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Prof Trevor Marshall
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The trickle of information about how the antibiotics used in the MP are actually affecting the disease process is swelling into a flood:


There is a new paper out: "Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition"

http://www.ncbi.nlm.nih.gov/pubmed/22306153

"RESULTS: Minocycline significantly reduced the inflammatory response in LPS-challenged monocytes, decreasing LPS-induced transcription of pro-inflammatory tumor-necrosis factor alpha (TNF-α), interleukin-1 beta, interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), and the LPS-stimulated TNF-α, IL-6 and PGE(2) release. Minocycline inhibited LPS-induced activation of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), NF-κB, LPS-induced TNF-α factor (LITAF) and the Nur77 nuclear receptor. Mechanisms involved in the anti-inflammatory effects of minocycline include a reduction of LPS-stimulated p38 mitogen-activated protein kinase (p38 MAPK) activation and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway."

(thanks to Bane for finding this for me)

Now we are not as interested in the TLR4 pathway as with the TLR2, but both are active within the cytoplasm. 

All of the mechanisms listed in this paper are significant in the chronic disease process, and my colleagues have been keeping their eye on them. Many more pieces of the clinical puzzle are now falling into place,

Let's use this thread to bring together the best papers describing the action of Minocycline in the human body :)

..Trevor..

Jigsaw
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Here are some of uncertain quality. The most relevant is the one on PXR function by Dubrac which reports that PXR  activates SOCS1 (suppressor of cytokine signalling 1). This could account for some of the effects reported above for mino.


Clinical Trial of Doxycycline for Matrix Metalloproteinase-9 Inhibition in Patients With an Abdominal Aneurysm: Doxycycline Selectively Depletes Aortic Wall Neutrophils and Cytotoxic T Cells -- Lindeman et al. 119 (16): 2209 -- Circulation
The influence of tetracyclines on T cell activatio... [Clin Exp Immunol. 1995] - PubMed result

Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction -- Giuliani et al. 78 (1): 135 -- Journal of Leukocyte Biology

 Modulation of T Lymphocyte Function by the Pregnane X Receptor -- Dubrac et al. 184 (6): 2949 -- The Journal of Immunology
 Antibiotic appears safe for stroke patients and good companion for tPA, study suggests
 Minocycline inhibits the growth of glioma by induc... [Autophagy. 2011] - PubMed - NCBI

Last edited on Thu Feb 16th, 2012 16:24 by Jigsaw

Bane
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Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and -independent programmed cell death.
http://www.ncbi.nlm.nih.gov/pubmed/22108958
This study investigated these alternative pathways in SH-SY5Y cells, a human dopaminergic cell line, challenged with 6-hydroxydopamine (6-OHDA). Minocycline exhibited neuroprotection and inhibition of the toxin-induced caspase-3-like activity, DNA fragmentation, and chromatin condensation, hallmarks of apoptosis.


Inactivation of the Human Vitamin D Receptor by Caspase-3
http://endo.endojournals.org/content/150/2/679.abstract
In conclusion, our results demonstrate that the human VDR is a target of caspase-3 and suggest that activation of caspase-3 may limit VDR activity.

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Does minocycline, an antibiotic with inhibitory effects on microglial activation, sharpen a sense of trust in social interaction?
http://www.ncbi.nlm.nih.gov/pubmed/21956241
METHODS:Forty-nine healthy volunteers were administered minocycline or placebo over four days, after which they played (1) a trust game, in which they decided how much to trust an anonymous partner, and (2) a dictator game, in which they decided how to divide resources between themselves and an anonymous partner.

CONCLUSIONS:These results suggest that minocycline led to more rational decision-making strategies, possibly by increasing emotion regulation. Since minocycline is a well-known inhibitor of microglial activation, our findings may open a new optional pathway for treating mental states in which a component of rational decision making is impaired.

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Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline.
http://www.ncbi.nlm.nih.gov/pubmed/21967886
"LH rats showed significantly higher serotonin turnover in the orbitofrontal cortex and lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus than control rats. However, these alterations in serotonin turnover and BDNF expression remained unchanged after treatment with minocycline. On the contrary, minocycline treatment of LH rats induced significant increases in the levels of dopamine and its metabolites in the amygdala when compared with untreated LH rats. Taken together, minocycline may be a therapeutic drug for the treatment of depression"

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Minocycline as potent anticonvulsant in a patient with astrocytoma and drug resistant epilepsy.
http://www.ncbi.nlm.nih.gov/pubmed/22265576
"We present the case of a patient with marked reduction in seizure frequency during minocycline therapy with severe symptomatic epilepsy due to an astrocytoma"

Last edited on Thu Feb 16th, 2012 18:54 by Bane

Bane
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Cryotherapy and topical minocycline as adjunctive measures to control pain after third molar surgery: an exploratory study.
http://www.ncbi.nlm.nih.gov/pubmed/21802812

CONCLUSIONS: Data from this exploratory study suggest that adjunctive therapy to decrease postoperative pain-cryotherapy or topical minocycline-might be effective at moderating the patient's highest pain levels after third molar surgery. The topic should be studied further in a multicenter, prospective, randomized trial.

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Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2412862/

"Minocycline blocked LPS-stimulated inflammatory cytokine secretion in the BV-2 microglia-derived cell line and reduced LPS-induced Toll-like-receptor-2 (TLR2) surface expression on brain microglia. Moreover, minocycline facilitated the recovery from sickness behavior (i.e., anorexia, weight loss, and social withdrawal) and prevented anhedonia in adult mice challenged with LPS. Furthermore, the minocycline associated recovery from LPS-induced sickness behavior was paralleled by reduced mRNA levels of Interleukin (IL)-1β, IL-6, and indoleamine 2, 3 dioxygenase (IDO) in the cortex and hippocampus. Finally, in aged mice, where exaggerated neuroinflammation was elicited by LPS, minocycline pretreatment was still effective in markedly reducing mRNA levels of IL-1β, TLR2 and IDO in the hippocampus"

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Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells.
http://www.ncbi.nlm.nih.gov/pubmed/21282105

"These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent"


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Minocycline Modulates Neuroinflammation Independently of Its Antimicrobial Activity in Staphylococcus aureus-Induced Brain Abscess
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1988870/

Minocycline exerts beneficial immune modulatory effects in several noninfectious neurodegenerative disease models; however, its potential to influence the host immune response during central nervous system bacterial infections, such as brain abscess, has not yet been investigated. Using a minocycline-resistant strain of Staphylococcus aureus to dissect the antibiotic’s bacteriostatic versus immune modulatory effects in a mouse experimental brain abscess model, we found that minocycline significantly reduced mortality rates within the first 24 hours following bacterial exposure. This protection was associated with a transient decrease in the expression of several proinflammatory mediators, including interleukin-1β and CCL2 (MCP-1). Minocycline was also capable of protecting the brain parenchyma from necrotic damage as evident by significantly smaller abscesses in minocycline-treated mice. In addition, minocycline exerted anti-inflammatory effects when administered as late as 3 days following S. aureus infection, which correlated with a significant decrease in brain abscess size. Finally, minocycline was capable of partially attenuating S. aureus-dependent microglial and astrocyte activation. Therefore, minocycline may afford additional therapeutic benefits extending beyond its antimicrobial activity for the treatment of central nervous system infectious diseases typified by a pathogenic inflammatory component through its ability to balance beneficial versus detrimental inflammation.

