Antiviral effects of menthol against coxsakievirus B

[Kalina]

https://res.mdpi.com/d_attachment/viruses/viruses-12-00373/article_deploy/viruses-12-00373.pdf

 

[Hip]

Looks like an interesting new paper, @Kalina.

I will take me some time to read and understand it, to see if there might be any benefits of taking menthol orally for coxsackievirus B.

Menthol of course is found in peppermint oil. You can buy pure menthol crystals quite cheaply (although you have be careful, because menthol can actually chemically burn the skin).

 

[junkcrap50]

Inducing “cold” by stimulating transient receptor potential cation channel subfamily M member 8 (TRPM8) with menthol led to reduced infection and also resulted in lower levels of mitochondrial fission during infection. Additionally, menthol stabilized levels of mitochondrial antiviral signaling (MAVS) which is known to be tied to mitochondrial dynamics. Taken together, this highlights a novel pathway wherein CVB relies on TRPV1 to initiate proviral mitochondrial fission, which may contribute to the disruption of antiviral immunity.

Seems like this information may tie in very well with Prusty's research. Perhaps menthol would normalize the Ron Davis's nanochip.

 

[Kalina]

I suppose there is no harm in trying a peppermint oil capsule supplement. Is there any possibility that it would harm an already inflamed pancreas?

 

[Hip]

I suppose there is no harm in trying a peppermint oil capsule supplement. Is there any possibility that it would harm an already inflamed pancreas?

I've use peppermint oil capsules to treat my IBS-D, and it does help the IBS, but I have not noticed any benefit for my ME/CFS which associated with coxsackievirus B4 infection.

Maybe higher doses of peppermint oil might work; but higher doses can be toxic, as menthol is toxic in high amounts.

 

[Hip]

Seems like this information may tie in very well with Prusty's research. Perhaps menthol would normalize the Ron Davis's nanochip.

Yes, the paper says some interesting things about coxsackie B virus (CVB) and mitochondria, which I was not aware of before:

It was reported that certain viruses induce mitochondrial fission to support infection. We documented that CVB triggers mitochondrial fission and blocking mitochondrial fission limits infection.

Our preliminary findings suggest that CVB relies on TRPV1-mediated mitochondrial fragmentation

Other viruses have also been shown to rely on mitochondrial fission and mitophagy to further infection. Hepatitis B virus induces fission and mitophagy as a method to impair antiviral apoptosis

Cytomegalovirus has been shown to induce mitochondrial fission via the viral antiapoptotic protein vMIA

Menthol treatment reduces mitochondrial fission basally and during CVB infection- HeLa cells were treated with 1 mM menthol and then examined after 6 h.

 

[junkcrap50]

More stuff on TRPM8

Beneficial Effects Induced by TRPM8 Channels Activation to Treat Myocardial Infarction
https://academic.oup.com/ajh/article-abstract/33/3/214/5680165

It is possible that the activation of TRPM8 by menthol coupled sarcoplasmic reticulum Ca 2+ release to mitochondrial Ca 2+ uptake, which promotes the activity of pyruvate dehydrogenase (PDH) and mitochondrial oxidative phosphorylation (OXPHOS), inhibiting reactive oxygen species (ROS) generation.

Can't find or get the full paper. This quote is from the results in google.

Activation of Transient Receptor Potential Melastatin Subtype 8 Attenuates Cold‐Induced Hypertension Through Ameliorating Vascular Mitochondrial Dysfunction
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586416/

In vitro, we confirmed that sarcoplasmic reticulum–resident TRPM8 participated in the regulation of cellular and mitochondrial Ca2+ homeostasis in the vascular smooth muscle cells. TRPM8 activation by menthol antagonized angiotensin II induced mitochondrial respiratory dysfunction and excess reactive oxygen species generation by preserving pyruvate dehydrogenase activity, which hindered reactive oxygen species–triggered Ca2+ influx and the activation of RhoA/Rho kinase pathway.
...
Mitochondria, Ca2+, and reactive oxygen species (ROS) are each integral to vascular function and are thought to be involved in the development of hypertension. Pyruvate dehydrogenase (PDH) and several complexes of electron transport have been reported to be Ca2+ dependent.8 Increased physiological levels of mitochondrial Ca2+ uptake is the coordinated upregulation of the entire oxidative phosphorylation activity.9 PDH is one of the key dehydrogenases of the tricarboxylic acid cycle, the activity of which is blunted by Angiotensin II (Ang II) by increasing PDH phosphorylation in vascular smooth muscle cells (VSMCs).10 Meanwhile, mitochondrial matrix Ca2+ overload impairs mitochondrial function and leads to ROS generation.11 Excessive mitochondrial ROS is implicated in the development of vascular dysfunction.12 Ang II–induced mitochondrial ROS generation promotes Ca2+ influx and, subsequently, contraction in arterial smooth muscle.13 Under pathological conditions of cytosolic Ca2+ overload, mitochondria are capable of taking up large amounts of Ca2+.14 This vicious cycle might be an important factor contributing to the excess mitochondrial ROS production in VSMCs. Indeed, ROS‐mediated upregulation of the RhoA/Rho kinase pathway promotes vasoconstriction and contributes to high blood pressure (BP).15 It is worth investigating whether ameliorating mitochondrial dysfunction disrupts this vicious cycle and attenuates vascular dysfunction in hypertension.

