Can anyone make sense of this to explain to a layperson?

[[cs...]]

Hi Terry, here is a summary, which I will add to and explain in further detail later.  Perhaps Someone will get full access to the paper.

 

More importantly I want to explain how the NO/ONOO- model , upon which the Benzodiazaphine paper is based, pertains to high blood pressure.  I know that you’ve been searching for an answer as to how Benzodiazaphine wd could have caused it.  Perhaps this might help

 

 

+see my reply to RST above

 

EDIT ADD: here’s that video on the ON/ONOO- cycle

The first 20 minutes are on the cycle dynamics (It’s a 2 hour lecture.)

 

 

 

 

 

 

 

 

 

 

1.  Summary of abstract of the Benzodiazaphine article

 

 

A bit more detail:

 

BH4  (tetrahydrobiopterin) is a necessary cofactor substrate for NO synthase (NOS) in the production of NO.  BH4 is oxidized (chemically reduced )by peroxynitrate. As we will see, this isn’t good.    With reduced levels of BH4,  due to excessive peroxynitrate production, NO synthases (NOSs) will produce superoxide (rather than NO), because NOS is no longer coupled with its cofactor or substrate, BH4.(this is called NOS uncoupling)

This is true for eNOS and nNOS synthases.

 

Superoxide is normally scavenged by SOD , but when it’s produced in high amounts the superoxide rapidly and readily combines with NO to produce more peroxynitrate.

 

Peroxynitrate plays a critical role in the Benzodiazaphine hypothesis link that you sent.  Based on the NO/ONOO- (nitric oxide/Peroxynitrate) CFS/ME hypothesis for chronic fatigue ( a lot of people are probably familiar with this theory), the authors of that piece postulate that Benzodiazaphines disrupt normal intracellular Calcium homeostasis(via glutamatergic NMDAR sensitization and excessive VGCC activation that occur  post withdrawal) to create feedback loops that incite excessive Peroxynitrate production.

 

Excessive intracellular Ca2+ (caused by the NMDAR sensitization and excessive VGCC activation )causes an increase in calcium dependent NO synthases (these are nNOS and eNOS).  Normally in the presence of adequate BH4, these synthases yield more NO, but when BH4 is lacking from excessive Peroxynitrate, these synthases yield even more superoxide . 

 

Quote

 

Potentiation of L-type voltage-gated calcium channels and excessive N-methyl-D-aspartate receptor activity both result in calcium influx into the cell that triggers nitric oxide synthesis. In pathophysiological conditions(dm123: for example low BH4), such increased nitric oxide synthesis leads to peroxynitrite formation.

 

End quote

 

    More Peroxynitrate production reduces (oxidizes)BH4 even further making it more likely that NOSs (remember, the NOSs are excessive due to high intracellular Calcium) produce more superoxide (rather than NO). 

 

More superoxide makes it more likely that the NO will combine with the superoxide to yield more Peroxynitrate.  As you can see this spirals out of control and is a self perpetuating loop of depleted BH4, elevated superoxide , reduced NO, and elevated Peroxynitrate. All bad.

 

Peroxynitrate , in and of itself , is pro inflammatory and pro oxidant and causes oxidative stress and further disruptions in intracellular Calcium homeostasis.

 

 

I will dissect the Benzodiazaphine article in much more detail relative to the NO/ONOO- feedback loops later along with therapeutic regimens, for breaking these feedback loops.(hoping someone will get full access to the article)

 

The stressors to this NO/ONOO-  model are in the form of oxidative stress and mitochondrial dysfunction.  Instigators of iNOSs could be viruses (EBV for example), parasites , bacterial infections (Lyme disease, for example), tumor growth.  Instigators of eNOSs and nNOSs are  primary oxidative stress from psychosocial negative stressors, or negative physical stress (too much exercise or lack of rest, etc….).  We’ve discussed negative stressors a lot on this thread.   

 

The Benzodiazaphine paper hypothesizes Benzodiazaphine post withdrawal as another instigator of excessive nNOS and eNOS via the path described above.    Genetically, some may be predisposed to this feedback cycle due  to genetically compromised low BH4 production (that’s one of many theories in CFS).  There’s a lot more to this story to be explored. (Differences between eNOS,iNOS,and nNOS will be explained at a later time)

 

So in summary, what I posted to RST,

 

…..another path in the NO/ONOO- model that incites calcium dependent NOSs (nitric oxide synthases) such as nNOSs and eNOSs.  These are increased when the intracellular Calcium influx increases vastly.  The Benzodiazaphine hypothesis link posted above postulates that first dysfunction in VGCCs, and then subsequent sensitization of NMDARs predispose individuals to this high influx of Ca2+ into the neurons and cells.  The abstract also mentions decompensation of GABAaRs as well, occurring after onset, which would certainly increase the probability of perpetuating the bias towards depolarization.. 

 

There’s an overlap with the current Benzodiazaphine model in that the glutamatergic and GABAergic pillars are involved in this hypothesis, and the stress pillar is destabilized via oxidative stress and mitochondrial dysfunction.  Certainly negative stressors.

 

The main crux of the hypothesis is a persistent overproduction of Peroxynitrate (ONOO-) which , in and of itself is pro oxidant.  It oxidizes a substrate called BH4, which is essential for conversion of NOSs to NO.  When BH4 gets low, more and more of the NOS converts to superoxide rather than NO.  The problem with that is that superoxide very rapidly and forcefully reacts with any NO in the proximate tissues to form more Peroxynitrate.  You can see that a viscous cycle ensues perpetuating the oxidative stress.

 

 

 

 

 

 

 

 

 

2.    ON/ONOO- cycles, Peroxynitrate, and Blood pressure

 

 

I’ve listed a lot of material on how elevated Peroxynitrate levels affect hypertension etiology.  In light of the above, if  Benzodiazaphines do affect Peroxynitrate levels as described above, this would perhaps explain the PWS hypertension.

