minocycline - the only antioxidant neuroprotective antibiotic i have seen

asecin · Apr 14, 2017

this one confused the hell out of me, the only antibiotic i have seen that has such potent antioxidant effect of any ever described out there. just read many of its sources; https://en.wikipedia.org/wiki/Minocycline#Anti-inflammatory_and_neuroprotective

so many, reliable sources even thought its wikipedia. this stuff is mind blowing for the antibiotics, which are known toxins. what the hell gives, how do you just replace it with something similar thats easily obtainable? since its semi synthetic, it has natural sources, which are they??

asecin · Apr 14, 2017

this is amazing; https://www.ncbi.nlm.nih.gov/pubmed/28391017

i was about to get into ketamine studies for depression, but fell short. anyway, ketamine is one of the most promising antidepressants of the current generation and YET, prethreatment with minocycline might prevent some neurodegenerative problems associated with it. amazing find, and its one of the newest studies out there! now now, before the bash, i understand its neonatal RATS, but check this "Minocycline exerts neuroprotection against a wide range of toxic insults in neurodegenerative diseases models"

if it helps the neonatal brain and others cannot, which are likely the future of antidepressant medicine, then what does that really say about minocycline??

asecin · Apr 15, 2017

what im interested in knowing is, how is this antibiotic so much different than others and how come no other antibiotic has this neuroprotective activity this one has?

Charles_Voynich · Apr 15, 2017

asecin said:
this is amazing; https://www.ncbi.nlm.nih.gov/pubmed/28391017

i was about to get into ketamine studies for depression, but fell short. anyway, ketamine is one of the most promising antidepressants of the current generation and YET, prethreatment with minocycline might prevent some neurodegenerative problems associated with it. amazing find, and its one of the newest studies out there! now now, before the bash, i understand its neonatal RATS, but check this "Minocycline exerts neuroprotection against a wide range of toxic insults in neurodegenerative diseases models"

if it helps the neonatal brain and others cannot, which are likely the future of antidepressant medicine, then what does that really say about minocycline??

I actually wasn't aware of any neurodegenerative effects of ketamine in adult animals (including humans). Make sure you draw a distinction here between neonatal exposure and adult exposure; neonatal exposure to almost anything on the planet is usually detrimental in some way. As far as my research goes, ketamine is one of the absolute safest drugs you can give a person, with the only long-term side effect I'm aware of being some mild nephrotoxicity.

serotonin2A · Apr 15, 2017

Charles_Voynich said:
As far as my research goes, ketamine is one of the absolute safest drugs you can give a person, with the only long-term side effect I'm aware of being some mild nephrotoxicity.

Ketamine is certainly a relatively safe anesthetic drug, but it is far from being one of the safest drugs you could administer to a patient. The safety of ketamine as an anesthetic is offset by the possibility of severe emergence reactions, although that property can be mitigated by proper pretreatment. There are a variety of concerns about neural alterations produced by acute and chronic administration, including cortical atrophy (1), Olney's lesions (2), and changes in parvalbumin expression (3,4,5). There can also be a deterioration of mental health after chronic use of ketamine, including apparently dependence-like phenomena and chronic behavioral disturbances. Some of these effects are not conclusive, and ketamine is relatively safe, but not one of the safest drugs.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713393/

2. Olney JW, Latruyere J, Price M.(1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science; 244:1360-1362

3. https://www.ncbi.nlm.nih.gov/pubmed/15183509

4. https://www.ncbi.nlm.nih.gov/pubmed/24973145

5. http://www.psy-journal.com/article/S0165-1781(15)30646-6/abstract

Charles_Voynich · Apr 15, 2017

serotonin2A said:
Ketamine is certainly a relatively safe anesthetic drug, but it is far from being one of the safest drugs you could administer to a patient. The safety of ketamine as an anesthetic is offset by the possibility of severe emergence reactions, although that property can be mitigated by proper pretreatment. There are a variety of concerns about neural alterations produced by acute and chronic administration, including cortical atrophy (1), Olney's lesions (2), and changes in parvalbumin expression (3,4,5). There can also be a deterioration of mental health after chronic use of ketamine, including apparently dependence-like phenomena and chronic behavioral disturbances. Some of these effects are not conclusive, and ketamine is relatively safe, but not one of the safest drugs.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713393/

