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INOSINE antinociceptive, antidepressant, anti neurogenic detrusor overactivity

Discussion in 'Other Health News and Research' started by pattismith, Nov 12, 2018.

  1. pattismith

    pattismith Senior Member

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  2. pattismith

    pattismith Senior Member

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    Some extracts:

    About pain inhibition:

    "Collectively, these data indicate that inosine is an agonist for A1Rs with antinociceptive properties and a potency similar to adenosine and can be considered another endogenous ligand for this receptor."

    "Taken together, these data suggest that the antinociceptive effect of inosine is mediated,
    in part, by pertussis toxin-sensitive G-protein coupled receptors and the subsequent activation of voltage gated K+ channel, large conductance Ca2+-activated and ATP-sensitive K+ channels or inactivation of voltage-gated Ca2+ channels.
    Finally, small conductance Ca2+-activated K+ channels are not involved in the antinociceptive effect of inosine."

    "It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice.
    These effects seem to be related, at least partially, to the modulation of A1 adenosine receptors."

    About effect on Detrusor activity:

    "Inosine is a naturally occurring purine nucleoside with neuroprotective, neurotrophic and antioxidant effects that is known to improve motor function in preclinical models of Spinal Cord Injury.
    These findings demonstrate that inosine prevents the development of detrusor overactivity and attenuates existing overactivity following SCI, and may achieve its effects through modulation of sensory neurotransmission"

    "Our results indicate that inosine treatment attenuated the injury-induced increase in TRPV1 immunoreactivity, both with immediate and delayed administration, in parallel with significant improvements in detrusor overactivity. Together, these findings suggest that inosine achieves its effects, at least in part, through inhibition of TRPV1 expression and/or activity."

    "Inosine is also known to act through interaction with members of the adenosine receptor family [24,25,26] For example, the anti-nociceptive effects of inosine in diverse models of pain were found to be mediated via A1 and A2A subtypes, resulting in inhibition of protein kinase C [25] and protein kinase A, as well as modulation of KATP, Kv and BK channels [26]. A2A receptor activation was also implicated in relaxation of bladder muscle strips via KATP activation and elevation of intracellular cAMP [27], as well as in the immunosuppressive activity of inosine in experimental models of inflammation [24]"

    Our findings implicate A2B in mediating the beneficial inhibitory effect of inosine on spontaneous activity in tissues from rats with NDO. Interestingly, a recent report implicated A2B in adenosine-mediated relaxation of precontracted detrusor strips from the rat bladder31. Together with observations that decreases in expression of the A2B receptor have been reported to contribute to a reduction in evoked detrusor relaxation with aging and with declining estrogens30,32, these findings emphasise the potential for inosine as a pharmacologic agonist of A2B as well as a strategy for modulating bladder activity."

    "Inosine inhibits spontaneous activity in bladder tissue from SCI rats through a mechanism mediated by A2B adenosine receptors that impinges on large conductance BK channels"
     
    Last edited: Nov 12, 2018
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  3. pattismith

    pattismith Senior Member

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    About antidepressant effect:

    "These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders."
    @Iritu1021

    "Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A1 and A2A receptors."

    "Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3β. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression."

    "Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies."
     
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  4. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @pattismith you and I are on the same page as usual. I just began looking into nucleoside analogs myself yesterday.

    I will look into inosine but the one I found was cordycepin. You may remember that I had a strange experience when after taking a lot of cordyceps extract my ACTH shot up from 6 to 398 (!). At that time I couldn't explain it so I wrote it off as a lab error. However, I've been looking more into that and found that cordycepin - the ingredient in cordyceps - is actually a nucleoside analog that blocks viral replication by substituting by adenosine and halting DNA transcription. It also has adenosine and the ratio of cordycepin to adenosine varies by strain (C.militaris > C.sinensis). Synthetic pure cordycepin is being studied an s anti-tumor agent.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303894/
     
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  5. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I read that uridine also had some success in the treatment of bipolar depression.
     
  6. Iritu1021

    Iritu1021 Breaking Through The Fog

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  7. pattismith

    pattismith Senior Member

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    Yes, I discovered here on PR that Inosine is often used to fight viral infections (enterovirus) by ME specialists.
    This is why we need to know more about this molecule.
    We need to know if it is effective through its antiviral activity, or through its other properties;

    You wrote that Cordiceps contain adenosine, and interestingly adenosine is metabolized to inosine via deamination by
    Adenosine Deaminase.
     
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  8. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I initially assumed that my response to Cordyceps was due to adenosine. I'm going to try to test it to see which one is responsible by comparing two different strains.

    The Cordyceps I used by NOW brand is "counterfeit" Cordyceps which is grown in bags on grain for mass production.

    The original wild Cordyceps sinensis that only grows in Tibeth is rich in adenosine and low in cordycepin and has been used for thousands of years to enhance athletic performance and libido. This Cordyceps sells for $1200 - 1500 per ounce and is hard to come by in the West. Cordyceps sinensis sold as supplements is chemically different from the wild in its chemical composition but it's still low in cordycepin.