Last edited on Thu Feb 16th, 2012 18:59 by Bane

Bane
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Minocycline Helps Developmental Delay

http://www.youtube.com/watch?v=t3PF-pOMzc8

Prof Trevor Marshall
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..Just a few notes to explain what I have done in-silico

I did manage to partially confirm the in-vitro study which said that Minocyline and Cilindamycin were PXR receptor agonists.

There were measuring expression of CYP3A4, which is supposed to come wholly from PXR expression, but which may not IMO (there are 52 nuclear receptors, many of them with unknown function).

I found that Minocycline docked with high affinity in a very similar position to a known agonist, but Clindamycin is a much larger molecule, and must require a different configuration of PXR's prolific binding pocket, if it does indeed dock at all.
 

mvanwink5
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Just a reminder of PXR-AR cross talk (if I'm understanding this paper right, activated PXR should reduce AR transcribed AMP's?).
http://www.ncbi.nlm.nih.gov/pubmed/20599793

paper title: Cross-talk between androgen receptor and pregnane and xenobiotic receptor reveals existence of a novel modulatory action of anti-androgenic drugs.

Abstract
The androgen receptor (AR) is a member of nuclear receptor superfamily (NRs) and plays a critical role in prostate cancer development and progression. Therefore, anti-androgens that repress AR activity remain a critical mainstay for prostate cancer therapy. However, molecular mechanisms by which anti-androgens exert their therapeutic effects are not clearly elucidated and hence are a major area of scientific pursuit. Here, we demonstrate that another member of NRs, pregnane and xenobiotic receptor (PXR), not only acts as a molecular sensor of anti-androgens but also influences the outcome of therapeutic regimen with anti-androgenic drugs via a novel AR-PXR cross-talk. Using 'gain- and loss-of-function' studies, we identified a distinct role of PXR as a potent repressor of AR-regulated transcription. Our study implicates PXR as a key determinant of anti-androgen action since down-regulation of PXR diminishes the potency of the anti-androgenic drugs and enhances transcriptional actions of androgens. In addition, our subcellular localization studies revealed that ligand-activated AR induces nuclear localization of PXR and the two receptors colocalize at discrete sites in nucleus and mitotic chromatin. Finally, we report a distinct antagonist-induced interaction between AR and PXR defining a hitherto unidentified mode of action of AR antagonist. In this perspective, the study may help in designing and development of novel AR antagonists offering improved avenues in prostate cancer therapy.

Jigsaw
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This bookmarking seems to have been miscoded in my previous post

Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction

mvanwink5
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Jigsaw,
My confusion here is that I thought we were using sub inhibitory levels of Minocycline to avoid such immune system effects. In this study, in fact, 200 mg/day were administered as 100 mg b.i.d. Furthermore, I wonder what would be the effect of strong olmesartan mediated VDR activation on such studies. Perhaps our 100 mg Minocycline dose schedule will have a commensurate immunomodulating effect, or not. Is there some thought of trying 100 mg Mino b.i.d for extra CNS palliation?

Best regards as ever,
Mike

Jigsaw
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  I have thought the sub-inhibitory levels were to turn off the bacterial protein synthesis to release their control of the immune system just enough to achieve some bacterial killing: but not so much that the bacterial breakdown products over-activated our TLRs and gave us excessive IP. 
  The immuno-suppressive effect through PXR I see as something that has evolved to protect us against the chance that some xenobiotic might be too harmful to our microbiome for our comfort.
  I think that strong VDR mediated activation would make sudden high dose minocycline dangerous.

Last edited on Fri Feb 17th, 2012 19:27 by Jigsaw

mvanwink5
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Jigsaw,
The ribosome interference MP thought is clear, but that it is not just bacterial replication that is being targeted, but also their ability to interfere with the immune system, is a new thought for me. My memory of MPKB abx discussion does not mention the targeting of bacterial immune system interference. Thank you for pointing that out. Maybe I just missed it.

Are you saying that the PXR immunosuppression pathway suggested by the paper requires too high a Minocycline dose to provide heavy CNS immune activation protection for the MP protocol or just that 100mg b.i.d is just too high for the MP? I'm just pondering the MS and ALS folk's issues with immune action that is too heavy, and 100 mg/day just does not seem to be providing adequate help (for some reports)?
Thanks again,
Mike

Jigsaw
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I am saying that the high levels of mino coupled with immune activation through the VDR by 25d depletion and olmesartan could lead to runaway IP. If the mino dosage was slowly increased it might work. However it might be an unstable situation. Unliganded PXR is a repressor of its target and becomes an activator on ligand binding. Also it can go from activator to repressor by the action of inflammatory cytokines (the ones it suppresses through SOCS1), at least in liver and intestine.
 Phosphorylation and Protein-protein Interactions in PXR-mediated CYP3A Repression
Pregnane X receptor is required for interleukin-6 mediated down-regulation of cytochrome P450 3A4 in human hepatocytes

This may be part of why people find that mino varies in its exacerbating or palliative effects on IP.

mvanwink5
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Jigsaw,
The take away from these papers might be that it is not likely a smart way to purposely repress PXR as a central palliation strategy as the PXR is deeply regulated for essential and multiple purposes. If a particular drug really clobbers it, it is not likely to be a good strategy because of the side issues. Further, one should not be surprised to find such palliation via the PXR is unreliable (and such unreliability seems to be borne out by MP cohort reports). Would you say that is fair?

Best regards,
Mike

Prof Trevor Marshall
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It is worth remembering that the primary agonist for PXR, the classic agonist, is Rifampin, which was isolated from bacteria which were observed to be pathogenic to Mycobacteria tuberculosis.

PXR activation may not be all bad, as it upregulates glutathione metabolites (normally depressed in Th1 disease). Like all bodily metabolism, everything tends to be not so black and white as we have pictured it in the past. The Interactome is complex, still a semi-infinite space to science...

The problem with understanding the action of physiological (clinical) minocycline concentrations on the bacterial Ribosome is that I was never really convinced that it targeted 30S very effectively. Unlike Clindamycin, and the macrolides, which clearly affect the ability of 50S to do its job, the papers describing minocycline's modes of action on 30S, described by the Max Planck Ribosomal researchers were less convincing (primarily due to the low binding affinities and multiple putative binding sites). Additionally, mino in the bloodstream has to cross the cell wall, and then the vacuole exoskeleton, before it gets to the persistent microbiota, and both transitions would likely result in a concentration gradient (just as I explained for 25-D and Olmesartan in the last  web-conference).

..Trevor..
 