2. Olney JW, Latruyere J, Price M.(1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science; 244:1360-1362

3. https://www.ncbi.nlm.nih.gov/pubmed/15183509

4. https://www.ncbi.nlm.nih.gov/pubmed/24973145

5. http://www.psy-journal.com/article/S0165-1781(15)30646-6/abstract

Alright, then I guess you and I disagree on the definition of "safe". I wasn't really thinking of psychiatric side-effects, more in terms of the overall physical safety of the drug. As for your sources, I'm always wary of any kind of MRI study as most of them seem to be absolute crap, and I'm also not really ready to buy into one of Olney's studys from 1989. The parvalbumin issue is a concern for sure, however I counter your last reference with this:

http://www.nature.com/tp/journal/v5/n9/full/tp2015136a.html

serotonin2A · Apr 15, 2017

Charles_Voynich said:
Alright, then I guess you and I disagree on the definition of "safe". I wasn't really thinking of psychiatric side-effects, more in terms of the overall physical safety of the drug. As for your sources, I'm always wary of any kind of MRI study as most of them seem to be absolute crap, and I'm also not really ready to buy into one of Olney's studys from 1989. The parvalbumin issue is a concern for sure, however I counter your last reference with this:

http://www.nature.com/tp/journal/v5/n9/full/tp2015136a.html

The ability of ketamine to alter PV expression arguably reflects on the physical "safety" of ketamine.

I'm not following how the reference you cited counters the other publication -- both papers showed that S- but not R-ketamine produces effects on PV interneurons. There is definitely interest in the possibility of using R-ketamine as an antidepressant. However, I'm not sure how the relative safety of R-ketamine addresses whether ketamine itself is a safe drug.

The silver staining methods origionally used to detect degeneration following Olney's lesions still represent the most reliable method for visualizing degenerating soma, axons, and terminals. There were many other publications that confirmed the effect, and there is a consensus in the literature that ketamine and other NMDA-R antagonists can induce Olney's lesions in rodents. The controversy has always been regarding whether such effects occur in humans, and I think it is probable that humans do not experience Olney's lesions. However, given that the effects of NMDA-R antagonists on PV interneurons follow the same basic mechanism as Olney's lesions, I think there is some reason to be concerned about more subtle effects on cortex. Which is why the MRI observations should probably not be dismissed so casually.

As I said, none of this is conclusive in humans. But even if you completely disregard such fears, there is always the bladder damage. Asprin and caffeine are generally recognized by toxicologists as being extremely safe drugs and I would argue that ketamine does not have the same safety profile.

Cotcha Yankinov · Apr 15, 2017

Charles_Voynich said:
with the only long-term side effect I'm aware of being some mild nephrotoxicity.

I was under the impression that the neurogenic bladder can get pretty bad in abusers or people with preexisting urinary issues

asecin · Apr 15, 2017

ok, the topic was about an antibiotic that is pretty interesting, but thanks for the amazing chat about ketamine

Charles_Voynich · Apr 17, 2017

serotonin2A said:
The ability of ketamine to alter PV expression arguably reflects on the physical "safety" of ketamine.

I agree.

I'm not following how the reference you cited counters the other publication -- both papers showed that S- but not R-ketamine produces effects on PV interneurons. There is definitely interest in the possibility of using R-ketamine as an antidepressant. However, I'm not sure how the relative safety of R-ketamine addresses whether ketamine itself is a safe drug.

If the stereoisomer which is responsible for antidepressant effects is found to not produce the same neurodegeneration as the racemate, I would consider use of R-ketamine as an antidepressant as safe. Obviously there are issues, which is why we need to pin down exactly which isomer is responsible for what effects and what negative effects each one produces independently. You're free to disagree, but I'm all about taking these drugs with therapeutic value and perfecting them through medicinal chemistry until we can confidently use them in humans.

However, given that the effects of NMDA-R antagonists on PV interneurons follow the same basic mechanism as Olney's lesions, I think there is some reason to be concerned about more subtle effects on cortex. Which is why the MRI observations should probably not be dismissed so casually.

NDMA receptor antagonism is not necessary for ketamine's antidepressant effects, which makes this inconsequential.

https://www.ncbi.nlm.nih.gov/pubmed/27144355

As I said, none of this is conclusive in humans. But even if you completely disregard such fears, there is always the bladder damage. Asprin and caffeine are generally recognized by toxicologists as being extremely safe drugs and I would argue that ketamine does not have the same safety profile.

Considering that racemic ketamine is at phase III clinical trials, I think that decision is now in the hands of the FDA.

Cotcha Yankinov · Apr 17, 2017

Charles_Voynich said:
NDMA receptor antagonism is not necessary for ketamine's antidepressant effects, which makes this inconsequential.

https://www.ncbi.nlm.nih.gov/pubmed/27144355

I feel like this needs to be replicated in humans though, especially if pure NMDA antagonists function as temporary antidepressants in humans, and I seem to remember something about other NMDA antagonists being investigated for depression.

