Resource PLX3397: let's kill off the microglia!

loki

Well-Known Member
wow, that account activation went fast! is it possible to send PMs? I have CFS from high continous dosages of peg Interferon alpha2 for 12 weeks. It's like my brain is fried. I had success with tumeric in form of a high bioavailable capsule but i want a complete healing. My theory is, that the CNS innert immune cells, microglia, got primed through the Interferon and now go haywire, produce reactive oxygen species, interferons and so on and that is attacking the nerve cell tissue, leading to symptoms. The point is, if i could afford $10.800 i would buy 37.000 mg of PLX3397. That's a microglia killer. The surprising thing is, that after a microglia eradication after 21 days of treatment, a new microglia set appears after 21 days of recovery!
There are some articles in the internet that cover the story.
INFLM2.jpg
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
wow, that account activation went fast! is it possible to send PMs? I have CFS from high continous dosages of peg Interferon alpha2 for 12 weeks. It's like my brain is fried. I had success with tumeric in form of a high bioavailable capsule but i want a complete healing. My theory is, that the CNS innert immune cells, microglia, got primed through the Interferon and now go haywire, produce reactive oxygen species, interferons and so on and that is attacking the nerve cell tissue, leading to symptoms. The point is, if i could afford $10.800 i would buy 37.000 mg of PLX3397. That's a microglia killer. The surprising thing is, that after a microglia eradication after 21 days of treatment, a new microglia set appears after 21 days of recovery!
There are some articles in the internet that cover the story. View attachment 853
:)

How interesting. Do you mind if I ask if you had hepatitis? I don't know if you know but Andrew Miller at Emory University has found the same brain dysfunction involving the basal ganglia in people taking interferon for hepatitis as in ME/CFS. He's found that dopamine gets whacked in both diseases and some evidence suggests that the brain becomes hypersensitive to inflammation.

In fact interferon can so wipe people out that it was interferon that demonstrated to researchers that the immune system causes "sickness behavior". Not everyone who gets interferon gets ME/CFS but a significant number come down with something similar. I didn't know that it lasted past the interferon treatment period though.

I will definitely check out PLX3397..

That's good news about the fast-turning over microglia :)
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
:)

How interesting. Do you mind if I ask if you had hepatitis? I don't know if you know but Andrew Miller at Emory University has found the same brain dysfunction involving the basal ganglia in people taking interferon for hepatitis as in ME/CFS. He's found that dopamine gets whacked in both diseases and some evidence suggests that the brain becomes hypersensitive to inflammation.

In fact interferon can so wipe people out that it was interferon that demonstrated to researchers that the immune system causes "sickness behavior". Not everyone who gets interferon gets ME/CFS but a significant number come down with something similar. I didn't know that it lasted past the interferon treatment period though.

I will definitely check out PLX3397..

That's good news about the fast-turning over microglia :)
Yes, you should be able to send PM's.
 

loki

Well-Known Member
hi! I'm from germany
Yes, i had HCV for 5 years and eagerly waited for new drugs to come out of the pipelines. So, after the 5 years there was a new drug out called Sovaldi(Sofosbuvir) and it reduced the IFN, Ribavirin cocktail treatment time from 6-12months with 60% chance of clearance to 12 weeks treatment time with a chance of 95% to clear the virus. Unfortunatley i wasn't aware of the fact that Interferon is really really hard stuff. I asked my doctor about the heart breaking storys about Interferon and that it destroys peoples lives but he didn't care much. He said you just have some 'flu like symptoms' that you get over after some time. here's the script, just take Tylenol.
I was left with flu like symptoms. And hallucinations, depersonalization, bottomless dark deep depression, blurred vision, black outs, tinnitus, balance problems, memory problems (so much) and more...
After 12 months i went crazy and had to check in mental healthcare. They brought me down with hands full of lorazepam and other tranquilizers but my state doesn't change much. I'm in bed most of the day, don't speak to people because i can't form sentences, i lost my hobbys, i lost my occupation (programmer in c++), i lost my mind, my soul, my shape... there isn't much to live for now. It's really sad but i try so hard to find a solution to get back to the one i was before i sticked the Interferon needle in my belly
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
hi! I'm from germany
Yes, i had HCV for 5 years and eagerly waited for new drugs to come out of the pipelines. So, after the 5 years there was a new drug out called Sovaldi(Sofosbuvir) and it reduced the IFN, Ribavirin cocktail treatment time from 6-12months with 60% chance of clearance to 12 weeks treatment time with a chance of 95% to clear the virus. Unfortunatley i wasn't aware of the fact that Interferon is really really hard stuff. I asked my doctor about the heart breaking storys about Interferon and that it destroys peoples lives but he didn't care much. He said you just have some 'flu like symptoms' that you get over after some time. here's the script, just take Tylenol.
I was left with flu like symptoms. And hallucinations, depersonalization, bottomless dark deep depression, blurred vision, black outs, tinnitus, balance problems, memory problems (so much) and more...
After 12 months i went crazy and had to check in mental healthcare. They brought me down with hands full of lorazepam and other tranquilizers but my state doesn't change much. I'm in bed most of the day, don't speak to people because i can't form sentences, i lost my hobbys, i lost my occupation (programmer in c++), i lost my mind, my soul, my shape... there isn't much to live for now. It's really sad but i try so hard to find a solution to get back to the one i was before i sticked the Interferon needle in my belly
OMG Loki - what a story.