Currently, application of ROS scavengers, which eliminate the total levels of tissue and cellular ROS, has not generally achieved favorable effects on ameliorating cardiovascular diseases.16 Using mitochondria‐targeted antioxidants to alleviate mitochondrial oxidative stress might efficiently attenuate hypertension.
....
To further examine the effect of TRPM8 activation on mitochondrial ROS mediated RhoA/Rho kinase activation, we performed studies in primary cultured aortic VSMCs. It showed that mitochondrial‐targeting ROS scavenger MitoTEMPO efficiently inhibited Ang II–induced RhoA/Rho kinase pathway activation (Figure 6G through through6J).6J). Menthol treatment similarly inhibited the activation of RhoA pathway in VSMCs from WT but not Trpm8−/− mice (Figure 6G through through6J).6J). These results suggest that the activation of TRPM8 by menthol prevents excessive mitochondrial ROS‐mediated RhoA/Rho kinase pathway activation in the vasculature from CIH.

Lots of stuff in there that sounds it might be relevant to CFS. Have to reread and read more about TRPM8. Also reread about Calcium in ME/CFS. But menthol sounds like it can act as a mitochondrial antioxidant.

 

[sometexan84]

Bump

@Hip Did you ever find anything more? Oral menthol treatment?

 

[Hip]

@Hip Did you ever find anything more? Oral menthol treatment?

Have not looked into it any more as yet, but oral menthol I don't think is going to work to reduce mitochondrial fission, as the in vitro experiment used a menthol concentration of 1 mM, which is a high concentration, and I would not think that can be achieved in vivo, because menthol is quite toxic ay higher doses, although I have not looked at the pharmacokinetics of menthol in detail.

It's interesting that menthol can actually cause 3rd degree chemical burns, because is an irritant and is water insoluble, and is not therefore washed away when placed on the skin.

 

[dreamydays]

I have been taking 300mg menthol x2 daily, which I ground down and capsulated with gloves. and I feel it could be having a beneficial effect but always hard to be sure. Its only very occasionally I have took something and it have an instant affect (although it does happen sometimes). It does help with sleep a little, probably due to its affects on GABA, its actually got quite a few mechanisms. I would be interested to know more about concentrations needed as its got a low lethal dose, so I have been cautious.

 

[Hip]

I have been taking 300mg menthol x2 daily, which I ground down and capsulated with gloves.

Because of the skin burn effect of menthol, I was wondering whether pure menthol powder could burn the stomach lining a bit if the stomach was empty, with no fat in the stomach. When you buy peppermint oil capsules, which contain menthol, this menthol is dissolved within the peppermint oil (menthol is fat soluble but water insoluble).

So I decided to make my own "peppermint oil" by dissolving some menthol powder into warm sunflower cooking oil (the oil heated on the gas stove), such that one tablespoon (15 ml) of this oil provides 240 mg of menthol. I keep this oil in a glass bottle, and dispense a tablespoon of it when I want to take menthol. This is cheaper than buying peppermint oil capsules.

I found peppermint oil capsules (and my own menthol in cooking oil mixture) helps my IBS-D, that's why I take it.

 

[dreamydays]

@Hip
We both haven't felt any burning or discomfort. Occasionally we can feel it in our throat and its like a cooling sensation. The research and mitochondrial effects sound very promising, but do you think dosing is impossible?

 

[Hip]

The research and mitochondrial effects sound very promising, but do you think dosing is impossible?

No, I don't think you will be able to obtain the concentrations used in the in vitro study, which were 1 mM (one thousandth of a mole per liter). Which is the same as 1000 μM.

This pharmacokinetic study found that after adults took a peppermint oil capsule, the peak blood concentration of menthol was 698 ng/mL, which converts to 4.5 μM.

A blood concentration of 4.5 μM is much smaller than the 1000 μM concentration used in vitro.


(And that does not even take in account plasma protein binding, which further reduces effective blood concentrations).

 

[dreamydays]

@Hip
Thanks for the information. I would not want to take more than 600mg at a time. What kind of concentration do you believe that would achieve? I feel like this forum needs a boost, I remember some politics causing a loss of posters. We need all the patients and research we can assemble. It's time for us to really push things forward and support each other.

 

[Hip]

Thanks for the information. I would not want to take more than 600mg at a time. What kind of concentration do you believe that would achieve?

The study I mentioned used peppermint oil capsules containing 187 mg of menthol. So if 187 mg of oral menthol results in a blood concentration of 4.5 μM, then 600 mg oral will achieve about 14 μM.

Which is much lower than the 1000 μM concentration used in vitro, in the mitochondrial study. And this does not even take into account plasma protein binding effects, where ingested substances bind to proteins in the blood, and are effectively lost. Once you take into account protein binding, the effective menthol blood concentration will be even lower than 14 μM.

So unfortunately I don't think there is the remotest chance of obtaining the 1000 μM concentration used in vitro.

 

[dreamydays]

The study I mentioned used peppermint oil capsules containing 187 mg of menthol. So if 187 mg of oral menthol results in a blood concentration of 4.5 μM, then 600 mg oral will achieve about 14 μM.

Which is much lower than the 1000 μM concentration used in vitro, in the mitochondrial study. And this does not even take into account plasma protein binding effects, where ingested substances bind to proteins in the blood, and are effectively lost. Once you take into account protein binding, the effective menthol blood concentration will be even lower than 14 μM.

So unfortunately I don't think there is the remotest chance of obtaining the 1000 μM concentration used in vitro.

I appreciate you calculating the pharmacokinetics for us. So my next obvious thought is what else activate TRPM8?

What does anyone know about Icilin? https://en.wikipedia.org/wiki/Icilin