The below explains why angiotensin inhibitors (like losartan) are so effective in this context, as well as other therapeutics.  By the way BH4 is available as a supplement but undergoes peroxidation in oral form, so it might be more harmful than good.  BH4 precursors like biopterin and sepiapterin are helpful in raising BH4.  People on a CFS forum might be able to help you find it.

 

 

 

 

Quote

 

Hypertension is thought to be caused by shifting the ratio of nitric oxide to peroxynitrite, towards excessive peroxynitrite, something that is produced by the action of the central couplet (dm123: BH4 Peroxynitrate tradeoff). This role in hypertension is a consequence of the following: whereas nitric oxide is a vasodilator, peroxynitrite is a vasoconstrictor, acting in part by raising the levels of isoprostanes, which are potent vasoconstrictors. For example, vasopressin II acts to produce hypertension by inducing higher levels of NADPH oxidase, an enzyme whose activity produces superoxide.17 The reaction of superoxide with nitric oxide will produce peroxynitrite and thus turn on the central couplet. Depletion of BH4 levels has been shown to have an important role in causing hypertension.18-20

 

End quote

 

 

 

After the cycles get going one is left with low BH4, lower NO, higher superoxide, and escalating Peroxynitrate.  This is bad for blood pressure.

 

 

 

 

 

 

 

3……..a bit more on NOS uncoupling

 

https://www.ncbi.nlm.nih.gov/pubmed/24180388

 

Quote

 

Nitric oxide (NO) is a gaseous signaling molecule and effector in various biological processes. In mammalian cells, NO is produced by a family of NO synthases (NOS). Three NOS isoforms have been identified as: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). In addition to NO, NOS also produces superoxide anion. This phenomenon is named NOS uncoupling as superoxide generation mainly occurs when NOS is not coupled with its cofactor or substrate.

 

nNOS was first found to produce superoxide under L-arginine depletion condition. Further studies demonstrated that superoxide production is a general feature of all three NOS isoforms. In particular, superoxide generated from uncoupled eNOS has been found to play critical roles in the process of various cardiovascular diseases. Although NOS was first found to produce superoxide only when uncoupled with its cofactor or substrate, recent studies reveal that oxygen reduction to superoxide is an intrinsic process amid NO synthesis.

 

 

(b]Tetrahydrobiopterin (dm123: BH4) [/b]plays a controlling role in preventing superoxide release from the eNOS oxygenase domain. Besides tetrahydrobiopterin, the regulation of eNOS uncoupling by the interactions with other proteins, protein phosphorylation, S-glutathionylation, and endogenous L-arginine derivatives, will be discussed in this review.

 

End quote

 

 

 

 

 

 

 

 

 

4.  From the second link you sent

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248324/

 

 

Peroxynitrate and heart disease

 

Blood pressure

 

Quote

 

Endothelial cells in response to various physical and chemical stimuli (e.g., shear stress, change in pressure and pH), circulating hormones, cytokines, drugs, and substances released by sensory and autonomic nerves or platelets produce vasoactive relaxing substances (e.g., NO, endothelium-derived hyperpolarizing factor, prostacyclin, adenosine, C-natriuretic peptide) and contracting substances (e.g., angiotensin II, endothelin-1, thromboxane A2, isoprostanes) that regulate vascular tone and permeability, hemostasis, angiogenesis, and inflammation (381). The vascular endothelium sustains the balance between prevention and stimulation of platelet aggregation, thrombogenesis and fibrinolysis, promotion and inhibition of the smooth muscle cell proliferation and migration, and also between vasoconstriction and vasodilation (289). The disruption of this tightly controlled balance leads to the development of endothelial dysfunction, a multifaceted disorder, which represents a predominant early feature of diabetes, hypertension, heart failure, and atherosclerosis and makes this population prone to cardiovascular complications and microthrombus formation (166, 381, 731). Although the hallmark of endothelial dysfunction is impairment of the endothelium-dependent vasodilation, other alterations (e.g., inflammation, increased lipoprotein oxidation, vascular smooth muscle proliferation and migration from the media to the intima, extracellular matrix deposition or lysis, platelet activation, and thrombus formation) associated with this disorder have also been described (365). Accumulating evidence supports the view that the endothelial dysfunction associated with diabetes, hypertension, heart failure, and atherosclerosis is related to the local formation of reactive oxygen and nitrogen species in the vicinity of the vascular endothelium (reviewed in Refs. 365, 478, 630, 757, 775, 996, 1004, 1306, 1378, 1380, 1381).

 

As already mentioned previously and summarized in Table 3, peroxynitrite may contribute to vascular pathophysiology by various mechanisms including triggering apoptosis and/or PARP-dependent cell death in endothelial (319, 879) and vascular smooth muscle (755, 756) cells, inducing upregulation of adhesion molecules in endothelial cells, endothelial glycocalyx disruption, enhancing neutrophils adhesion (424, 723, 1178, 1447, 1477), inhibiting voltage-gated K+ K(v) and Ca2+-activated K+ channels in coronary arterioles (754, 786) and vascular prostacyclin synthase (228, 290, 1466, 1467, 1472, 1475), and dependent on the environment stimulating or inhibiting platelet aggregation (908, 953).

 

Additionally, peroxynitrite-mediated oxidation of tetrahydrobiopterin(dm123: this is the BH4 discussed above), a critical cofactor for NO synthase, may represent a pathogenic cause of uncoupling of NO synthase, leading to production of superoxide rather than NO (405–407, 734). Furthermore, clinically relevant concentrations of 3-nitrotyrosine (present in various pathophysiological diseases, Table 4) result in concentration-dependent impairment of acetylcholine- induced, endothelium-dependent vascular relaxation and induce DNA damage in vascular endothelial cells (879, 1473).