I know someone with ME/CFS who took Interferon and he lost several years because of it. He just went down! Mood disorders are common with IFN treatment. Again, IFN really showed the medical world how the immune system was contributing to "sickness behavior" - flu-like symptoms and mood disorders. They are trying to figure out which patients will have a back reaction to IFN but lots more research needs to be done.

Another way to get ME/CFS! This is the first time I've heard of IFN doing this but I'll bet there are plenty of stories out there.

Hang in there man! Keep searching and know you are not alone!
 

loki

Well-Known Member
thank you it's sad on one side but good to know on the other, that there are people out that have the same symptomatic.
I think it's the same system in nearly every CFS case. Wether it's caused by IFN or by infection or by vaccination, there's always a deeper cause that drives the symptoms and i begin to believe that the bottom cause of the symptom is an immune system gone haywire. But not the body's immune system... the brain immune system!
I think it was you who wrote an article about microglia priming and what it does to the brain. And i really believe that's the cause!
Viruses who infiltrate the CNS cause different reactions in the chemical environment in the brain. These cells, microglia, they patrol through the nerve tissue and constantly search for pathogens like bacteria, amyloid.. and viruses. So, as soon as a virus particle is discovered by the microglia, they get active and produce an array of chemicals to destroy the virus RNA. That's the CNS defense mechanism. edit// and the chemicals that destroy the virus also cause damage to the nerve tissue and drive symtoms. I speak of reactive oxygen species like Nitrous Oxide...So, if the activation of the microglia is constant over a long period of time, the state of the micrgolia changes. From sleeping and sometimes active to always active. That's called microglia priming. And as soon as these cells are primed there's no way back. Microglia cells originate from the yolk sac in early development. They colonize the CNS before the blood brain barrier is formed! The PLX3397 chemical wiped out the microglia and their resettlement of the CNS does not originate from the bloodstream! The wipeout revealed a microglia progenitor INSIDE the nerve tissue! That reveals the biggest stem cell pool ever found!:woot::D
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
thank you it's sad on one side but good to know on the other, that there are people out that have the same symptomatic.
I think it's the same system in nearly every CFS case. Wether it's caused by IFN or by infection or by vaccination, there's always a deeper cause that drives the symptoms and i begin to believe that the bottom cause of the symptom is an immune system gone haywire. But not the body's immune system... the brain immune system!
I think it was you who wrote an article about microglia priming and what it does to the brain. And i really believe that's the cause!
Viruses who infiltrate the CNS cause different reactions in the chemical environment in the brain. These cells, microglia, they patrol through the nerve tissue and constantly search for pathogens like bacteria, amyloid.. and viruses. So, as soon as a virus particle is discovered by the microglia, they get active and produce an array of chemicals to destroy the virus RNA. That's the CNS defense mechanism. edit// and the chemicals that destroy the virus also cause damage to the nerve tissue and drive symtoms. I speak of reactive oxygen species like Nitrous Oxide...So, if the activation of the microglia is constant over a long period of time, the state of the micrgolia changes. From sleeping and sometimes active to always active. That's called microglia priming. And as soon as these cells are primed there's no way back. Microglia cells originate from the yolk sac in early development. They colonize the CNS before the blood brain barrier is formed! The PLX3397 chemical wiped out the microglia and their resettlement of the CNS does not originate from the bloodstream! The wipeout revealed a microglia progenitor INSIDE the nerve tissue! That reveals the biggest stem cell pool ever found!:woot::D
Interesting...very interesting....

Ya - I would put my money on immune activation in the brain. Really looking forward to the brain inflammation studies. I think the Japanese one has probably already started and Van Elzakker has started his CNS inflammation study as well.

Crossing my fingers something big pops up! If it does we're in pretty damn good company because neuroinflammation is big in other diseases as well.
 

loki

Well-Known Member
you're absolutely right. neuroinflammation drives so many other diseases like AD, MS, Parkinson et al. it's amazing!
 

loki

Well-Known Member
i don't know! :woot:
It sure would have some kind of effect but it will be hard to find a doctor that's writing me a script i guess...
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
you're absolutely right. neuroinflammation drives so many other diseases like AD, MS, Parkinson et al. it's amazing!
That's why we have to keep an eye on treatments for those diseases. This is off the track of this thread but someone emailed me and said that after she was misdiagnosed with MS she did great on Cepalazone or whatever it is. She felt great for 6 weeks - fatigue was much reduced - and then had an allergic reaction to the drug.