Bane
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Minocycline modulates antigen-specific CTL activity through inactivation of mononuclear phagocytes in patients with HTLV-I associated neurologic disease

http://www.ncbi.nlm.nih.gov/pubmed/22335964
http://en.wikipedia.org/wiki/Human_T-lymphotropic_virus_1
http://en.wikipedia.org/wiki/Tropical_spastic_paraparesis
http://en.wikipedia.org/wiki/Degranulation

The activation of mononuclear phagocytes (MPs), including monocytes, macrophages and dendritic cells, contribute to central nervous system inflammation in various neurological diseases. In HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), MPs are reservoirs of HTLV-I, and induce proinflammatory cytokines and excess T cell responses. The virus-infected or activated MPs may play a role in immuneregulation and disease progression in patients with HTLV-I-associated neurological diseases. Results: Phenotypic analysis of CD14+ monocytes in HAM/TSP patients demonstrated high expression of CX3CR1 and HLA-DR in CD14lowCD16+ monocytes, compared to healthy normal donors (NDs) and asymptomatic carriers (ACs), and the production of TNF-alpha and IL-1beta in cultured CD14+ cells of HAM/TSP patients. CD14+ cells of HAM/TSP patients also showed acceleration of HTLV-I Tax expression in CD4+ T cells. Minocycline, an inhibitor of activated MPs, decreased TNF-alpha expression in CD14+ cells and IL-1beta release in PBMCs of HAM/TSP patients. Minocycline significantly inhibited spontaneous lymphoproliferation and degranulation/IFN-gamma expression in CD8+ T cells of HAM/TSP patients. Treatment of minocycline also inhibited IFN-gamma expression in CD8+ T cells of HAM/TSP patients after Tax11-19 stimulation and downregulated MHC class I expression in CD14+ cells. Conclusion: These results demonstrate that minocycline directly inhibit the activated MPs and that the downregulation of MP function can modulate CD8+ T cells function in HAM/TSP patients. It is suggested that activated MPs may be a therapeutic target for clinical intervention in HAM/TSP.

Last edited on Sat Feb 18th, 2012 04:17 by Bane

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Concentration-dependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells.

http://www.ncbi.nlm.nih.gov/pubmed/21980070

BACKGROUND:

Toxins contribute to the pathogenicity of Staphylococcus aureus infections by inducing a dysregulated inflammatory response. This study evaluated the impact of anti-staphylococcal antibiotic exposures over an increasing concentration range on cytokine production from peripheral blood mononuclear cells (PBMCs) after S. aureus toxin exposures.

RESULTS:

At concentrations approximating serum C(max), tigecycline decreased IL-6 by 52%-57% and IFN-γ production by 43%-53% compared with toxin alone (P ≤ 0.05) and linezolid inhibited TNF-α by 12%-35% and IL-8 by 25%-42% (P ≤ 0.02). However, trimethoprim/sulfamethoxazole increased TNF-α and IL-8 production (P = 0.002). Clindamycin, daptomycin, vancomycin and azithromycin had no consistent significant effect at approximate serum C(max) concentrations. All antibiotics had a concentration-dependent effect on cytokine production, with tigecycline, clindamycin and trimethoprim/sulfamethoxazole being the most potent inhibitors of cytokine production at concentrations exceeding 25 mg/L.

CONCLUSIONS:

S. aureus toxins stimulate production of inflammatory cytokines in PBMCs. Antimicrobials with high tissue penetration, including tigecycline, clindamycin, trimethoprim/sulfamethoxazole and linezolid, reduced cytokine production, which, along with their antimicrobial effects, may have importance in the therapeutic outcome of severe infections.

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Comparison of the Effects of Human β-defensin 3, Vancomycin, and Clindamycin on Staphylococcus aureus Biofilm Formation.

http://www.ncbi.nlm.nih.gov/pubmed/22229614

Despite improvements in surgical techniques and implant design in orthopedic surgery, implantation-associated infections are still a challenging problem for surgeons. In 2006, trace quantities of human β-defensin 3 (hBD-3) were found in human bone tissue and bone cells. Human β-defensin 3 is a 45-amino-acid peptide that is considered the most promising class of defensin antimicrobial peptides and may help in the prevention and treatment of implantation-associated infections. Studies of the effectiveness of hBD-3 against Staphylococcus aureus showed that hBD-3 was more potent at low concentrations than other antibiotics. The effect of hBD-3 on S aureus biofilms has not been reported. We studied the effect of hBD-3, vancomycin, and clindamycin on S aureus biofilms and on the survival of the bacteria in the biofilms. Staphylococcus aureus biofilms were examined with confocal scanning laser microscopy. Staining with LIVE/DEAD BacLight viability stain (Molecular Probes Europe BV, Leiden, The Netherlands) differentiated between live and dead bacteria within the biofilms, and extracellular polymeric substances (slime) from the biofilms was evaluated after staining with calcofluor white (Sigma Chemical Company, Rocky Hill, New Jersey). Human β-defensin 3 and clindamycin reduced the S aureus biofilm area. Human β-defensin 3 was significantly more effective against bacteria from the S aureus biofilms than was clindamycin. Vancomycin did not reduce the S aureus biofilm area.

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Effects of minocycline on accumulation of cyclic AMP in cerebral cortex of rat. A comparison with lithium.

http://www.ncbi.nlm.nih.gov/pubmed/8413842

"Minocycline and lithium dose-dependently inhibited noradrenaline-stimulated formation of cAMP in slices of cortex, but only lithium inhibited the formation of cAMP induced by forskolin. In contrast to lithium, minocycline did not affect either noradrenaline- or Ca(2+)-stimulated activity of adenylate cyclase in a preparation of cortical membranes"


A comparative study on the effects of tetracyclines and lithium on the cyclic AMP second messenger system in rat brain.

http://www.ncbi.nlm.nih.gov/pubmed/7708928

This study was aimed at investigating the effects of demeclocycline (DMC), minocycline (MC), and lithium (Li) in vitro on cyclic AMP (cAMP) accumulation in rat cerebral cortex stimulated by noradrenaline, forskolin, and ouabain. 2. DMC, MC, and Li dose-dependently reduced noradrenaline-stimulated cAMP formation in cortical slices, but only Li inhibited the cAMP formation induced by forskolin. 3. In contrast to Li, DMC and MC did not affect noradrenaline-stimulated adenylate cyclase activity in cortical membranes. 4. In cortical slices, ouabain stimulated the cAMP production (required the presence of extracellular Ca2+ and was blocked by verapamil). Ouabain-stimulated cAMP accumulation in cortical slices was inhibited by DMC, MC, and Li. 5. DMC and MC do not seem to interact directly with the adenylate cyclase as reported for Li. It is concluded that the tetracyclines, DMC and MC, affect the cAMP signaling system in rat brain by mechanisms that differ from that of Li. The decreased receptor agonist-stimulated cAMP production in cortical slices in the presence of DMC and MC may be due to the Ca(2+)-chelating ability of these tetracyclines.

Bane
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an oldie...