Maybe there is synergy between NMDA antagonism -> glutamate release and HNK's upregulation of AMPA, or synergy between psychoactive effects and HNK.

Charles_Voynich · Apr 17, 2017

Cotcha Yankinov said:
... especially if pure NMDA antagonists function as temporary antidepressants in humans...

I've never seen any study which suggests selective NMDA receptor antagonists are useful antidepressants, either in animals or in humans.

EDIT: I should probably expand on this a bit. There are a number of NMDA receptor antagonists which do not produce an antidepressant effect in animals or humans. Dr. Ronald Duman (pretty much the world's expert on ketamine and depression) has a great review that outlines his proposed mechanism underlying ketamine's antidepressant effects: https://www.ncbi.nlm.nih.gov/pubmed/26937618. Though it's a great review, I have some serious qualms with his explanation of the mechanism. The crux of his hypothesis is that ketamine binds to NMDA receptors on GABA-ergic interneurons, causing a glutamate release which ultimately induces mTOR signaling and BDNF release, and thus the antidepressant actions.

However, I see no reason with this mechanism why any NMDA receptor antagonist shouldn't work, when many of them do not. There's some limited evidence to suggest that Sigma1R agonists can facilitate BDNF release on their own, and many of them have been shown to possess mild antidepressant effects in their own right https://www.ncbi.nlm.nih.gov/pubmed/22337473. Despite this, neurotrophic factors like BDNF do little on their own unless they're paired with some kind of cortical stimulation. Ketamine may be operating by inducing neurotrophic factor secretion via a Sigma1R-mediated mechanism while causing cortical activation via blockade of GABA-ergic interneurons.

Cotcha Yankinov · Apr 17, 2017

Charles_Voynich said:
I've never seen any study which suggests selective NMDA receptor antagonists are useful antidepressants, either in animals or in humans.

EDIT: I should probably expand on this a bit. There are a number of NMDA receptor antagonists which do not produce an antidepressant effect in animals or humans. Dr. Ronald Duman (pretty much the world's expert on ketamine and depression) has a great review that outlines his proposed mechanism underlying ketamine's antidepressant effects: https://www.ncbi.nlm.nih.gov/pubmed/26937618. Though it's a great review, I have some serious qualms with his explanation of the mechanism. The crux of his hypothesis is that ketamine binds to NMDA receptors on GABA-ergic interneurons, causing a glutamate release which ultimately induces mTOR signaling and BDNF release, and thus the antidepressant actions.

However, I see no reason with this mechanism why any NMDA receptor antagonist shouldn't work, when many of them do not. There's some limited evidence to suggest that Sigma1R agonists can facilitate BDNF release on their own, and many of them have been shown to possess mild antidepressant effects in their own right https://www.ncbi.nlm.nih.gov/pubmed/22337473. Despite this, neurotrophic factors like BDNF do little on their own unless they're paired with some kind of cortical stimulation. Ketamine may be operating by inducing neurotrophic factor secretion via a Sigma1R-mediated mechanism while causing cortical activation via blockade of GABA-ergic interneurons.

I'm all for ketamine therapy, but I'm not convinced that more selective NMDA antagonists have nothing to offer humans with depression. It doesn't necessarily have to be due to neurotrophic effects mediated more directly by NMDA antagonist induced glutamate release as well, benefits could be due to alterations of neural circuitry that may be hard to see in mice, or maybe the benefits are only relevant in a ruminating human that has learned language.

I realize there is a lot of hocus pocus about the mystical experiences and the role they play in mediating therapeutic effects, but it could be beneficial for somebody to enter a K-hole for a while purely on a circuit-wide activity level, rather than a molecular mTOR stimulation via HNK level. Alterations of the subgenual cingulate, insula, claustrum and default mode network type stuff.

I think there are some other NMDA antagonists that may show promise. But this isn't something that I've read into

https://www.ncbi.nlm.nih.gov/m/pubmed/26867988/

https://www.ncbi.nlm.nih.gov/m/pubmed/24818801/

I'll point out that there could be differences due to low trapping - high trapping effects at NMDAr and also off target effects. But people find a wide range of NMDA antagonists abuseable anecdotally.

You may argue that that just makes an NMDA antagonist more like amphetamine as an antidepressant, but I'm under the impression that ketamine does a good job of pooping out as well. I'm curious why that is, if the benefits are really due to neurotrophic effects (shouldn't the benefits stick around like SSRI's benefits do? Is this just a confounder because we're seeing it used in treatment resistant depression, and the benefits are retained in milder depression?)