End quote

 

 

 

 

More on BP

 

 

Quote

 

Arterial hypertension, the chronic elevation of blood pressure, is a major public health concern even though it is not a disease per se. Untreated hypertension leads to premature morbidity and mortality due to stroke, accelerated coronary arterial disease, myocardial infarction, and cardiac and renal failure. In the majority of cases, the principal cause of the disease remains elusive (primary, essential, or idiopathic hypertension), and therapy, therefore, is symptomatic rather than preventive (506). The vascular effects of the chronic elevation of blood pressure are complex and comprise both local effects on the vascular endothelium and smooth muscle and effects mediated by the CNS and increased production of various neurohumoral factors (e.g., angiotensin II, catecholamines, endothelin, etc.) (499, 698, 1035).

 

 

Accumulating evidence suggests that alterations in NO synthesis and NO-sGC-cGMP signaling or a reduction in the bioavailability of endothelium-derived NO by increased oxidative stress are key contributors to the pathogenesis of hypertension (reviewed in Refs. 365, 372, 698, 964, 1004, 1379). Numerous experimental studies using animal models of disease [e.g., angiotensin II infusion, deoxycorticosterone with a high salt diet (DOCA salt), Dahl hypertensive rats, spontaneously hypertensive rats (SHR), chronic inhibition of eNOS, and aortic banding] and clinical reports have established that hypertension is associated with increased superoxide production, dysregulation of NOS, and endothelial dysfunction. However, the exact molecular mechanisms of these processes are not fully understood (95, 166, 167, 172, 269, 416, 535, 699, 733, 889, 1065, 1180, 1305, 1335, 1343).

 

……

 

Compelling evidence has emerged supporting the importance of endogenous peroxynitrite formation and protein nitration in the pathogenesis of arterial hypertension (reviewed in Refs. 365, 1300). Increased superoxide formation, gene expression of several subunits of NAD(P)H oxidases, eNOS, and nitrotyrosine were markedly increased in the aorta segment above aortic coarctation (hypertensive zone) and in hearts of aortic-banded rats and mice compared with normotensive controls (65, 125, 724, 1324). Interestingly, substantial changes in endothelial dysfunction were only observed when NOS expression and superoxide production were simultaneously increased and were associated with enhanced nitrotyrosine formation (125, 1300), suggesting that enhanced superoxide production alone is not sufficient to produce endothelial dysfunction. Increased peroxynitrite formation or protein nitration was also reported in the serum (643, 1402), vasculature (269, 565, 643, 776, 815, 1217, 1252), and kidneys (1080) of SHR rats, malignant stroke-prone spontaneously hypertensive rats (M-SHRSP), and SHR/ND-mcr-cp (SHR/cp) rats (genetic model of the metabolic syndrome).

 

Antioxidant-rich diet (1080), the SOD mimetic M40403 (269), the polyphenol chlorogenic acid (1217), the angiotensin-converting enzyme inhibitor ramipril (776), the adrenoceptor blocker with antioxidant properties carvedilol (815), and the cofactor of eNOS tetrahydrobiopterin (565) attenuated hypertension and nitrotyrosine formation in vasculature and kidneys and improved compromised vascular function and end-organ damage.

 

Angiotensin II, a well-known factor in the pathogenesis of most cardiovascular disorders and a natural regulator of blood pressure, can induce superoxide formation mediated at least in part by vascular NAD(P)H oxidases (416, 478, 733, 889, 1065). Reactive oxidant species in turn can exert direct oxidative effects, but can also signal through pathways such as mitogen-activated protein kinases, tyrosine kinases, and transcription factors and lead to events such as inflammation, hypertrophy, remodeling, and angiogenesis (478, 969, 1004). Recent studies have demonstrated that angiotensin II can also induce peroxynitrite formation and PARP activation in endothelial cells in vitro (880, 1236) and in aorta, heart, and kidneys of rats (492, 656, 1236, 1349) and mice (1159, 1342) following chronic infusion in vivo. Protein nitration correlated with the extent of endothelial dysfunction (1349), and both were attenuated by supplementation with tetrahydrobiopterin (656).

 

Remarkably, in most of these conditions, the decrease in blood pressure and improvement in hypertension-associated endothelial dysfunction and end-organ damage to various drugs or interventions aiming to reduce blood pressure and decrease oxidative stress (e.g., vitamin E, losartan, tempol, carvediol, diet, etc.) was always associated with reduction of 3-NT in vasculature, heart, and various other organs (170, 327, 1323, 1325). Thus it appears that peroxynitrite plays an important role in the pathophysiology of hypertension.

 

In conclusion, multiple lines of evidence discussed above and listed in Table 4 suggest that peroxynitrite plays an important role in various forms of cardiovascular dysfunction and injury; pharmacological neutralization of this reactive oxidant or targeting the downstream effector pathways may represent a promising strategy to treat various cardiovascular disorders.

 

End quote

[[Te...]]

Thank you very much, dm123!! I'm sorry, something came up today and I haven't been able to read it. But I will tomorrow!

 

P.S. I got the results of my blood test, and norepinephrine is off the charts! Doesn't bode well, I know...

[[Re...]]

dm123, THANK YOU.  YOUR CONTRIBUTIONS HERE ARE A BLESSING FOR US ALL.  Many of us would be so lost without contributions such as yours.     

 

 

-RST

[[Ms...]]

Full text if anyone wants to read along. Thanks for doing this DM

 

https://authors.elsevier.com/a/1XGRQ15pGbvb~T

[[Ca...]]

Ty..

A bit easier to read than some...