Acne Drug Prevents HIV Breakout

http://www.hopkinsmedicine.org/news/media/releases/Acne_Drug_Prevents_HIV_Breakout

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Janice Clements on the discovery of minocycline for treating HIV-related cognitive disorders

http://www.youtube.com/watch?v=RvpJ9itcyXo


Minocycline Does Not Improve HIV-Associated Neurocognitive Disorder

http://www.natap.org/2011/CROI/croi_110.htm

The ACTG researchers suggested several reasons why minocycline may not have improved cognitive function in this trial: (1) minocycline may be ineffective in treating HIV-associated neurocognitive disorders, (2) treatment was too brief, (3) the 100-mg dose is not high enough to penetrate the central nervous system adequately, (4) cognitive impairment in these people may be caused by factors not addressed by minocycline, such as comorbid conditions or medication side effects, or (5) minocycline-induced neuroprotection may be reflected only in cerebrospinal fluid markers or by neuroimaging. The investigators are evaluating neuroprotection markers in cerebrospinal fluid markers now.


Minocycline fails to modulate cerebrospinal fluid HIV infection or immune activation in chronic untreated HIV-1 infection: results of a pilot study

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117676/

"For those meeting entry criteria, this also served as the baseline visit, and they starting minocycline 100 mg twice daily orally for the next 8 weeks. At four and eight weeks, and after a 6-week washout period off minocycline, subjects underwent repeated evaluation similar to the baseline, including LP and CSF analysis. Treatment adherence was assessed at each on-study visit by direct questioning and pill count"


Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial.

http://www.ncbi.nlm.nih.gov/pubmed/21900636

OBJECTIVE:
We conducted a study of minocycline to assess its safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment.

METHODS:
HIV-1-infected individuals with progressive neurocognitive decline were enrolled in a double-blind, placebo-controlled study of minocycline. Participants were randomized to receive minocycline 100 mg or matching placebo orally every 12 hours. The primary efficacy measure was change in a neuropsychological test composite z score (NPZ-8) from baseline to week 24. Measures of safety included the frequency of adverse events and changes over time in laboratory tests. After 50% of participants completed the double-blind phase, an interim analysis of futility for the primary outcome measure was performed, and our Data and Safety Monitoring Board recommended early study termination.

RESULTS:
A total of 107 HIV-1-infected individuals with cognitive impairment were enrolled. The minocycline group did not show improvement in the primary outcome measure (NPZ-8) (mean 24-week change = 0.12) compared to placebo (mean 24-week change = 0.17) (95% confidence interval = [-0.26, 0.39], p = 0.70). There were few severe adverse events or laboratory abnormalities in either treatment group.

CONCLUSION:
Minocycline was safe and well-tolerated in individuals with HIV-associated cognitive impairment, but cognitive improvement was not observed. Classification of evidence. This interventional study provides Class II evidence for the safety, tolerability, and efficacy of minocycline for the treatment of HIV-associated cognitive impairment.

Last edited on Sat Feb 18th, 2012 17:17 by Bane

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Minocycline Inhibition of Monocyte Activation Correlates with Neuronal Protection in SIV NeuroAIDS

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071838/


Results

Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/Cr (neuronal injury) and circulating CD14+CD16+ and CD14loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation.


Conclusion

Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation.

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But how do the monocytes penetrate this mythical "blood-brain barrier" :) ?
 

Jigsaw
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The take away from these papers might be that it is not likely a smart way to purposely repress PXR as a central palliation strategy as the PXR is deeply regulated for essential and multiple purposes. If a particular drug really clobbers it, it is not likely to be a good strategy because of the side issues. Further, one should not be surprised to find such palliation via the PXR is unreliable (and such unreliability seems to be borne out by MP cohort reports). Would you say that is fair?

   
I have not thought about the possibility of repressing PXR as such, or how it could be done. I think it may be constitutive. IMO what can happen is that PXR can be programmed to act as a suppressor or as an activator of its target genes. Minocycline would also have double roles (rapid suppression of cytokines via PXR and SOCS1 and slow depletion of microbial defences by partial inhibition of their protein synthesis). With pressure from anti-microbial peptides arising from VDR activation, the latter effect could allow enough microbial damage to trigger enhanced inflammatory cytokine activity via TLRs. Having inflammatory cytokines dominant  could induce inversion of the role of PXR from activator to suppressor of SOCS1 production and the inflammation (IP) would become endemic. Removal of the mino would allow the microbes to restore their defences and the IP could ease as the source of TLR activators dried up. The preceding is part of a scenario I posted as "A mino drama in 4 Acts".  Coffee, mino & rebound IP - Prof. Marshall's Members' Only Topics - MEMBER DISCUSSION - The Marshall Protocol Study Site
   I don't think it is fair to say that palliation via PXR, if that is the way mino is really working) is unreliable if you learn to use it properly.

Last edited on Sat Feb 18th, 2012 20:44 by Jigsaw

mvanwink5
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Jigsaw,
My experience is when I stop Minocycline that IP immediately increases, and this is even when it is being dosed q48h. Indeed, common cohort experience is that reduction of Minocycline must be done slowly and such dose reduction is commonly termed "weaning." From this experience, it seems to me the simple description of what is happening with Minocycline's mode of action as one of interfering with pathogen chemical machinery is missing essential and prominent subsurface biochemistry that looks a lot like immunosuppression hidden by other immune action (perhaps such as interference with the PXR). So, what is really happening to the pathogens and the immune system is unclear, at least to my fogged mind. It just seems to me that with all this cellular biochemical attempts at self regulation that the less tinkering, the easier it may be for the immune system to reestablish itself as perhaps it should function.

It just seems to me that if it is possible to keep intervention simple, then unintended dramas might be avoided (such as heavy stage 5). Just some thoughts, perhaps just wishful thinking.

Best regards,
Mike

Last edited on Sun Feb 19th, 2012 06:21 by mvanwink5

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I avoid mino or any abx as it has done its job well enough.
Although i have yet to try using less as in the beginning.
Anybody got any time release micro dose mino?
Use a calcium buffer? and a grain of salt?:)
M -A dommergues http://www.ncbi.nlm.nih.gov/pubmed/14568022

Last edited on Mon Feb 20th, 2012 04:38 by jlunn247

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Scientists shocked to find antibiotics alleviate symptoms of schizophrenia

http://tiny.cc/671jf

"The National Institute for Health Research is funding a £1.9m trial of minocycline, which will begin recruiting patients in the UK next month. The research follows case reports from Japan in which the drug was prescribed to patients with schizophrenia who had infections and led to dramatic improvements in their psychotic symptoms"

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The use of minocycline to lower inflammation for schizophrenia is interesting.

My own recent experience with frequent minocycline is similar to my experience at the beginning of the MP. When I take 100mg dosing the neurological symptoms (similar to what is commonly known as migraine) are very strong. My whole nervous system feels on edge. Insomnia is a real problem. The frequency of dosing does not change this effect. If I lower the dose to 50mg, at any frequency, these symptoms fade within a few days.