Coolwhip · Apr 17, 2017

I can't remember where I read it, but some study proposed the MoA of ketamines AD effect was caused by a metabolite of R-Ketamine acting on either the AMPA or Kainate receptors(it clarified which and which subtype, I just can't remember).

And as far as effects wearing off, you could easily chalk that up to people not making the proper changes in their lifestyle to stay healthy and happy and continuing the behaviors and remaining in the environment which lead to their extreme depression in the first place as the culprit. I just look at like ketamine unlocks a door, but if you don't open and then walk through it your brain is going to lock it again.

edit: and yes, I'd like this thread to get back on topic, what do we know about minocyclines CNS effects and MoA, and can they be found/replicated in other drugs that aren't antibiotics?

serotonin2A · Apr 18, 2017

Charles_Voynich said:
I agree.

If the stereoisomer which is responsible for antidepressant effects is found to not produce the same neurodegeneration as the racemate, I would consider use of R-ketamine as an antidepressant as safe. Obviously there are issues, which is why we need to pin down exactly which isomer is responsible for what effects and what negative effects each one produces independently. You're free to disagree, but I'm all about taking these drugs with therapeutic value and perfecting them through medicinal chemistry until we can confidently use them in humans.

Charles_Voynich said:
NDMA receptor antagonism is not necessary for ketamine's antidepressant effects, which makes this inconsequential.

https://www.ncbi.nlm.nih.gov/pubmed/27144355

I guess I don't understand what any of that has to do with the safety of ketamine... Whether or not ketamine works as an antidepressant through NMDA-R, or whether safer alternatives can be developed, has no bearing on the safety of ketamine.

Charles_Voynich said:
I've never seen any study which suggests selective NMDA receptor antagonists are useful antidepressants, either in animals or in humans.

EDIT: I should probably expand on this a bit. There are a number of NMDA receptor antagonists which do not produce an antidepressant effect in animals or humans.

Cotcha Yankinov · Apr 18, 2017

Coolwhip said:
what do we know about minocyclines CNS effects and MoA

Microglial inhibitor, inhibits iNOS, can cause psychiatric symptoms in some people. Its kinda known for causing depression for some reason.

Charles_Voynich · Apr 18, 2017

serotonin2A said:
I guess I don't understand what any of that has to do with the safety of ketamine... Whether or not ketamine works as an antidepressant through NMDA-R, or whether safer alternatives can be developed, has no bearing on the safety of ketamine.

There are many preclinical studies that have demonstrated that NMDA-R antagonists have such effects. Drug companies never would have moved forward with trials of lanicemine and other NMDA-R antagonists if there was no preclinical evidence.

I'm not posting these studies because I necessarily agree with the data, only to show that there is evidence that a variety of NMDA-R antagonists have antidepressant-like effects.

https://www.ncbi.nlm.nih.gov/pubmed/24126931 [AZD6765]
https://www.ncbi.nlm.nih.gov/pubmed/23206319 [AZD6765]
https://www.ncbi.nlm.nih.gov/pubmed/19011431 [CP-101,606]
https://www.ncbi.nlm.nih.gov/pubmed/22722512 [MK-0657]
https://www.ncbi.nlm.nih.gov/pubmed/7821340 [MK-801 and CGP 37849]
https://www.ncbi.nlm.nih.gov/pubmed/8012477 [MK-801]
https://www.ncbi.nlm.nih.gov/pubmed/21440043 [memantine]
https://www.ncbi.nlm.nih.gov/pubmed/17643398 [MK-801 and Ro25-6981]
https://www.ncbi.nlm.nih.gov/pubmed/21292242 [Ro 25-6981]
https://www.ncbi.nlm.nih.gov/pubmed/1685448 [ACPC]
https://www.ncbi.nlm.nih.gov/pubmed/8545484 [eliprodil]
https://www.ncbi.nlm.nih.gov/pubmed/19954760 [memantine]
https://www.ncbi.nlm.nih.gov/pubmed/2171955
https://www.ncbi.nlm.nih.gov/pubmed/14724037

In doing about 10 minutes of searching, I found that almost all of those compounds are not selective for the NMDA receptor, and most of them either have known affinity for Sigma receptors or possess the pharmacophore necessary to be one. MK-0657 was the only one I looked through that was claimed to possess negligible affinity for SigmaR.

So no, selective NMDAR antagonists are not effective antidepressants, and most of this has to due with the extreme promiscuity of the SigmaR. This may help;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947205/

There's also the problem that animal models of depression are, to be frank, total crap.