 

 

[[li...]]

dm123,

 

What about that article ? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

'Benzodiazepines’ action on voltage activated calcium channels appear to play an important role in benzodiazepine dependency and withdrawal [12]. Benzodiazepine administration can regulate L-type voltage-gated calcium channel (L-type VGCC) expression [12]. Benzodiazepines can directly inhibit L-type VGCC-mediated calcium influx and high voltage-activated (HVA) currents [13], [14], [15]. Benzodiazepines’ inhibition of L-type VGCC’s may partially explain the therapeutic effect of clonazepam, a benzodiazepine class drug, in the treatment of ME/CFS, in lowering over-activity of the brain [16].' I haven't read much about benzo's effects on calcium channels in modern literature.

 

And it mentions clonazepam.

 

[[cs...]]

Hi all,

 

I posted this on the other thread on NO/OONO- cycle.   

 

http://www.benzobuddies.org/forum/index.php?topic=205249.10

 

The benzdiazaphine model in this thread is extensible, meaning pillars can be added (think of pillars as the x axis), and systems or components upon which they act, can be added (think of systems or components as y axis).  Ive known about NO and NOSs effects on tolerance and wd for some time, in addition to some other pillars listed below, but haven’t had the time to incorporate them into this benzdiazaphine model.

 

A summary of the model so far is on page 40 of this thread.  Once I read through the NO/ONOO- doc I will incorporate it into this larger model.

 

 

It fits in very well.    I will also pull in some therapeutics, but the CFS forums have much more information  on therapeutics.

 

My post from the NO/ONOO- thread::

==========

 

Hi intendtobeoff

 

1. Just so that i answer you correctly, can you tell me if you are in PWS, or if you are  currently tapering?

 

2. Also relative to the cluster of those 4 major stressors, were you on benzodiazaphines at the time, or did you start after the cluster stress event?

 

The very short answer to your question is that the stress system is the critical link between the layman’s benzodiazaphine model and the NO/ONOO- model proposed in that link above.  Both models have benzodiazaphines as the initial inciting force that causes destabilization.

 

The NO/ONOO- dysfunction ultimately results in “ cellular stress” ( persistent oxidative stress and mitochondrial dysfunction) which serve as more negative inputs into the “stress system” of the laymans benzodiazaphine model.

 

In the laymans thread there are many “other systems” that directly influence benzodiazaphine tolerance, wd , and PWS.  I have only mentioned them briefly in that thread so far.

 

Some addtional pillars are:

 

1. NO and NOS system (ie, the NO/ONOO- cycle above)

2. GPCRs (5-ht, DA, ACh, etc)

3. Neurotrophic factors

4. Kindling

5. And some others.

 

So far Ive only covered the glutamatergic , GABAergic, and stress hormone pillars in the laymans thread.  All the pillars interact with one another, and destabilizing one has the potential to destabilize some of the others.  Once the pillars are destabilized stress resiliency deteriorates and this perpetuates symptoms (PWS).

 

The NO and NOS system would be added as a 4th pillar alongside the 3 that I have covered.

 

The important thing for you is to minimize negative stressors during your recovery.  There are a lot of CFS supplements that can help restore the NO/ONOO- cycle back to normalcy, but PWS, like CFS, is a syndrome, ie a constellation of symptoms with a complex etiology.    Benzodiazaphine PWS is also  due to additional adverse neuroplastic and neurogenic ( adult neurogenesis) changes that can take a long time to resolve.

 

I haven’t read the complete hypothesis document cited above, but the author does state that the ailments that occur in benzdiazaphine PWS may at least in part be due to NO/NOS cycle dysfunction.  I believe it’s part of the much larger model, as described above.

 

 

[[cs...]]

dm123,

 

What about that article ? https://www.sciencedirect.com/science/article/pii/S0306987718303645

 

'Benzodiazepines’ action on voltage activated calcium channels appear to play an important role in benzodiazepine dependency and withdrawal [12]. Benzodiazepine administration can regulate L-type voltage-gated calcium channel (L-type VGCC) expression [12]. Benzodiazepines can directly inhibit L-type VGCC-mediated calcium influx and high voltage-activated (HVA) currents [13], [14], [15]. Benzodiazepines’ inhibition of L-type VGCC’s may partially explain the therapeutic effect of clonazepam, a benzodiazepine class drug, in the treatment of ME/CFS, in lowering over-activity of the brain [16].' I haven't read much about benzo's effects on calcium channels in modern literature.

 

And it mentions clonazepam.

 

Hi liberty,

 

Yes, I’ve been posting on that thread for the last few days.  If you recall, we have those “other systems” that I haven’t gotten to.  See my post above.  I’ve known about NO and the others for quite a while.  NO was listed in a Hindawi article that you and I exchanged around 9 months ago, and it’s been in my notes.    The Benzodiazaphine model is extensible and the NO and NOSs are a 4th pillar that can be added.    The component (system) that they affect will be called Cellular integrity/Cellular homeostasis.  The disruptions that benzdiazaphines cause via dysfunctional NOS and Peroxynitrate cycle dynamics output:

 

mitochondrial dysfunction and

More oxidative stress. 

 

These “cellular stresses”are inputs into the larger benzdiazaphine model’s “stress system” pillar.  This further magnifies the problems exemplified in the benzdiazaphine model. 

[[cs...]]

dm123, THANK YOU.  YOUR CONTRIBUTIONS HERE ARE A BLESSING FOR US ALL.  Many of us would be so lost without contributions such as yours.     

 

 

-RST

 

Hi Terry and RST

 

Im wondering if some of us can get the blood test for ONOO- decomposition product

 

3-nitrotyrosine

 

CFS folks can probably tell us who does these tests and where to get them done.

 

I believe that some (but not all) of those in PWS might have elevated levels if the hypothesis is true.

 

I wanted to post another link that many have probably already seen.  It has therapeutics.