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Joyful wrote:
When I take 100mg dosing the neurological symptoms (similar to what is commonly known as migraine) are very strong. My whole nervous system feels on edge. Insomnia is a real problem. The frequency of dosing does not change this effect. If I lower the dose to 50mg, at any frequency, these symptoms fade within a few days.

I think we're going to have a really hard time explaining/understanding that!

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Man, if I had to have an explanation for everything I've experienced on the MP,
I would have lost it years ago. ;)

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Minocycline prevents impaired glial glutamate uptake in the spinal sensory synapses of neuropathic rats.


http://www.ncbi.nlm.nih.gov/pubmed/20678556


Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

http://www.molecularpain.com/content/5/1/35


Whats up with the glial, glutamate, and minocycline?

Last edited on Sat Mar 10th, 2012 06:01 by seanlane

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Whats up with the glial, glutamate, and minocycline?
you forgot to ask about the cannabinoids :) :)
 

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Dr Trevor Marshall wrote:
Whats up with the glial, glutamate, and minocycline?
you forgot to ask about the cannabinoids :) :)

I think we can handle hearing about the cannabinoids ;)

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Because mino seems to damp down the glial action in the CNS ... would it be a good idea for me to start taking mino again?  I have read of MS patients who get some relief from taking mino. 

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I don't know Chris. I know that for me a certain dose puts me "on edge" and the lower dose doesn't seem to "do" anything.

If I wasn't tinkering with other factors, I might experiment with frequent 50mg dosing again.

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Chris did you get some palliation from Mino in the past?  I think that would probably be the best predictor of how you might respond now.

I recently embarked on Q24 hour 50 mg Mino, to make sure my immune system noticed any new microbes I might have gotten along with a new tick bite.  I made it through just two doses, with IP well into the intolerable range and escalating, and quit the Mino after that.  But I have a history of being unable to tolerate Mino on a continuing basis.  Every few months I try again, to see where things are at.

All best to you my warrior friend,
Dody

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Thanks Dody.  I really have not felt any difference when taking mino in the past.  If it does down modulates the glial in the CNS ... that could be good or bad depending on how you look at it.  A weakened glial response would stop some loss of neurons.. but that might slow eventual recovery.  Like always .... this is a balancing game ... trial and error being the order of the day for us MP pioneers!  But, I may try taking some mino along with the Volvic water to see if it lessens the IP I am getting from the water.

Good health! 

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Bane wrote: Scientists shocked to find antibiotics alleviate symptoms of schizophrenia

http://tiny.cc/671jf

"The National Institute for Health Research is funding a £1.9m trial of minocycline, which will begin recruiting patients in the UK next month. The research follows case reports from Japan in which the drug was prescribed to patients with schizophrenia who had infections and led to dramatic improvements in their psychotic symptoms"

Minocycline benefits negative symptoms in early schizophrenia; a randomised double-blind placebo-controlled clinical trial in patients on standard treatment.

http://www.ncbi.nlm.nih.gov/pubmed/22526685

"The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation"

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Efficacy of combination oral antimicrobial agents against biofilm-embedded methicillin-resistant Staphylococcus aureus.

http://www.ncbi.nlm.nih.gov/pubmed/22572005

"The activity of minocycline was concentration-dependent and more effective against MRSA isolates that demonstrated weak biofilm formation. The effect of minocycline seems to be further enhanced when used in combination with either fusidic acid or linezolid at low concentrations, with the obtained results equal to those obtained with rifampicin-based regimens (p<0.001). Rifampicin plus minocycline was also effective against MRSA in biofilm"

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They are still drawing conclusions from in-vitro work. Bad habits die slowly, I guess...

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Bane wrote:Does minocycline, an antibiotic with inhibitory effects on microglial activation, sharpen a sense of trust in social interaction?

http://www.ncbi.nlm.nih.gov/pubmed/21956241

METHODS:Forty-nine healthy volunteers were administered minocycline or placebo over four days, after which they played (1) a trust game, in which they decided how much to trust an anonymous partner, and (2) a dictator game, in which they decided how to divide resources between themselves and an anonymous partner.

CONCLUSIONS:These results suggest that minocycline led to more rational decision-making strategies, possibly by increasing emotion regulation. Since minocycline is a well-known inhibitor of microglial activation, our findings may open a new optional pathway for treating mental states in which a component of rational decision making is impaired.

Minocycline modulates human social decision-making: possible impact of microglia on personality-oriented social behaviors.

http://www.ncbi.nlm.nih.gov/pubmed/22808165

CONCLUSIONS/SIGNIFICANCE: Our results suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Early-life events may activate human microglia, establish a certain neuro-synaptic connection, and this formation may determine each human's personality and personality- oriented social behaviors in later life. To explore these mechanisms, further translational research is needed.

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What about mino in bipolar dz?  Is there any relation there?  How about in narcolepsy?  I just finished a thread about that that pulled some of my strings.

My stepson has bipolar dz, but it is seasonal.  As spring approaches, he becomes manic, as fall and winter approaches, he retreats into his cave with depression.  He is "controlled" on Zyprexa, but that is not a real solution.

I have a dx of sleep apnea, use a CPAP faithfully, but still fall asleep if I am not stimulated.  Is narcolepsy a consideration?

I'm only doing Benicar qid now, but am giving some thought to giving the mino another try.

Last edited on Mon Jul 23rd, 2012 07:57 by madwolf

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Hey, Madwolf, have you had a look at our YouTube channel recently? You might be interested in Titta's presentation at the Singapore conference:

http://www.youtube.com/watch?v=3PL8f3aCZCU

and my most recent presentation:

http://www.youtube.com/watch?v=_rFmAMDdbjs

They cover many of these topics :)

..Trevor..
 

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Since minocycline is a well-known inhibitor of microglial activation
This was a disturbing comment that the paper makes about minocycline, at least in my thinking.

Best regards,
Mike

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Mike, when one looks at the complexity of the human body with only historic pragma in one's eyes, it is easy to misinterpret what one sees. Indeed, 99% of the papers which cross my desk suffer from this problem. So I wouldn't get any more hung up about microglial activation than I would about 'vitamin D deficiency' :)

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Dr.Marshall,
Thanks, I took a look at some of what was written about the effect of Mino on microglial activation and it is much more complex than what "inhibition" might imply. Thanks and sorry for not looking into this further first.