Later they decided she had ME/CFS - not MS. I'll have a blog on this coming out.
 
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Cort

Founder of Health Rising and Phoenix Rising
Staff member
cephalosporine? the antibiotic? I can't find it:woot:
Sorry - Copaxone -

This medication is used to treat a certain type of multiple sclerosis (relapsing multiple sclerosis-MS). It is a protein that is thought to work by preventing your immune system from attacking the nerves in your brain and spinal cord. This effect can decrease the number of periods of disease worsening (relapses) and prevent or delay disability. It is not a cure for MS.
It didnt do particularly well in MS trial but it really well for her


Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids found in myelin basic protein. The mechanism of action for glatiramer acetate is unknown. Administration of glatiramer acetate shifts the population of T cells from proinflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response.[11] Given its resemblance to myelin basic protein, glatiramer acetate may also act as a decoy, diverting an autoimmune response against myelin. The integrity of the blood brain barrier, however, is not appreciably affected by glatiramer acetate, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of multiple sclerosis exacerbations.[12]

The mechanism(s) by which glatiramer acetate exerts its effects in patients with Multiple Sclerosis (MS) is (are) not fully elucidated. However, it is thought to act by modifying immune processes that are currently believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a condition induced in several animal species through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.[13]
 

Paw

Well-Known Member
Re minocycline: I've noticed it's cheaply available through overseas pharmacies, but I've been wary of trying it, not knowing the risk of unintended consequences. But there do seem to be solid studies supporting its positive effects on brain inflammation.

Re misdiagnosis of MS: As this is apparently a fairly common occurrence, I'm wondering what the downsides are for someone with ME moving forward on an MS protocol. Cort's copaxone example seems inconclusive, since the ME patient turned out to be allergic.

In preparing for a brain MRI (which has been ordered for me but not yet scheduled) I'm finding two-year-old research that points to an imaging profile specific to ME (e.g., certain white-matter proportions, as well as distribution, pattern, and size of lesions), distinct from MS.

Any advice from people who have experience reading MRIs -- so I know what to look for?
 

loki

Well-Known Member
I would love to try out minocyclin just for fun but i can't get any money at the moment:bag: if someone sends me some minocyclin i would try it out and write down and post my experience here;)
 

loki

Well-Known Member
I have some info on Microglia and their elimination

Microglia are the primary immune cells of the CNS, and are highly similar to peripheral macrophages. They act as the major inflammatory cell type in the brain, and respond to pathogens and injury by becoming “activated” – a process whereby they rapidly change morphology, proliferate and migrate to the site of infection/injury where they phagocytose and destroy pathogens as well as remove damaged cells. As part of their response they secrete cytokines and chemokines, as well as prostaglandins, NO and reactive oxygen species, which help to elevate and direct the immune response. Additionally, they are instrumental in the resolution of the inflammatory response, through the production of anti-inflammatory cytokines such as Il-10. While seeking out and destroying pathogens is an important and protective role, microglia have also been extensively studied for their harmful roles in neurodegenerative diseases and brain injuries, such as Alzheimer’s disease, Parkinson’s disease, ischemic injury, and traumatic brain injuries.
We have discovered that microglia in the adult brain are fully dependent upon Colony-Stimulating Factor 1 receptor (CSF1R) signaling for their survival, and that we can take advantage of this dependency through the administration of specific CSF1R inhibitors that cross the blood brain barrier. Administration of CSF1R inhibitors results in the rapid elimination of microglia from the adult brain – within 7 days of continuous treatment ~80% of all microglia are eliminated, and by 21 days of continual treatment >95% of all microglia are eliminated.

MCG.jpg


The above image shows sections through 2-month old wild-type mice that have been treated with the CSF1R inhibitor PLX3397 for 21 days. Each microglia has been marked with a white dot, showing the remarkable and sustained elimination of microglia from the entire CNS with CSF1R inhibitors. Microglia remain eliminated for as long as we continue CSF1R inhibitor treatment. Thus, our finding allows for rapid and sustained elimination of microglia from the adult brain regardless of age or genotype and permits studies into microglial function that have not been previously possible.
Mice depleted of microglia are healthy, fully viable, and have no measurable or obvious defects. Furthermore, no impairments in behavior, cognition or motor function result from long-term microglial-elimination, showing that microglia are not overtly necessary for these functions in the adult brain. We are continuing to study the consequences of microglial-elimination and in doing so uncover some of the functions of microglia in the healthy brain.
Microglia are negatively implicated in Alzheimer’s disease. Parkinson’s disease, Huntington’s disease, Frontal Temporal dementias, ALS, Traumatic Brain Injuries, Ischaemic Strokes, Epilepsy, and many more. Thus, this approach can be applied to a number of conditions as a potential therapeutic, but can also be used to understand the role of microglia in these diseased states, as well as in the healthy adult brain.
 

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