"Pyridostigmine (MESTINON) can initiate a prolonged neurodegeneration"

pattismith

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Muscarinic receptor-mediated pyridostigmine-induced neuronal apoptosis.
Li L1, Gunasekar PG, Borowitz JL, Isom GE.
2000
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333, USA.

Abstract
Pyridostigmine is a reversible cholinesterase (ChE) inhibitor that is associated with neurologic dysfunction involving both central and peripheral nervous systems.

To determine the neurotoxic potential of pyridostigmine, rats were sacrificed at intervals after drug administration (0.5-1.85 mg/kg, i.p., twice daily for 4 days) and brains examined histologically. ChE inhibition was used as a biomarker of pyridostigmine activity. Using the in situ terminal deoxynucleotidyl transferase nick-end labeling of DNA fragments (TUNEL) method and electron microscopy, apoptotic brain cell death was noted in cerebral cortex over a dose range of 0.5-1.85 mg/kg and at the higher dose (1.85 mg/kg), apoptosis was also noted in striatum and hippocampus.

These responses were blocked by pretreatment with atropine. Rat cortical cells in culture also underwent apoptosis when exposed to pyridostigmine (250 microM for 24 hr), indicating that the pyridostigmine can initiate apoptosis, independent of peripheral mechanisms.

Pretreatment of cells with atropine (10 microM) inhibited pyridostigmine-induced apoptosis, confirming the response was mediated by muscarinic receptors.

Short term treatment of rats with pyridostigmine (1.85 mg/kg twice daily for 4 days) induced a prolonged apoptotic response, which was evident in rat cortex up to 30 days after the last dose.
Active apoptosis persisted, despite recovery of serum ChE activity.

These in vivo and in vitro observations indicate that pyridostigmine can initiate a prolonged neurodegeneration.
 

pattismith

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Acetylcholinesterase inhibitors and Gulf War illnesses.
Golomb BA1.
2008
1Department of Medicine, University of California, San Diego, CA 92093-0995, USA. bgolomb@ucsd.edu

Abstract
Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents.

Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose-response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis.
Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV.
 

pattismith

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Wow that first study didn’t even use high doses at all! I take twice what they used as high dose 2 times daily (30mg x2 a day).

Good to know but concerning to say the least.
the study is done with rat, so we have no idea about the toxicity for human, but Gulf war illness was suspected to be associated to pyridostigmine and other cholinesterase inhibitors, so I guess we should be aware of a potential toxicity.
I was myself exposed to organophosphate pesticides during some years just before a worsening of my condition.
 

Sushi

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the study is done with rat, so we have no idea about the toxicity for human, but Gulf war illness was suspected to be associated to pyridostigmine
This is alarming! I wonder if Dr. Systrom has commented. I recently started taking this and, for me, it stopped my very frequent migraines—which was unexpected. Anyone have an inkling why?

We need to know more.
 

ryan31337

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I may be biased because I am finding some improvement from taking Pyridostigmine....but its worth keeping in mind that Pyridostigmine has been around for 70 years and is used extensively for other conditions. Not suggesting it cannot cause problems (just like with any other medicine), but I wouldn't be too alarmed at this stage.
 

SlamDancin

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This is alarming! I wonder if Dr. Systrom has commented. I recently started taking this and, for me, it stopped my very frequent migraines—which was unexpected. Anyone have an inkling why?

We need to know more.
When I started researching it after Systrom’s talk at Stanford(?) I found it was a fascinating drug with several potential methods of action. Excuse me for not linking to papers right now because I’m malaised but not only does it inhibit AChE, it activates the alpha7 nicotinic receptor which is strongly anti inflammatory and I think that applies to neuroinflammatory markers, it activates the parasympathetic nervous system through the vagus nerve and it activates M3 muscarinic receptor in the heart which activates AMPK pathway. Lots of us, me included, have (auto)immunity at M3, And I still think Dr Schienbogen (sp?) thinks these antibodies are agonistic meaning in my mind that our body is desperately activating those receptors for a reason and a drug can do this may help.
 

Gingergrrl

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I had respiratory depression from 1/8th of a Mestinon pill in 2014 and was curious if that would relate to these new studies in any way? In theory, I should have been a responder to Mestinon based on my autoantibodies. Although at the time that I tried Mestinon in 2014, I was trying it for POTS, and I didn't even learn that I had any of these autoantibodies until 2016.
 

SlamDancin

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I had respiratory depression from 1/8th of a Mestinon pill in 2014 and was curious if that would relate to these new studies in any way? In theory, I should have been a responder to Mestinon based on my autoantibodies. Although at the time that I tried Mestinon in 2014, I was trying it for POTS, and I didn't even learn that I had any of these autoantibodies until 2016.
Yup I think I have a possible explanation. I was meantioning muscarinic receptors before and M3 does this according to Wikipedia. Let me know if this sounds to you like a possibility.

The M3 muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. Because the M3 receptor is Gq-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during bronchoconstrictionand bladder voiding.[21] However, with respect to vasculature, activation of M3on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M3 mediates vasconstriction in pathologies wherein the vascular endothelium is disrupted.[22] The M3receptors are also located in many glands, which help to stimulate secretion in, for example, the salivary glands, as well as other glands of the body.
Like the M
1 muscarinic receptor, M3receptors are G proteins of class Gq that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.[4]
Complicated paradoxical effects happening could have produced a *possible* freak event. I only say that because it seems to help me as long as I get the dosage right. Still working with that. Always before bed because muscarinic receptors are necessary for REM sleep. Dr Moreau from Ron Davis’ click presented data that a twin with CFS had significantly less REM sleep than the healthy twin the night after some kind of challenge I can’t remember exactly which kind.

It doesn’t surprise me that something that yet another thing we don’t do correctly apparently is linked to these same muscarinic receptors. We haven’t heard the last of them that’s for sure.