Best regards,
Mike

Last edited on Mon Jul 23rd, 2012 11:19 by mvanwink5

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Minocycline modulates cytokine and chemokine production in lipopolysaccharide-stimulated THP-1 monocytic cells by inhibiting IκB kinase α/β phosphorylation.

http://www.ncbi.nlm.nih.gov/pubmed/23108365

Minocycline, which is a member of the broad-spectrum bacteriostatic tetracycline antibiotics group, has also recently been shown to have additional effects that are separate from their antimicrobial function; however, the detailed mechanisms involved remain unknown. We examined the effects of minocycline on cytokine and chemokine production and the expression levels of intracellular phosphorylated proteins in a lipopolysaccharide (LPS)-induced cytokine response model in vitro. In the present study, 3 cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and interferon [IFN]-γ) and 7 chemokines (IL-8, interferon inducible protein [IP]-10, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1α, MIP-1β, regulated upon activation normal T-cell expressed secreted [RANTES], and eotaxin) were suppressed by minocycline in a dose-dependent manner. Moreover, the phosphorylation of inhibitor of nuclear factor-κB alpha (IκBα) and IκB kinase (IKK)α/β, which is located upstream from IκBα, was significantly suppressed by minocycline, whereas the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), p38, and TGF-β-activated kinase (TAK)1 were not affected. Thus, minocycline appears to inhibit the signaling pathway at the level of IKKα/β phosphorylation. In conclusion, minocycline was found to reduce the production of multiple cytokines and chemokines by inhibiting LPS-induced IKKα/β phosphorylation. That is, minocycline appears to be a potent inhibitor of IKKα/β phosphorylation. From a clinical and translational significance point-of view, these findings suggest that the use of minocycline offers the advantage of providing both antimicrobial and anti-inflammatory effects, which may be key in treating certain types of infectious diseases, particularly those that lead to hypercytokinemia and chronic inflammatory disorders.

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Bane wrote: Minocycline modulates cytokine and chemokine production in lipopolysaccharide-stimulated THP-1 monocytic cells by inhibiting IκB kinase α/β phosphorylation.

http://www.ncbi.nlm.nih.gov/pubmed/23108365

Minocycline, which is a member of the broad-spectrum bacteriostatic tetracycline antibiotics group, has also recently been shown to have additional effects that are separate from their antimicrobial function; however, the detailed mechanisms involved remain unknown. We examined the effects of minocycline on cytokine and chemokine production and the expression levels of intracellular phosphorylated proteins in a lipopolysaccharide (LPS)-induced cytokine response model in vitro. In the present study, 3 cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and interferon [IFN]-γ) and 7 chemokines (IL-8, interferon inducible protein [IP]-10, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1α, MIP-1β, regulated upon activation normal T-cell expressed secreted [RANTES], and eotaxin) were suppressed by minocycline in a dose-dependent manner. Moreover, the phosphorylation of inhibitor of nuclear factor-κB alpha (IκBα) and IκB kinase (IKK)α/β, which is located upstream from IκBα, was significantly suppressed by minocycline, whereas the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), p38, and TGF-β-activated kinase (TAK)1 were not affected. Thus, minocycline appears to inhibit the signaling pathway at the level of IKKα/β phosphorylation. In conclusion, minocycline was found to reduce the production of multiple cytokines and chemokines by inhibiting LPS-induced IKKα/β phosphorylation. That is, minocycline appears to be a potent inhibitor of IKKα/β phosphorylation. From a clinical and translational significance point-of view, these findings suggest that the use of minocycline offers the advantage of providing both antimicrobial and anti-inflammatory effects, which may be key in treating certain types of infectious diseases, particularly those that lead to hypercytokinemia and chronic inflammatory disorders.

  These effects are consistent with an action through SOCS-1 (suppressor of cytokine signalling-1). Suppressor of Cytokine Signaling (SOCS) 1 Inhibits Type I Interferon (IFN) Signaling via the Interferon α Receptor (IFNAR1)-associated Tyrosine Kinase Tyk2

SOCS-1 is reported to be induced by activation of PXR.  Modulation of T Lymphocyte Function by the Pregnane X Receptor -- Dubrac et al. 184 (6): 2949 -- The Journal of Immunology

Last edited on Thu Nov 1st, 2012 04:23 by Jigsaw

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Jigsaw wrote:

  These effects are consistent with an action through SOCS-1 (suppressor of cytokine signalling-1). Suppressor of Cytokine Signaling (SOCS) 1 Inhibits Type I Interferon (IFN) Signaling via the Interferon α Receptor (IFNAR1)-associated Tyrosine Kinase Tyk2

SOCS-1 is reported to be induced by activation of PXR.  Modulation of T Lymphocyte Function by the Pregnane X Receptor -- Dubrac et al. 184 (6): 2949 -- The Journal of Immunology

You're called Jigsaw for a reason ;)

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Minocycline blocks asthma-associated inflammation in part by interfering with the T Cell receptor-NF-κB-GATA-3-IL-4 axis without a prominent effect on PARP.

http://www.jbc.org/content/early/2012/11/26/jbc.M112.419580.long

Minocycline protects against asthma independently of its antibiotic function and was recently reported as a potent PARP inhibitor. In an animal model of asthma, a single administration of minocycline conferred excellent protection against ovalbumin-induced airway eosinophilia, mucus hypersecretion, and Th2 cytokine production (IL-4/IL-5/IL-12(p70)/IL-13/GM-CSF) and a partial protection against airway hyperresponsiveness. These effects correlated with pronounced reduction in lung and sera allergen-specific IgE. A reduction in poly(ADP-ribose)-immunoreactivity in lungs of minocycline-treated/ovalbumin-challenged mice correlated with decreased oxidative DNA damage. Minocycline's effect on PARP may be indirect as the drug failed to efficiently block direct PARP activation in lungs of N-methyl-N'-nitro-N-nitroso-guanidine-treated mice or H2O2-treated cells suggesting. Minocycline blocked allergen-specific IgE production in B cells potentially by modulating T cell-receptor (TCR)-linked IL-4 production at the mRNA level but not through a modulation of the IL-4-JAK-STAT-6 axis, IL-2 production, or NFAT1 activation. Restoration of IL-4, ex vivo, rescued IgE production by minocycline-treated/ovalbumin-stimulated B cells. IL-4 blockade correlated with a preferential inhibition of the NF-κB activation arm of TCR but not GSK3, Src, p38 MAPK, or ERK1/2. Interestingly, the drug promoted a slightly higher Src and ERK1/2 phosphorylation. Inhibition of NF-κB was linked to a complete blockade of TCR-stimulated GATA-3 expression, a pivotal transcription factor for IL-4 expression. Minocycline also reduced TNF-α-mediated NF-κB activation and expression of dependent genes. These results show a potentially broad effect of minocycline but may block IgE production in part by modulating TCR function particularly by inhibiting the signaling pathway leading to NF-κB activation, GATA-3 expression, and subsequent IL-4 production.


http://en.wikipedia.org/wiki/Interleukin_4

Functions
 
It has many biological roles, including the stimulation of activated B-cell and T-cell proliferation, and the differentiation B cells into Plasma Cells.
 
It is a key regulator in humoral and adaptive immunity.
 
IL-4 induces B-cell class switching to IgE, and up-regulates MHC class II production. It also induces B cell class switching to IgG4.
 
IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell IL-12.
 
Overproduction of IL-4 is associated with allergies.

Last edited on Fri Nov 30th, 2012 06:52 by Bane

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Does minocycline have antidepressant effect?



