microglia, even if it was not started in the opposite way that we shut it down.

The prednisone studies don't look promising then, though l suggest specifically exploring what it does for people with MS. I don't know if you really have something in the MS spectrum but I think it's a good kind of pathology to explore options for you with and the MS studies and drugs will be relevant to you.

Take care goodluck with the 5-HTP! I would try 200mg for a couple days before doubting it.

 

[Cotcha Yankinov]

Also I feel it's important to mention that you might have excess amyloid beta and similar plaques because of previous microglial activation but maybe your microglia aren't still activated very much. I think amyloid beta and the plaques/ neurofibrillary tangles are extremely important and could be a large portion of your problem. This would be unfortunate but it's a possibility we should consider. Can you tell me how old you are and how your sleeping habits have been throughout your life? Any history of neurodegenerative disease in the family? Also did you ever get Parkinsonism symptoms with neuroleptics? I hear that naltrexone inhibits the dopamine projections (this is efficacy for alcoholism) and I wonder if some of your movement problems were due to a shortage of dopamine.

Have you ever been on solely neuroleptics such as haldol without benztropine?

A lot of the pathology of Parkinson's overlaps with Alzheimer's.

I would consider the possibility that you have pathology more similar to Alzheimer's and such rather than MS.

 

[Cotcha Yankinov]

I would MOST DEFINITELY look into GSK-3. It could be the key here. Even just reviewing the Wikipedia on GSK-3 it looks very promising for controlling inflammation and plaques.

 

[lookbehindyou]

i'm 27 and i remember being on sodium valproate. I remember that it was shortly after the IFN administation ended and that it really helped with the muscle spasms, they gave me hands full of lorazepam and i remember being in a state of total confusion but the sodium valproate was good. I stopped it because i always tried to get well without any drugs because it affected my gameplay on instruments. well, we don't have parkinsonism, alzheimer or any other neurodegenerative disease in our family tree as well as i know. We have cases of depression in the family whichi doesn't affect the brain pathology. I was short on Haldol and switched to Risperidone to get over the psychosis that manifested with the time. On IFN i was on Dipiperone all day which is similar to Haldol. Before IFN i was sleeping like a baby and after it, every night was pure terrorism. Until i explored Curcumin, Naltrexon and DXM. With it i sleep normal and good, nightmares are still present but i don't care. The possibility that A-beta is present could be true, that would be totally devastating but i can't test it. My theory is that the IFN made the microglia super sensitive, like a gun that gets loaded. When you load a gun it's armed all day. The same goes for the microglia, the IFN armed them like mines and now they react to chemicals, stress et cetera. But it's just a theory of mine.Sorry i don't have knowledge about 5HT and Microglia connectivity, i think there is a connection somehow but more indirect than direct.i hope this helps

 

[lookbehindyou]

the movement problems were indeed a shortage of dopamine, as you say that! i was given L-DOPA to control the spasms and though they gave me not much it was a world of difference. I experience movement problems as soon as i quit either the DXM or the curcumin. sorry my head is spinning so fast, i have to take a nap

 

[Cotcha Yankinov]

https://en.m.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase

Read through "function" on that Wiki!!!!! An IDO inhibitor might be just what you need, though for now 5-HTP might at least help with the tryptophan shortage. A lot of dopamine fires through serotonin heterodimers, you might be running low on dopamine in some brain projections because of tryptophan shortage. Have you given COX 2 inhibitors a decent try?

Are the movement problems that were solved by L dopa that same movement problems that are solved by DXM/curcumin? DXM could be affecting dopamine through one or more pathways (sigma/NMDA?) and curcumin could be affecting dopamine through increased serotonin from inhibition of IDO.

http://www.ncbi.nlm.nih.gov/m/pubmed/14592780/

I think depression can be far more chemical than psychological in many cases, most often depression is caused by inflammation or shifts in tryptophan metabolism related to kynurenine pathway dysfunction, and out of kynurenine pathway dysfunction you get not only serotonin shortages but quinolinic acid which is an excitotoxicic NMDA agonist. Curcumin is an IDO inhibitor that was suggested by another bluelight member (with a study behind it) to be helpful for kynurenine pathway problems because of its effect on IDO. I can't find the darn post though. DXM on the other hand has so many different effects it's really hard to say what's causing what.

Anyways I would say that depression physiology in the family (even if their depression was triggered by something bad happening in their lives) does have implications for your pathology, you might be running high on inflammation and thus were predisposed to problems from microglia activation.

I still think GSK-3 is another interesting target to look into as well.