 

http://www.townsendletter.com/FebMarch2010/cureNO0210.html

 

 

I’ve tried high dose methylcobalamin(active b12) in the past and it made things worse

Same with methylfolate.    So one has to be careful. I do take a lot of antioxidant like vit C, CoQ10,:etc.

 

 

Here are some additional therapeutics mentioned in the MAB posted NO/ONOO- article. See table 1 to ascertain when to take these (ie, during wd vs. after wd, etc.....)

 

(In addition please see my post to Terry above for those with HBP.  BH4 precursors.  The MAB NO article states direct BH4 but I’ve read BH4 peroxidizes readily in the body, so it’s best to use precursors )

 

Nimodipline.  A VGCC antagonist that is used for HBP and some other indications.  It binds to the L type VGCCs, and interestingly is an antagonist on MRs, ie anti-mineralocorticoid activity.

 

We know about NMDAR antagonists ketamine and memantine.  Need doctor’s supervision on these.

 

We know gabapentin acts on VGCCs

 

Antioxidants mentioned in Dr Palls article (link above)

 

 

[[cs...]]

Thank you very much, dm123!! I'm sorry, something came up today and I haven't been able to read it. But I will tomorrow!

 

P.S. I got the results of my blood test, and norepinephrine is off the charts! Doesn't bode well, I know...

 

Hi Terry, I think the norepinephrine is so high because your stress system is on autopilot.  I had mine done 4 years ago when my problems started and it was 3 times the upper range.  It was around 1500 or 2000.  The stress system is what ties everything together.  Hope you read the HBP post above.

 

If you could get tested for 3-nitrotyrosine that would be helpful.

[[cs...]]

Full text if anyone wants to read along. Thanks for doing this DM

 

https://authors.elsevier.com/a/1XGRQ15pGbvb~T

 

Thanks MAB for starting your thread.  It pushed me into adding that 4th pillar to the benzdiazaphine model in this thread.  GPCRs are another pillar that needs to be added.

 

Thanks again

[[cs...]]

dm123, THANK YOU.  YOUR CONTRIBUTIONS HERE ARE A BLESSING FOR US ALL.  Many of us would be so lost without contributions such as yours.     

 

 

-RST

 

Hi RST

 

Thanks.

 

I think the transient receptor potential cation channel (TRP receptor in The NO/ONOO- cycle diagram) is worth looking into for neuropathic pain.    There’s tons of literature on pain sensitization and these channels.  It’s worth looking into.....relative to neuropathic pain.

[[li...]]

I know I wrote about this in a PM ... maybe it fits into this thread

 

Something I read on another forum, discovered by accident.

 

'A vast majority of CRH neurons (>94.5%) were found to express transcripts specific for the the alpha2, beta1 and beta3 subunits; mRNAs for the alpha1 and beta2 subunits of the GABA(A) receptor were detected within 53.3% and 65.7% of PVN CRH neurons, respectively.''

 

https://www.ncbi.nlm.nih.gov/pubmed/10723009

 

I'm sure lorazepam had a much greater affinity for alpha 1, I'd guess that lorazepam also had a greater affinity for alpha 2 than clonazepam. That might be a piece of the puzzle as to why I'm experiencing hormonal issues of which at least some are equivalent to functional hypercorticolism/hyperglucocorticoid activity.

 

Honestly, it scares me. I don't know if you have an opinion about this. It seems real, although I do not fully understand that mRNA issue. I had been pondering about the equivalent of a 'cold turkey'. I can't do the 'I'm fine, just tapering based on symptoms' thing.

 

 

[[Re...]]

Hello, everyone.

 

dm, I'll look see what is available for the 3-nitrotyrosine test in my area.

 

Many more pieces to consider.  I wish I had your knowledge as I know that as much as I research I am sure I am missing a lot along the way that could be helpful in 'focusing the picture'. 

 

All the best.

 

-RST

[[cs...]]

I know I wrote about this in a PM ... maybe it fits into this thread

 

Something I read on another forum, discovered by accident.

 

'A vast majority of CRH neurons (>94.5%) were found to express transcripts specific for the the alpha2, beta1 and beta3 subunits; mRNAs for the alpha1 and beta2 subunits of the GABA(A) receptor were detected within 53.3% and 65.7% of PVN CRH neurons, respectively.''

 

https://www.ncbi.nlm.nih.gov/pubmed/10723009

 

I'm sure lorazepam had a much greater affinity for alpha 1, I'd guess that lorazepam also had a greater affinity for alpha 2 than clonazepam. That might be a piece of the puzzle as to why I'm experiencing hormonal issues of which at least some are equivalent to functional hypercorticolism/hyperglucocorticoid activity.

 

Honestly, it scares me. I don't know if you have an opinion about this. It seems real, although I do not fully understand that mRNA issue. I had been pondering about the equivalent of a 'cold turkey'. I can't do the 'I'm fine, just tapering based on symptoms' thing.

Hi Liberty

 

Yes, I’ve written about this extensively.  It’s the reciprocal relationship between the stress system and the GABAERGIC system pillars in the model.

 

Too bad this thread is not indexed.

 

The two pillars have a multitude of interrelationships.

 

This is a more recent paper (2012) that I wrote about extensively, as I developed the model on page 40 of this thread.

The mRNAs is just a fancy way of stating that certain subunit GABAaRs (GABAa receptors)are expressed on the cell membrane surfaces  of CRH neurons and interneurons (in the region of the brain called the PVN).  Given this the paper describes how there’s a reciprocal relationship between the GABAERGIC system and the stress system,

 

This is the link.  You can download the full pdf for free.  It’s by a very good neuroscientist McGuire in Boston.

 

https://www.frontiersin.org/articles/10.3389/fncel.2012.00004/full

 

 

The stress system pillar in the model plays a core role in PWS perpetuation. 