@duke.edu
Abstract
Only one-third of patients undergoing monotherapy with an antidepressant achieve remission of their depressive symptoms and gain functional recovery. Therefore, further exploration of antidepressant mechanisms of action is important in order to facilitate the development of antidepressants with new modes of action. Preclinical and clinical studies have demonstrated that major depression is associated with impaired inflammatory responses and deficient neuroprotection. In this regard, we propose that the second-generation tetracycline "minocycline" may hold a potential as a new treatment for major depression. Emerging findings in animal and human studies of minocycline reveal that it has antidepressant-like neuroprotective and anti-inflammatory actions, and minocycline has been shown to perform as an antidepressant in an accepted animal model (forced swimming test). Anecdotal evidence supports minocycline's efficacy for augmentation of antidepressants in major depressive disorder. The following review describes the evidence supporting the consideration of minocycline as a potential antidepressant. We suggest that minocycline may be particularly helpful in patients with depression and comorbid cognitive impairment, as well as depression associated with organic brain disease. We also describe the antinociceptive effect of minocycline and propose a role for minocycline in the treatment of patients with major depression and prominent somatic discomfort and somatoform spectrum disorders. The lack of clinical studies of minocycline for depression is noted. Further studies of the potential therapeutic mechanism of minocycline and its therapeutic implications for major depression are warranted, and may substantially contribute to the development of newer and more effective antidepressants.

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Sean,

I always have more motivation/desire to do things the day after I have taken a 100mg mino the previous evening. I would consider the effect it has on me as mildly anti-depressive (although I do not suffer from major depression or any officially diagnosed depression for that matter).

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Yes...I find the same thing.

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This is very interesting indeed.  Perhaps I could use mino instead of the AD I currently take.  I'll have to talk this one over with my MP doc.

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A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4.

http://www.ncbi.nlm.nih.gov/pubmed/23523650

Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca2+; Mg2+) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100 mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50 mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines.

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So, are they saying that minocycline reduced both expression and signaling of TLR2 and TLR4? Sometimes I have trouble understanding researcher language. (I would have read the paper to illuminate what was being said but all I could read was the abstract).

Last edited on Thu Mar 28th, 2013 03:23 by mvanwink5

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Ok, got the paper, thank you. First, it is a murine study, so I don't know what it means to humans, but for the mice, "Minocycline or PMIN inhibits also TLR2 and TLR4 signaling. TLRs are transmembrane pattern-recognition receptors, which respond to both exogenous and endogenous ligands. The exogenous ligands that are mainly recognized by TLR2 are lipoproteins from gram-positive bacteria, whereas TLR4 recognizes predominantly endotoxin (LPS) from gram-negative bacteria."

(bolding added)

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which for us dummies means what?  Is it palliative or is it killing bugs?  For me it appears to be palliative.  I take it when my pain becomes too intense, but I never have been able to figure out whether my intense pain was IP or my Lyme!?  Any ideas?

Dian

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In my last webconference I explained why its concentration inside the cells did not reach levels which would kill many bugs... Nice to have the study supporting my own conclusions, however...

Knocking out TLR2 and TLR4, if it is repeated in humans, would most definitely be palliative as it would significantly knock-down intraphagocytic innate immunity.

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Thanks Dr. Marshall.......

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Bane wrote: A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4.

http://www.ncbi.nlm.nih.gov/pubmed/23523650
  Intraperitoneal minocycline (100 mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75 mg/kg, 47.50 mg/kg or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell culture

   Could PMIN be a PXR agonist like mino?

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A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome.

http://www.ncbi.nlm.nih.gov/pubmed/23572165

OBJECTIVE:: Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Previous open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. METHOD:: Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, aged 3.5 years to 16 years (n = 55, mean age 9.2 [SD, 3.6] years). Participants were randomized to minocycline or placebo for 3 months and then switched to the other treatment. RESULTS:: Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared with placebo (2.49 ± 0.13 and 2.97 ± 0.13, respectively, p = .0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analog Scale (minocycline: 5.26 cm ± 0.46 cm, placebo: 4.05 cm ± 0.46 cm; p = .0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding, and preliminary efficacy analysis results known to investigators. CONCLUSIONS:: Minocycline treatment for 3 months in children with FXS resulted in greater global improvement than placebo. Treatment for 3 months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.

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Bane wrote:
Bane wrote:Does minocycline, an antibiotic with inhibitory effects on microglial activation, sharpen a sense of trust in social interaction?

http://www.ncbi.nlm.nih.gov/pubmed/21956241

METHODS:Forty-nine healthy volunteers were administered minocycline or placebo over four days, after which they played (1) a trust game, in which they decided how much to trust an anonymous partner, and (2) a dictator game, in which they decided how to divide resources between themselves and an anonymous partner.

CONCLUSIONS:These results suggest that minocycline led to more rational decision-making strategies, possibly by increasing emotion regulation. Since minocycline is a well-known inhibitor of microglial activation, our findings may open a new optional pathway for treating mental states in which a component of rational decision making is impaired.

Minocycline modulates human social decision-making: possible impact of microglia on personality-oriented social behaviors.

http://www.ncbi.nlm.nih.gov/pubmed/22808165

CONCLUSIONS/SIGNIFICANCE: Our results suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Early-life events may activate human microglia, establish a certain neuro-synaptic connection, and this formation may determine each human's personality and personality- oriented social behaviors in later life. To explore these mechanisms, further translational research is needed.





Minocycline, a microglial inhibitor, reduces ‘honey trap’ risk in human economic exchange :D

http://www.nature.com/srep/2013/130418/srep01685/full/srep01685.html

Recently, minocycline, a tetracycline antibiotic, has been reported to improve symptoms of psychiatric disorders and to facilitate sober decision-making in healthy human subjects. Here we show that minocycline also reduces the risk of the ‘honey trap’ during an economic exchange. Males tend to cooperate with physically attractive females without careful evaluation of their trustworthiness, resulting in betrayal by the female. In this experiment, healthy male participants made risky choices (whether or not to trust female partners, identified only by photograph, who had decided in advance to exploit the male participants). The results show that trusting behaviour in male participants significantly increased in relation to the perceived attractiveness of the female partner, but that attractiveness did not impact trusting behaviour in the minocycline group. Animal studies have shown that minocycline inhibits microglial activities. Therefore, this minocycline effect may shed new light on the unknown roles microglia play in human mental activities.

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I read this and immediately thought of cats and mice and toxoplasmosis.  Mice infected with toxoplasmosis will run TOWARDS a cat rather than away. 

I wonder if they will try a design a similar experiment for women and mino, but what would the "honey trap" be?  Shoes?  Do you trust these shoes?  Or will you, after mino, recognize that they will kill your feet? Inquiring minds want to know.

mvanwink5
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A dose of mino before a date?

Joyful
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Gilly wrote:Do you trust these shoes? Or will you, after mino, recognize that they will kill your feet? Inquiring minds want to know.
LOLOLOLOLOL

David_in_UK
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I find that minocycline does have quite a profound effect on my mental state and improves my mood. It's a much better antidepressant than antidepressants.

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So, I'm asking for an opinion:

If I were to take minocycline for its anitdepressant effects only, would I be better off using a pulsed approach, or take it more regularly?  Should I start now before I'm off of these meds, or wait until I notice any uptick in IP?