    The modern artificially created strain Cordyceps militaris is at least ten fold higher in cordycepin. I just purchased some C.militaris powder and going to see how it compares to cheap C.sinensis It might turn out that for the purpose of fighting herpes viruses it is actually better than the expensive wild variety, assuming that cordycepin does to viruses what penicillin does to bacteria. I'll also see if I can score a small amount of wild C.sinensis somewhere at an affordable price for comparison, although it will be hard to vouch for its authenticity.

    I also started taking licorice root extract after I read that it has effect against EBV. And I now take Cordyceps together with Eleuthero (an adaptogen), to help prevent the wild swings in HPA that Cordyceps seems to trigger. But I think the main reason my ACTH overshot so much is because the dose was too high. I used to take six 750 mg pills per day per directions on the bottle, now I only take one pill per day and I think even that might be too much for me. I'm going to re-test my ACTH again. It did go back to borderline low last time after I stopped taking Cordyceps.

    And it will be interesting to compare the effects from these two strains to the effect of inosine. The only issue is that I think the anti-viral effects happen on a much slower time scale than those related to adenosine.
     
    Last edited: Nov 13, 2018
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  9. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Another option is dipyridamole which is a nucleoside uptake inhibitor.
    I found here that it has a synergistic effect with inosine in lowering cytokine production. http://www.jimmunol.org/content/164/2/1013

    And here it says that it has broad antiviral activity spectrum. The study is really old so it's strange that this has never really been explored further - maybe the patent ran out?.

    The antiviral activity of dipyridamole.
    Tonew M, Tonew E, Mentel R.
    Abstract
    Dipyridamole, a coronary vasodilatator, was found to possess antiviral activity against representatives of different families. The antiviral properties were studied in chick embryo, human diplid and FL cell cultures by the agar diffusion plaque inhibition and plaque reduction tests and one-step growth cycle experiments. The inhibition of the virus-induced cytopathic effect was estimated quantitatively. Dipyridamole significantly inhibited the yield of members of the viral families Picornaviridae, Togaviridae, Orthomyxoviridae, Paramyxoviridae, Herpetoviridae and Poxviridae, as well as of Chlamydiaceae (sheep abortion agent).
     
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  10. pattismith

    pattismith Senior Member

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  11. pattismith

    pattismith Senior Member

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  12. Iritu1021

    Iritu1021 Breaking Through The Fog

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    Whenever I checked my labs my potassium is always on the upper end of normal and sodium on the low end - consistent with my low cortisol (due to low ACTH). So Iicorice seems to be a good drug for me right now.

    I haven't seen adenosine spray anywhere. If I react so strongly to oral adenosine from Cordyceps, I'd be a little scared about the intranasal pure adenosine to be honest. I'd rather try dipyridamole first.
     
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  13. Iritu1021

    Iritu1021 Breaking Through The Fog

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    The problem is that everything has a million different mechanisms. Now I also find that cordyceps acts on M1mAChR which as we know is involved in calcium signaling. And subjectively I do feel like it shifts me into parasympathetic mode -too much so if I take more than one capsule. I feel like I constantly have to balance NE vs ACh and DA vs SE levels in my body because it's lost its ability to regulate them on its own...

    https://www.dovepress.com/effects-o...carinic-acetylcho-peer-reviewed-article-JRLCR

    Abstract: Cholinergic dysfunction is implicated in the pathogenesis of memory impairment related to Alzheimer’s disease (AD). Accordingly, regulation of M1 muscarinic acetylcholine receptor (M1 mAChR) has been one of the major targets in the development of novel drugs for AD. Utilizing an in vitro system for evaluation of the M1 mAChR, we have recently identified that extracts from Cordyceps sinensis (CS) promote M1 mAChR function. In this study, we examined the effect of pretreatment with several types of CS extracts in F11 neurohybrid cells on ERK phosphorylation induced by a muscarinic agonist, carbachol (CCh). A mixed extract of a hot water extract and an ethanol extract from CS augmented ERK phosphorylation by CCh presumably through upregulation of M1 mAChR function. We further examined the effect of oral administration of CS extracts on memory impairment induced by a muscarinic antagonist scopolamine in mice, finding that CS extracts ameliorated scopolamine-induced amnesia in vivo, consistent with the in vitro data. Thus CS extracts may contribute to the prevention of memory impairment related to AD.
     