It also explains why and how stress hormones get dysregulated as the GABAeric system becomes more dysfunctional during tolerance and wd.    The stress system hormones also include Neurosteroids, and Neurosteroid homeostasis affect the GABAERGIC pillar, because Neurosteroids are very potent PAMs.    I posted a long piece on the various Neurosteroids from a chemistry perspective a while back on this thread.

 

Please read the link above and let me know what you think.

 

 

Here is the abstract to the paper above for those who want a summary

 

 

Quote

 

Stress-derived steroid hormones regulate the expression and function of GABAA receptors (GABAARs). Changes in GABAAR subunit expression have been demonstrated under conditions of altered steroid hormone levels, such as stress, as well as following exogenous steroid hormone administration. In addition to the effects of stress-derived steroid hormones on GABAAR subunit expression, stress hormones can also be metabolized to neuroactive derivatives which can alter the function of GABAARs. Neurosteroids allosterically modulate GABAARs at concentrations comparable to those during stress. In addition to the actions of stress-derived steroid hormones on GABAARs, GABAARs reciprocally regulate the production of stress hormones. The stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis, the activity of which is governed by corticotropin releasing hormone (CRH) neurons. The activity of CRH neurons is largely controlled by robust GABAergic inhibition. Recently, it has been demonstrated that CRH neurons are regulated by neurosteroid-sensitive, GABAAR δ subunit-containing receptors representing a novel feedback mechanism onto the HPA axis. Further, it has been demonstrated that neurosteroidogenesis and neurosteroid actions on GABAAR δ subunit-containing receptors on CRH neurons are necessary to mount the physiological response to stress. Here we review the literature describing the effects of steroid hormones on GABAARs as well as the importance of GABAARs in regulating the production of steroid hormones. This review incorporates what we currently know about changes in GABAARs following stress and the role in HPA axis regulation.

 

GABAARs are regulated by stress-derived steroid hormones and neurosteroids [for review see Belelli et al. (2009); Maguire and Mody (2009); Gunn et al. (2011)]. Conversely, the HPA axis, and thus the production of stress-derived steroid hormones and neurosteroids, is under robust GABAergic control [for review see Herman et al. (2004); Gunn et al. (2011)].

 

End quote

[[cs...]]

Hello, everyone.

 

dm, I'll look see what is available for the 3-nitrotyrosine test in my area.

 

Many more pieces to consider.  I wish I had your knowledge as I know that as much as I research I am sure I am missing a lot along the way that could be helpful in 'focusing the picture'. 

 

All the best.

 

-RST

 

Great RST.  This will be very very interesting.  Please note the therapeutics I noted above , as well as additonal ones in the Pall Townsend article link above.

 

 

The TRP channels relative to neuropathic pain is something I still need to research, but from a quick search it looks like there is a link.

 

Also, the Townsend link above has a full diagram of the Pall NO/ONOO- cycle.  You can save the image and print it out.  MABs link to the full pdf of the hypothesis also has the Pall diagram.

 

I also posted a Pall 2 hour video above, the first 30 minutes getting into the various loop dynamics in the cycle.  Pall is a PhD. 

[[li...]]

Thanks, I get it now.

 

I get the feeling that I'm *****. If only I had done a CT five years ago. Doctors will kill you if nothing else will.

[[Re...]]

Hello, everyone.

 

dm, I'll look see what is available for the 3-nitrotyrosine test in my area.

 

Many more pieces to consider.  I wish I had your knowledge as I know that as much as I research I am sure I am missing a lot along the way that could be helpful in 'focusing the picture'. 

 

All the best.

 

-RST

 

Great RST.  This will be very very interesting.  Please note the therapeutics I noted above , as well as additonal ones in the Pall Townsend article link above.

 

 

The TRP channels relative to neuropathic pain is something I still need to research, but from a quick search it looks like there is a link.

 

Also, the Townsend link above has a full diagram of the Pall NO/ONOO- cycle.  You can save the image and print it out.  MABs link to the full pdf of the hypothesis also has the Pall diagram.

 

I also posted a Pall 2 hour video above, the first 30 minutes getting into the various loop dynamics in the cycle.  Pall is a PhD.

 

Hmmm....  So far I can only find testing in my area of the type that is considered inaccurate in the following paper:

 

https://www.ncbi.nlm.nih.gov/pubmed/19284298

 

  Quote:"Methods: Four commercially available nitrotyrosine-specific immunoassays were evaluated by parallel measurement of nitrotyrosine in 224 serum samples derived from 16 patients with type 2 diabetes and 12 healthy controls (13 male and 15 female, age: 33±11 years) following a standardized meal.

 

Results: The available ELISA tests were not applicable for nitrotyrosine determination in human plasma samples due to technical issues and implausible results. However, a competitive luminescence assay was able to provide sufficient sensitivity and lead to clinically meaningful results in our test samples.

 

Conclusions: All three ELISA methods were disqualified and conclusions previously derived from clinical experiments using these tests should be carefully reconsidered or reconfirmed. In the absence of a liquid tandem chromatography-mass spectrometry reference method, the luminescence test appears to be the method of choice for determination of nitrotyrosine in human plasma."

 

Clin Chem Lab Med 2009;47:483–8.

 

So, I'm still hunting for an accessible test in my area.  To be continued.....

 

The good news is I found a mold doctor.  She happens to be an ND and is quite knowledgeable and open to discussing all the pillars that you've presented here, dm123.  Interestingly, she was/is the only doctor who has ever asked me to forward any bit of research I have that might be relevant.

 

All the best

 

-RST

[[...]]

HI Dm123 and everyone .. I am SO behind on this thread! Another buddie reminded me to check in because of my tapering difficulties. My taper seems near impossible , less than 1% month and I still am hit with bad wds  most of the time.

 

I don;t think I have the brain to read through all the posts , but , DM , I am wondering if you might be so kind as to either direct me to a summary , and also to  the 'protocol' that you mentioned a few pages back? I would so appreciate that . I don;t want to you to have to repeat anything you have already covered though.

