Ampicillin increases GLT-1 expression

Hip

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@nandixon
Well spotted. So we can perhaps assume a factor of 2 increase in GLT-1expression from telmisartan. I think telmisartan is the only ARB proven to cross the blood-brain barrier. And if I remember rightly, the jury is still out on how well losartan crosses the BBB. Olmesartan (Benicar) crosses the BBB poorly.

I guess this 2-fold increase in GLT-1 is less that the 3 to 4-fold increase that some antibiotics achieve, but ARBs are probably better drug to take on along term basis.



I have tried a number of ARBs in the past. Most notably my 2 month trial of Benicar, to try out the Marshall Protocol (MP). This involved taking 40 mg of Benicar 3 times a day.

I did not take antibiotics on my version of the MP, as I think my ME/CFS is most likely underpinned by an intracellular non-cytolytic enterovirus infection, rather than an intracellular bacterial infection that Trevor Marshall assumes is responsible for a whole raft of chronic diseases.

Interestingly, cathelicidin, one of the two intracellular antimicrobial peptides the MP is supposed to up-regulate inside the cell, enables TLR-3 to respond to dsRNA. This may be useful, because the non-cytolytic enteroviruses linked to ME/CFS are in part thought to comprise dsRNA, and TLR-3 senses the presence of viral dsRNA in a cell, and then triggers the interferon response to destroy this dsRNA.

So conceivably, by inducing cathelicidin (which Benicar does via VDR activation), Benicar may usefully ramp up the interferon response against non-cytolytic enteroviruses. And in fact there are studies showing that ARB drugs due seem to ameliorate enterovirus infections:

This study found that Benicar reduced the number of viral genomes found in acute coxsackievirus B myocarditis (which enterovirus experts think may be a good model to study the coxsackievirus B infections found in ME/CFS).

Losartan was found to ameliorate chronic coxsackievirus B myocarditis (in chronic CVB myocarditis, there are no viral particles, only the intracellular non-cytolytic enteroviruses).

I wonder whether taking Benicar intranasally might increase BBB penetration, and so help target any coxsackievirus B infections in the brain. Or possibly switch to losartan, which probably more easily crosses the BBB.

Here are the estimated VDR activation abilities of various ARBs:
KI Receptor Affinity Values.png

You see that telmisartan binds to the VDR strongly (as it has the lowest Ki value for the VDR). Olmesartan (Benicar) binds to the VDR less strongly.




I found that I did become pretty light sensitive after two months on the MP, the most common side effect of the MP. I had to wear sunglasses on sunny days. I am not sure if that response indicates the MP was working. I wonder if healthy people would also become light sensitive if they took this dose level of Benicar.

Other than that I found no other side effects from the MP. I don't think my ME/CFS was improved after two months on the MP, but I did get the impression that my anhedonia and blunted affect (emotional flatness) symptoms were slowly improved by the MP. These anhedonia symptom I have as a comorbid condition to ME/CFS; they seemed to be triggered by the virus that precipitated my ME/CFS.

I also tried telmisartan, as it crosses the BBB easily, but interestingly this had the opposite effect, and worsened my anhedonia after just 2 days of 40 mg daily. I felt an unpleasant sort of mental anhedonic numbness with telmisartan, so I stopped it. I repeated this a few times, but got the same results.


Benicar is probably something I should try again, because the last time I tried it was 5 or 6 years ago. And you are supposed to do the MP for longer than just 2 months.
 
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nandixon

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@Hip, thanks!

That's interesting about the intranasal idea. I'd also seen this study here where they tried intranasal losartan in a mouse model, hoping to get a therapeutic effect in the brain at a lower dose than the ARB is typically used at to avoid its blood pressure-lowering effect. It seems like it might have some promise:

Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease

Just to mention that in the table of Ki's developed from the computer modeling that Marshall did, the values need to be looked at in a reverse way. So that the smaller the Ki, the greater the affinity the drug has at a particular receptor. So telmisartan would be the most potent for binding at the VDR.

I was wondering if you've had a chance to try ampicillin yet? I'm hoping to try both that and losartan in the next few weeks.
 
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Hip

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@nandixon
Many thanks for pointing out that error interpreting the Ki values. I have now edited my post to correct this.


I've tried both ampicillin and amoxicillin, for short periods.

Amoxicillin I took for four days at 6 grams per day (in three divided doses of 2000 mg). I read here that 6 grams in divided amounts is the maximum daily dose for amoxicillin. Other sources said 4 grams is the maximum daily dose.

On a different occasion, I took ampicillin (on empty stomach) for four days at 500 mg once daily. Though here you see that doses of 500 mg three times a day are used.

I did not notice any spectacular effects after four days on these antibiotics, but I noticed a reduction in anxiety, and more emotional and enthusiastic engagement while watching TV programs (I have blunted affect, which reduces emotional responses).

In terms of up-regulation of the GLT-1 protein expression induced by these antibiotics, this seems to occur quickly, within a couple of days:
Fifteen different β-lactam antibiotics, including penicillin and its derivatives, as well as cephalosporin antibiotics, were highly active in stimulating GLT1 protein expression (Fig. 1d). Increased expression could be seen as early as 48 h after drug treatment.

Source: β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression
So after my four days on these antibiotics, I am assuming that the up-regulation in my GLT-1 expression should have reached its maximum. However, I should really try these antibiotics for longer periods, just in case the up-regulation is slower than the study suggests.