I'm weaning off my HRT meds, and hopefully my AD meds eventually, and it would be nice to have something available to help if my neuro IP became too much.

David_in_UK
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GillyB wrote:
So, I'm asking for an opinion:

If I were to take minocycline for its anitdepressant effects only, would I be better off using a pulsed approach, or take it more regularly?  Should I start now before I'm off of these meds, or wait until I notice any uptick in IP?

I'm weaning off my HRT meds, and hopefully my AD meds eventually, and it would be nice to have something available to help if my neuro IP became too much.


I think regular rather than pulsed - within the MP guidelines up to 50mg every 12 hours is OK, which I find to be quite enough to have the desired effect.

I don't see why you shouldn't try it first without dropping your other meds - that would make sense to me.

Of course it might not work for everyone, but it definitely works for me.

Bane
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Oral Minocycline in Treatment of Cutaneous Sarcoidosis

http://archderm.jamanetwork.com/article.aspx?articleid=1698603

"Of 27 patients, 6 (22%) had complete remission; 14 (52%) had partial remission; and 7 (26%) had no remission. Of the 2 severe ulcerative cases, 1 achieved a partial remission and 1 no remission. In total, 20 of 27 (74%) patients showed response to the treatment, and the proportion of those who responded was significantly greater than those who did not respond. There was no difference in the response of minocycline across age, race, or sex"

--------------------------------------------------------------------

Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death

http://tiny.cc/yf6bzw

"Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked"

Bane
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Minocycline targets NF-kcyB pathway through suppression of TGF-β1-TAK1-IkcyB kinase axis in ovarian cancer: in vitro and in vivo studies.

http://www.ncbi.nlm.nih.gov/pubmed/23858099

"Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by down-regulation of NF-κB activity and endogenous protein levels of its dependent gene products. Our results reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-β-NF-κB pathway in ovarian cancer"

Kas
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http://www.purdue.edu/newsroom/releases/2013/Q3/researcher-finds-way-to-convert-blood-cells-into-autoimmune-disease-treatment.html


What do you all make of the above article?

Joyful
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So they are teaching your own white blood cells to stop attacking whatever your body was targeting?

I guess that would be call immune suppression.

Here was an interesting part of their story:Kim discovered that naïve T-cells cultured in the presence of the hormone progesterone can be induced to become suppressive T-cells.

Haven't we read many times that progesterone is an immune suppressor of some sort. Not that we aren't modulating our immune system all the time, but personally I've gone to a lot of trouble and expense to go onto a protocol that stimulates my immune system (the MP!). :)

leroybrown
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This is just off the top of my head so I might be wrong, but I thought that the MP will slowly make your immune system less reactive (by eliminating pathogens), therefore your suppressor T cells should increase, and the cytotoxic ones decrease.

The article doesn't address eliminating pathogens.

Deb

Bane
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Minocycline attenuates interferon-α-induced impairments in rat fear extinction

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928293/

Administering minocycline prevented IFN-α from impairing fear extinction. The immunohistochemical and biochemical results show that minocycline inhibited IFN-α-induced microglial activation and reduced IL-1β and TNF-α production.


Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879188/

When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency.

Prof Trevor Marshall
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Bane wrote: When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency.
 
And there you have 100% of the reason I moved away from antibiotic palliation in 2008. I decided it was best to let the body figure out what species it wanted to thin down without interference from ingested antibiotics.

That was a decade ago, and I didn't have this experimental data back then, but it was obvious (to me) how the drugs worked at the molecular level, and that they would cause the microbiome imbalance which has been documented in this study.



mvanwink5
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Antibiotics in food through treatment of animals is a problem. Plus the antibiotics distorts the animal's Microbiome, a double whammy.

Cairo123
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The existence of antibiotics in meat fed to animals is one of many good reasons to avoid meat and other animal products that comes off of the feedlot sometimes referred to as CAFOs. Most if not virtually all meat and other animal products bought in the supermarket will have this problem. This can be avoided by buying direct from a farmer that does not administer anti-biotics and only feeds his livestock grass.

mvanwink5
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For that reason I buy my cheese as 100% grass fed from:
http://simplycheese.net
I can't find it local so I have to order it.

Grateful Survivor
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Mike I checked their website and the grass fed cheeses look great--but I can't figure out how large their "units" are--how many ounces, do you know?  I know they're gonna cost more than at the store, but I want to know how much more....
Tx, Grateful

Cairo123
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Here is where I buy my organic grass fed cheese. They have confirmed that they do not fortify with A or D.

http://www.swisslandcheese.com/

mvanwink5
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Grateful,
I have been using 'Simply Cheese' for a couple of years and just recently they have raised their prices markedly. No idea why, market I suppose.

I am trying to switch to their normal cheese in hopes it is the same as their 'grass fed'. I can't get grass fed anywhere locally. Locally even milk is unavailable as 'grass fed.

'Units'? I am unsure what that is referring to, perhaps their discount? Anyway they do have a discount for repeat business, If I recall correctly I think it is about 5%. A bit tricky to apply to your order though. If you have trouble and need assistance PM me.

Joyful
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If you work with a local health food store, you might be able to get them to order what you want at a better price?

Looks like there are stores in Massachusetts that carry one my favorite brands: http://rumianocheese.com/
 

Last edited on Sat Aug 6th, 2016 17:40 by Joyful

Dmitry
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Here is some new data on TLR2 which expression is reduced with mino(https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-5-15)

https://www.ncbi.nlm.nih.gov/pubmed/27695100
Borrelia burgdorferi is transmitted into the skin of the host where it encounters and interacts with two dendritic cell (DC) subsets; Langerhans cells (LCs) and dermal DCs (DDCs). These cells recognize pathogens via pattern recognition receptors, mature and migrate out of the skin into draining lymph nodes, where they orchestrate adaptive immune responses. In order to investigate the response of skin DCs during the early immunopathogenesis of Lyme borreliosis, we injected B. burgdorferi intradermally into full-thickness human skin and studied the migration of DCs out of the skin, the activation profile and phenotype of migrated cells. We found a significant increase in the migration of LCs and DDCs in response to B. burgdorferi. Notably, migration was prevented by blocking TLR2. DCs migrated from skin inoculated with higher numbers of spirochetes expressed significantly higher levels of CD83 and produced pro-inflammatory cytokines. No difference was observed in the expression of HLA-DR, CD86, CD38, or CCR7. To conclude, we have established an ex vivo human skin model to study DC-B. burgdorferi interactions. Using this model, we have demonstrated that B. burgdorferi-induced DC migration is mediated by TLR2. Our findings underscore the utility of this model as a valuable tool to study immunity to spirochetal infections.

Prof Trevor Marshall
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Minocycline is a ligand for the PXR. It affects 100's of proteins, not just TLR2.

Reductionism is dangerous for just this reason - a narrow focus on input to, and output from, a study often bears little resemblance to the functioning of real, live, humans.



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