 

I've looked a lot at genetics and my variant genes, I have various genes/snps that likely affect how I deal with withdrawal from benzos , including SOD2 +/+ and MAO A +/+ and both COMT genes  +/+

 

I have recently started taking more hydroxy  B12 and also folinic acid . along with a lighter dose of a multi B with methyl B's. I actually think they are doing something to help.

With the SOD Gene  I believe I am more prone to oxidative stress,

 

Anyway , perhaps I diverge here , but I wonder if you would be so kind as to direct me to a summary of protocol(s)?

Oh I did read the papers on NO.....and the importance of BH4 in NO synthesis.

though I'm not altogether clear on how to support BH4

 

Much of this is over my head , so I am very much a laywoman laywoman!

 

many thanks DM for all your work here ,

 

MiYu

PS , were you saying that gabapentin could be helpful during a taper ? I'm already on it , but I have tapered it quite a bit , sometimes I take extra if the wds are particularly bad, and it does seem to help.

 

 

[[...]]

ps , my blood pressure is always very low when measured ....so does this mean no hypertension?? wondering how this fits in with it all.... I'm sorry if I've missed too much to have the right questions ... A lot of it is over my head so I guess I'm just hoping for some even more simple guidance relative to therapeutics.

I see DM  .you have posted a YouTube link with dDr Pall , I'll check that out thanks

 

 

Miyu

[[li...]]

A little experience last night. I'll skip the details.

I noticed how little has remained of what was once a muscle mass. Tiny threads. That clonazepam drug has the tendency to mask things, including suffering.

And there is some other embarassing physiological deterioration, which I'll skip here.

 

Good PDF. Aside from anything else, clonazerpam seems to induce some form of hypercortisolism/hyperglucocorticoid activity. As we all know, it's not just about daily circadian rhythm. Peak values can trigger a genetic switch, to put it simply.

Both exercise and lack thereof can do this. In theory, a perfect balance would prevent this.

But the damage has been done.

 

I'm by no means fine. I wasn't quite all right prior to the lorazepam, but everything went to hell after that. It could have been prevented if I had not let that GP discourage me that much.

 

Getting off the drug as a deux ex machina for recovery ? I never expected to be able to use psychiatric drugs for sleep. Clonazepam is unique. Dm123, I know you've been on that drug but not at that dose. Certainly not at my highest dose of 4 mg. I never took any other benzodiazepines, except the infrequent use of hypnotics (like temazepam) for sleep.

A long time ago I expected I had to taper off the drug based on stamina. I would have been off a long time ago if my highest dose had not exceeded 2 mg. About 5 years ago I considered cold turkey, but I didn't do it. Instead, I let a GP **** me up.

 

Seriously, the drug seems to interfere with protein synthesis on a practical level (one could venture that my mild hyperalbuminia has something to do with that, although sources suggest the cause would be dehydration but I drink 3 litres a day). From past experience I know that tapering causes loss of muscle mass while tapering, and being off the drug would not have magical recovery properties.

 

That motor cortex thingy. Things like complete muscle wasting (?) make everything much worse. And as this was more or less part of an exchange of PMs, mentally I was very resilient, physically much less so. I just managed to avoid emergencies that would have put me in the hospital.

 

I have a hard time seeing how diazepam would cover for this. I was more or less OK on diazepam for about 8 days early 2016, I lasted only 2.5 days early 2017. Librium is even weaker, I don´t even know the ´washout´ period of that drug. Diazepam about 2 months max. Probably not that different.

 

All very much physical, just not a 'disease by the book'. Local healthcare is ****. Fry my neurons by a CT, not to mention other aspects of my health ? I so much wish I had done a CT rather than switch to that GP.

[[...]]

Just to update- I listened to the YouTube presentation by Dr Martin Pall - very good , and very clarifying on this NO/ONOO thing .

I like his summary of supplemental protocols at the end , what to use , why and how .

I'm adding vitamin C to my regimen along with a little more Methyl folate today to see how I do .

 

With the genetic polymorphisms I have , it seems obvious that my body would need some hope with anti oxidizing . The especially with very little activity of the SOD enzyme

 

Thanks for everything. DM .

I will update if I feel improvements. I've already been taking ALCAR for a while , it's always felt really good for me , I see he has a caviat for it though which I have to revisit .

 

Hang in there everyone , make the most of today in whatever way you can ,

MiYu

[[cs...]]

Hello, everyone.

 

dm, I'll look see what is available for the 3-nitrotyrosine test in my area.

 

Many more pieces to consider.  I wish I had your knowledge as I know that as much as I research I am sure I am missing a lot along the way that could be helpful in 'focusing the picture'. 

 

All the best.

 

-RST

 

Great RST.  This will be very very interesting.  Please note the therapeutics I noted above , as well as additonal ones in the Pall Townsend article link above.

 

 

The TRP channels relative to neuropathic pain is something I still need to research, but from a quick search it looks like there is a link.

 

Also, the Townsend link above has a full diagram of the Pall NO/ONOO- cycle.  You can save the image and print it out.  MABs link to the full pdf of the hypothesis also has the Pall diagram.

 

I also posted a Pall 2 hour video above, the first 30 minutes getting into the various loop dynamics in the cycle.  Pall is a PhD.

 

Hmmm....  So far I can only find testing in my area of the type that is considered inaccurate in the following paper:

 

https://www.ncbi.nlm.nih.gov/pubmed/19284298

 

  Quote:"Methods: Four commercially available nitrotyrosine-specific immunoassays were evaluated by parallel measurement of nitrotyrosine in 224 serum samples derived from 16 patients with type 2 diabetes and 12 healthy controls (13 male and 15 female, age: 33±11 years) following a standardized meal.