If you look at figure 1d of that above-quote paper, you see that amoxicillin and penicillin are the most potent inducers of GLT-1 protein expression. Here is figure 1d (rotated around) for reference:
β-lactam antibiotics increase GLT-1.png


I happened to have some amoxicillin and ampicillin already, so that's why I tried these. Amoxicillin is quite cheap: you can get 500 x 500 mg capsules for around $60.
 

Hip

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Note that neurotoxicity can occur with antibiotics, especially if there is central nervous system disease, or renal insufficiency. See this paper: Neurotoxic effects associated with antibiotic use: management considerations. Kidney problems can result in antibiotics not being cleared from the blood as fast, allowing them to build up to neurotoxic levels.

I mention this as @physicsstudent13 said that after taking several antibiotics (rocephin, gentamicin, ampicillin, tinidazole, roxithromycin and doxycyline) recently, he developed severe aphasia and problems pronouncing words and processing words, and thinks it was from neurotoxic brain damage caused by one or more of these antibiotics.
 
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Hip

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I have just completed another course of amoxicillin: this time I did 10 days taking 2 grams of oral amoxicillin twice daily. This again was in order to try to increase glutamate transporter expression in the brain. Amoxicillin has reasonable blood-brain barrier penetration.

I cannot say that I have noticed much improvements during or after those 10 days. My anxiety was lower, which may be due to amoxicillin improving glutamate transport, thus better pumping out glutamate from the extracellular spaces in the brain (anxiety has been linked to glutamate).

But apart from that, my ME/CFS symptoms appear to be about the same.

Of course, it could be that this amoxicillin protocol of increasing glutamate transporter expression will work for some ME/CFS patients, but not others. One can speculate that some ME/CFS patients may have high extracellular glutamate levels, and in those patients, this amoxicillin protocol might provide benefits.
 

btdt

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@nandixon it is rs1114620 (GG) and I thought I had another one somehow linked to "glutamate" which I can not find / remember at the moment.

@physicsstudent13 I also feel a lot better if I adjust my diet- although it is not a cure. My "ideal" diet so far is close to paleo although potatoes and whole grains is also fine for me but on the other hand some types of vegetable not e.g. cabbage.

Thanks for the article! This looks interesting! I need some more time to read it in detail- what I have just seen: they say "Increased expression could be seen as early as 48h after drug treatment"...??
My rs1114620 is TT I am thinking this is the same as GG maybe but I very new to this so am not sure. Does this mean I will have high glutamate too?
 

btdt

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I have just completed another course of amoxicillin: this time I did 10 days taking 2 grams of oral amoxicillin twice daily. This again was in order to try to increase glutamate transporter expression in the brain. Amoxicillin has reasonable blood-brain barrier penetration.

I cannot say that I have noticed much improvements during or after those 10 days. My anxiety was lower, which may be due to amoxicillin improving glutamate transport, thus better pumping out glutamate from the extracellular spaces in the brain (anxiety has been linked to glutamate).

But apart from that, my ME/CFS symptoms appear to be about the same.

Of course, it could be that this amoxicillin protocol of increasing glutamate transporter expression will work for some ME/CFS patients, but not others. One can speculate that some ME/CFS patients may have high extracellular glutamate levels, and in those patients, this amoxicillin protocol might provide benefits.
I find I get red skin rash reaction to amoxicillin after 3 to four days?

Similar reaction I had to Septrin years ago back in 70s?

Could these reactions be from reactivation of herpes viruses as in DRESS or DISS?
 
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@nandixon
Many thanks for pointing out that error interpreting the Ki values. I have now edited my post to correct this.


I've tried both ampicillin and amoxicillin, for short periods.

Amoxicillin I took for four days at 6 grams per day (in three divided doses of 2000 mg). I read here that 6 grams in divided amounts is the maximum daily dose for amoxicillin. Other sources said 4 grams is the maximum daily dose.

On a different occasion, I took ampicillin (on empty stomach) for four days at 500 mg once daily. Though here you see that doses of 500 mg three times a day are used.

I did not notice any spectacular effects after four days on these antibiotics, but I noticed a reduction in anxiety, and more emotional and enthusiastic engagement while watching TV programs (I have blunted affect, which reduces emotional responses).

In terms of up-regulation of the GLT-1 protein expression induced by these antibiotics, this seems to occur quickly, within a couple of days:


So after my four days on these antibiotics, I am assuming that the up-regulation in my GLT-1 expression should have reached its maximum. However, I should really try these antibiotics for longer periods, just in case the up-regulation is slower than the study suggests.

If you look at figure 1d of that above-quote paper, you see that amoxicillin and penicillin are the most potent inducers of GLT-1 protein expression. Here is figure 1d (rotated around) for reference:
View attachment 10873

I happened to have some amoxicillin and ampicillin already, so that's why I tried these. Amoxicillin is quite cheap: you can get 500 x 500 mg capsules for around $60.
Wouldnt this Pic suggest that Penicilin might be even better at managing glutamate expression than Amoxicilin or Rocephin?
 

Hip

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Wouldnt this Pic suggest that Penicilin might be even better at managing glutamate expression than Amoxicilin or Rocephin?
The figure in question is from an in vitro study, and the actual in vivo potency would depend on factors such as dose, antibiotic bioavailability and plasma protein binding. So hard to tell which would be the most potent in vivo.