Coolwhip said:
I can't remember where I read it, but some study proposed the MoA of ketamines AD effect was caused by a metabolite of R-Ketamine acting on either the AMPA or Kainate receptors(it clarified which and which subtype, I just can't remember)

I've read that one. It was a cool paper and they had a lot of data (more data = better paper, right? right), but their method of "blocking" metabolism was incredibly dumb, and because of that, I don't really trust their result. Why on earth, if they thought that single metabolite was responsible for the antidepressant effects, did they not just inject animals with HNK and see if they showed an antidepressant response? Correct me if I'm wrong, but I'm pretty sure they didn't do that experiment.

EDIT: I'm going to stop this so we can get back on track. Obviously we disagree about the utility of NMDAR antagonists, and that's fine.

It looks like there's been some use of minocycline as an immunosuppressant drug due to it's ability to attenuate TNF-alpha signaling and pro-inflammatory cytokine secretion. I wonder if this would've been better than being on prednisone or if the dizziness and vertigo is too much of a pain to deal with long-term.

serotonin2A · Apr 18, 2017

Charles_Voynich said:
In doing about 10 minutes of searching, I found that almost all of those compounds are not selective for the NMDA receptor, and most of them either have known affinity for Sigma receptors or possess the pharmacophore necessary to be one. MK-0657 was the only one I looked through that was claimed to possess negligible affinity for SigmaR.

So no, selective NMDAR antagonists are not effective antidepressants, and most of this has to due with the extreme promiscuity of the SigmaR. This may help;

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947205/

There's also the problem that animal models of depression are, to be frank, total crap.

Just because a compound matches the sigma pharmacophore doesn' mean that it isn't a selective NMDA-R antagonist. By looking at the structures, you would have no way to know if the actual affinity would call into question the NMDA-R selectivity. The ligands might bind to sigma-1 receptors with much lower affinity compared to NMDA-R. Good selectivity is often defined by a 100-fold difference in affinity, and some of these compounds may bind to sigma-1 sites yet still show excellent selectivity for NMDA-R in vivo.

As an example, you seemed to lump MK-801 in with the other compounds. I have no idea if you think that MK-801 falls into the sigma-1 pharmacophore, but MK-801 has a Ki of ~14 uM for sigma-1 (https://www.ncbi.nlm.nih.gov/pubmed/2826686), making it highly selective for NMDA-R.

Until there is actually evidence for sigma-R involvement in these effects, it is premature to treat the studies as if they do not exist. The same is true with the issue of whether or not animal models of depression are translatable. It is common knowledge that such models have questionable validity. But that does not mean that studies using the models do not exist. I just think there is a big difference between saying "no evidence exists" and "evidence exists, but it is not compelling and should be disregarded".

EDIT: Thinking back over this topic, if you did identify one of the compounds as being selective for NMDA-R, then how did you reach the conclusion that "selective NMDAR antagonists are not effective antidepressants"? If one piece of evidence exists, it is still evidence that has appeared in the literature.

Charles_Voynich said:
I've read that one. It was a cool paper and they had a lot of data (more data = better paper, right? right), but their method of "blocking" metabolism was incredibly dumb, and because of that, I don't really trust their result. Why on earth, if they thought that single metabolite was responsible for the antidepressant effects, did they not just inject animals with HNK and see if they showed an antidepressant response? Correct me if I'm wrong, but I'm pretty sure they didn't do that experiment.

They did test HNK. Take a look at figures 3 and 4, for example. The metabolism study was just another piece of evidence to back up their conclusions.

Charles_Voynich said:
EDIT: I'm going to stop this so we can get back on track. Obviously we disagree about the utility of NMDAR antagonists, and that's fine.

EDIT: This isn't a disagreement over the utility of NMDA-R agonists, but rather a disagreement about how to discuss evidence in the literature that we do not personally find compelling. Even if I disagree with the validity of published findings, I would never approach a discussion of the topic by just ignoring the studies or acting like they do not exist; I think it is more appropriate to acknowledge their existence right at the start and explain why they are not valid. The reason why I feel that way is because the former approach presumes that there is a consensus about the topic that probably does not exist; there are some conclusions that can be treated as facts based on consensus, but other conclusions are informed opinions, and in my mind it is extremely important to make it clear which is which.

asecin · Apr 19, 2017

hey faggots, hate to break off your cock sucking playground, but check the damn topic name again, i made this fucking thread and it has nothing to do with what lots of you jerk offs continue talking about

Charles_Voynich · Apr 20, 2017

I've read your reply, but I'll hold-off so as not to piss off the OP. Thanks for the information.

minocycline - the only antioxidant neuroprotective antibiotic i have seen

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