 

Results: The available ELISA tests were not applicable for nitrotyrosine determination in human plasma samples due to technical issues and implausible results. However, a competitive luminescence assay was able to provide sufficient sensitivity and lead to clinically meaningful results in our test samples.

 

Conclusions: All three ELISA methods were disqualified and conclusions previously derived from clinical experiments using these tests should be carefully reconsidered or reconfirmed. In the absence of a liquid tandem chromatography-mass spectrometry reference method, the luminescence test appears to be the method of choice for determination of nitrotyrosine in human plasma."

 

Clin Chem Lab Med 2009;47:483–8.

 

So, I'm still hunting for an accessible test in my area.  To be continued.....

 

The good news is I found a mold doctor.  She happens to be an ND and is quite knowledgeable and open to discussing all the pillars that you've presented here, dm123.  Interestingly, she was/is the only doctor who has ever asked me to forward any bit of research I have that might be relevant.

 

All the best

 

-RST

 

Hi RST,

 

Yes, my main concern was the reliability of the test.  I’m sure the CFS forums know what tests are the most accurate for testing ONOO- overload.

 

Regarding the mold ND, that’s great.  Hopefully she can start you on some cholestyramine to start binding out the recirculating mold.

 

I hope your office and home have been remediated.  That’s the most critical thing right now. 

 

 

Please also mention Shoemakers protocol to her.  I’m sure she knows all about it already.

Survivingmold.com

 

Page 40 has pillars 1-3,and I’ve described how pillar 4 (NO and NOSs) ties into the model in several posts above.  Pillar 5 will be GPCRs.

 

Components that the pillars act on are listed on page 40

 

A fourth component system called “Cellular integrity and cellular homeostasis “ will be added to the model.  This component system is disturbed when benzdiazaphines throw off the NO/NOSs pillar and the glutamatergic pillar.  The output of this disregulated Cellular homeostasis is oxidative stress and mitochondrial dysfunction which feeds back into the “stress system” pillar on page 40 of this thread.

 

I hope the appt with the mold doctor goes ok.  SB mold needs to be taken care of.

[[cs...]]

HI Dm123 and everyone .. I am SO behind on this thread! Another buddie reminded me to check in because of my tapering difficulties. My taper seems near impossible , less than 1% month and I still am hit with bad wds  most of the time.

 

I don;t think I have the brain to read through all the posts , but , DM , I am wondering if you might be so kind as to either direct me to a summary , and also to  the 'protocol' that you mentioned a few pages back? I would so appreciate that . I don;t want to you to have to repeat anything you have already covered though.

 

I've looked a lot at genetics and my variant genes, I have various genes/snps that likely affect how I deal with withdrawal from benzos , including SOD2 +/+ and MAO A +/+ and both COMT genes  +/+

 

I have recently started taking more hydroxy  B12 and also folinic acid . along with a lighter dose of a multi B with methyl B's. I actually think they are doing something to help.

With the SOD Gene  I believe I am more prone to oxidative stress,

 

Anyway , perhaps I diverge here , but I wonder if you would be so kind as to direct me to a summary of protocol(s)?

Oh I did read the papers on NO.....and the importance of BH4 in NO synthesis.

though I'm not altogether clear on how to support BH4

 

Much of this is over my head , so I am very much a laywoman laywoman!

 

many thanks DM for all your work here ,

 

MiYu

PS , were you saying that gabapentin could be helpful during a taper ? I'm already on it , but I have tapered it quite a bit , sometimes I take extra if the wds are particularly bad, and it does seem to help.

 

Hi MiYu

 

The summary of the model is on page 40 of this thread.  (Pillars 1-3 and component systems 1-3)

 

The pillar 4 called “NO/NOSs” is added in the last few weeks of postings, and that’s acting on a 4th component system called “cellular integrity and cellular homeostasis “.  I described the tie in, into the model above to RST(post right above), and in some posts before that over the last few weeks.

 

A fifth pillar GPCRs is something I haven’t gotten to.

 

Regarding therapeutics for the NO/NOSs and disruption in the NO/ONOO-

 

The Pall video.

 

This article by Pall

http://www.townsendletter.com/FebMarch2010/cureNO0210.html

 

The MAB article on the benzdiazaphine hypothesis for PWS and NO/ONOO- cycle.(see full access link)

Table 1

 

CFS forums .  They know a lot about this.

 

Regarding BH4, I’ve read that oral BH4 peroxidizes , and it’s better to use precursors like biopterin and sepiapterin (see post to Terry page 52 of this thread)

 

It would be nice to get tested via 3-nitrotyrosine test.  RST is working in finding accurate test.  CFS forums might know which tests are good

 

Regarding methylcobalamin and methylfolate, I was on them for quite some time but stopped all of it several months back and feel better off of it.  This is probably because I don’t have ONOO-overload.  That’s why it might be a good idea to get tested.

[[cs...]]

ps , my blood pressure is always very low when measured ....so does this mean no hypertension?? wondering how this fits in with it all.... I'm sorry if I've missed too much to have the right questions ... A lot of it is over my head so I guess I'm just hoping for some even more simple guidance relative to therapeutics.

I see DM  .you have posted a YouTube link with dDr Pall , I'll check that out thanks

 

 

Miyu

 

Hi MiYu

 

I too tend to the lower side.  I posted a long post in Peroxynitrate and HBP on page 52.  I’m not sure if the low BP rules out NO/ONOO- dysfunction for you.  Typically once you get caught up in this loop Peroxynitrate rises, NO drops, superoxide rises and BH4 depletes.  The high Peroxynitrate and decreasing NO will usually tend to lead toward HBP, not low BP.    I don’t think I have NO/ONOO- dysfunction.    Also please note that the MAB article applies mostly to PWS.

 

It will be good to see if RST finds out if 3-nitrotyrosine can be accurately measured.