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  14. pattismith

    pattismith Senior Member

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    @Wonkmonk ,

    I read Inosine also have the property to raise intracellular calcium, but it has much more properties, and a clinical trial for ALS was just published that shows anti-oxydant effect via urate.
    The target level of urate was long to obtain (6 weeks), so the benefic effect I can notice from inosine myself is more likely the result of activity on intracellular calcium, glutamate inhibition, or on adenosine receptors.

    in this site other pathways of inosine and anti-inflammatory effect are quoted

    Upregulates GAP-43
    Probable N-kinase agonist
    Inhibits TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma

    Article here on the trial with inosine for ALS:


    "Oxidative stress has been implicated in ALS, a finding supported by the ability of antioxidant Radicava (edarvarone, by MT Pharma America) to slow disease progression. Levels of urate, a naturally occurring compound with proposed neuroprotective effects, may be increased upon treatment with Radicava.
    Studies have shown that high urate levels are associated with increased survival in ALS patients, as well as favorable outcomes in other neurodegenerative disorders.
    These findings warrant clinical trials testing urate, according to the authors, which can be conducted through the administration of urate’s precursor compound, inosine. This has already been done in Parkinson’s disease patients, with a Phase 2 trial (NCT00833690) showing that inosine raised urate levels in the serum and the cerebrospinal fluid (the liquid surrounding the brain and spinal cord) with a good safety profile. A Phase 3 study (NCT02642393) is ongoing."

    "For the first two weeks, patients took two daily 500 mg capsules of inosine — orally or through a feeding tube. The dose was then adjusted up to two capsules three times daily to achieve a urate level of 7-8 mg/dL."

    I read that people with already high urate in blood were not eligible for the trial.

    Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

    "Abstract
    Objective To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS). Methods This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores.


    Results Twenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up.
    Serum urate rose to target levels in 6 weeks.
    No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period.
    Observed changes in ALSFRS‐R did not differ from baseline predictions.
    Interpretation Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS."
     
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  15. Wonkmonk

    Wonkmonk Senior Member

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    This is interesting and especially the link with ALS, although I haven't seen any evidence that there could be a link between CFS and ALS. In fact the two diseases seem to be very different in many areas.

    At the moment, I want to try how to lower calcium rather than raise it, because one can, to some degree, raise it easily by supplementing calcium and Vitamin D and whenever I have done so, I worsened markedly.

    I'll probably make a try with miltefosine and calcium channel blockers next. That should target the voltage channels plus the Akt pathway, so it might help lower calcium. Then see what happens.

    I'm not optimistic, but I don't see anything else I could try.
     
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  16. Iritu1021

    Iritu1021 Breaking Through The Fog

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    @Wonkmonk, taking vitamin D and calcium (in the absence of overt deficiency) will have virtually zero effect on your intracellular calcium if the cellular settings are off. It will all just stay in the blood and be filtered out in your urine, increasing your risk for kidney stones. Regulation of intracellular calcium is much more complicated than that.
    But if you worsened from it that might imply over sensitive calcium channels (which respond to extracellular calcium). You might want to try gabapentinioids (gabapentin, pregabalin or phenibut) to stabilize them. Because if they are extra sensitive they usually swing both ways and blocking them completely might actually backfire.
     
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  17. pattismith

    pattismith Senior Member

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    @Wonkmonk
    blocking akt may be interesting by itself, but I prefer to target neuroinflammation and IL8, as this cytokine activates akt.

    Dipyridamole blocks entry of inosine in cells,

    http://www.jbc.org/content/273/45/29626.full
    "Two inhibitors of purine transport, NBTI and dipyridamole, were used to investigate whether inosine and guanosine must be transported into neurons to stimulate growth. At 20 μm, NBTI prevented both nucleosides from stimulating outgrowth (Fig. 4 b, lanes 4 and 6 versus lanes 3 and 5, respectively; p < 0.01) but had little effect on AF-1-induced growth (lanes 1, 2). Dipyridamole (10 μm) likewise blocked the effects of inosine completely (p < 0.01; guanosine not tested)."

    so I may lose the beneficial effect I get from inosine if i add Dipyridamole.(edit: but I will not lose anything if inosine activated receptors are outside the cell, which would be an interesting trial to do)

    I have already difficulties when trying to add Inosine to some other drugs like Ambroxol or Nimodipine, also neuroprotective, anti-inflammatory drugs.

    In fact I have to do several trials with only one at a time before trying any association.
     
    Last edited: Dec 1, 2018
  18. Wonkmonk

    Wonkmonk Senior Member

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    I had a different theory: It is known that herpes simplex depends on calcium for replication and cell entry and it seems to use Akt to increase calcium influx in the cell. I don't understand the biochemistry behind all this, but my simple thought is if more calcium is available in the blood, the virus has an easier time replicating.

    I do not know if this thinking has any merit, though.
     
  19. Iritu1021

    Iritu1021 Breaking Through The Fog

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    A virus is an intracellular organism so it is regulated by the calcium content inside the cell. If you were dealing with bacteria - which are extracellular organisms - it would be a different story. The calcium can manipulate your cells into increasing their intracellular calcium content but they will not be able to benefit directly from higher extracellular calcium since the body will keep a tight homeostasis for how much calcium it allows to enter the cell.
     
  20. Iritu1021

    Iritu1021 Breaking Through The Fog

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    I remember I had a hard time interpreting that study because in discussion their conclusion was that dipyridamole potentiated the effect or inosine but their findings seem to imply the opposite.

    To my recollection, Goldstein doesn't mention inosine anywhere but he did list dipyridamole as a drug he had good success with in his patient population.
     
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