Acetylcholine (ACh) – Related Damage

As I continued my research, using myself as a “case study” as well as doing the literature research, I eventually came to believe that many of my problems were also ACh related.  In a way, this should be no surprise, as the FDA February 2011 FDA Black Box Warning labeling change actually states that “Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis”.  Forget the part about Myasthenia Gravis for a moment, and just focus on the part that says:  “Fluoroquinolones have neuromuscular blocking activity”.   You can’t get any clearer or to the point than that.  It’s a stated fact, published by the FDA and the pharmaceutical companies who develop these drugs.  Not to mention that some quinolones, including Cipro and Levaquin, have a piperazine derivative attached to the quinolone pharmacore.   Piperazines (anti-parasiticals which kill parasites by paralyzing them) have neuromuscular effects which are thought to be caused by blocking acetylcholine at the myoneural junction.   (Plenty of pets have been poisoned with over the counter piperazine toxicity from wormers – so no, it’s not just helminths they affect).    Among the numerous properties of Piperazine derivatives, they are not only muscarinic antagonists, but also are the basis for recreational drugs with euphoria and stimulant properties, such as amphetamines, BZP, MDMA, and TFMPP, along with all the negative side effects of these drugs (no wonder I was hallucinating during my acute reaction).   So now we have a toxic neuromuscular agent with amphetamine/ecstasy-like effects (piperazine), along with a toxic iodine displacer (fluorine), attached to a chemotherapeutic agent with an intracellular, intranuclear, and intra-mitochondrial genotoxic mechanism of action (quinolone)  – a synthetic, fluoridated, neurotoxic, genotoxic chemotherapeutic poison masquerading as an antibiotic and being given en masse to the human and animal population.  In the millions of years that human and animal life has been evolving, our cells, proteome, microbiome, genome, and mitochondria have never before been subjected to such a consistent and massive onslaught of a foreign synthetic substance given to the healthy and physically fit populations for simple or presumed infections, prophylactically as a preventative, and chronically in subtherapeutic dosages in food animals, as in the past 30-50 years. Tack on all the other synthetic pesticides, insecticides, and pharmaceuticals, and is it any wonder that inexplicable CNS, ANS, PNS, endocrine, and autoimmune-like “mystery diseases” are on the rise?

So when I went looking for potential unifying mechanisms of damage, especially in light of the symptoms I was experiencing, ACh-related toxicity and damage seemed like a reasonable place to look.  This includes Acetylcholinesterase (AChE) inhibition or damage as a potential mechanism, resulting in a syndrome similar to organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). From Wiki:   “OPIDP occurs roughly two weeks after exposure (my note:  similar to FQT), and once the symptoms begin with shooting pains in both legs, the symptoms continue to worsen for 3–6 months.  COPIND appears with a delay and is long lasting. Symptoms associated with COPIND include cognitive deficit, mood change, autonomic dysfunction, peripheral neuropathy, and extrapyramidal symptoms (extrapyramidal symptoms are drug induced movement disorders that include dystonia (continuous spasms and muscle contractions), akathisia (motor restlessness), parkinsonism (characteristic symptoms such as rigidity, bradykinesia, and tremor), and tardive dyskinesia (irregular, jerky movements). The underlying mechanisms of COPIND have not been determined, but it is hypothesized that withdrawal of OP pesticides after chronic exposure or acute exposure could be a factor.”   Many flox victim’s symptoms are delayed and start after finishing the drug, perhaps due to a mechanism similar as with OP poisonings.

As I mentioned above, the Cipro that I took also has a piperazine derivative attached to it.   Piperazine derivatives are often attached to a wide variety of pharmaceuticals.  They appear to have a wide variety of pharmaceutical uses (antifungal, antipsychotic, antimicrobial, antioxidant, antimalarial, and anti-HIV).   However, they also are used as recreational drugs with euphoriant and stimulant properties.   They also have anti-muscarinic properties, and are considered to be neuromuscular blocking agents.  Here are some of the adverse effects one can experience from taking BZP (benzylpiperazine), a common piperazine recreational drug:    From Wiki:   “The major side effects include dilated pupils, blurred vision, dryness of the mouth, extreme alertness, pruritus, confusion, agitation, tremor, extrapyramidal symptoms (dystonia, akathisia), headache, dizziness, anxiety, insomnia, vomiting, chest pain, hallucinations, paresthesia, tachycardia, hypertension, palpitations, collapse, hyperventilation, sweating, hyperthermia and problems with urine retention.   The more severe toxic effects include psychosis or adverse psychiatric events, renal toxicity, respiratory failure, hyperthermia, serotonin syndrome, rhabdomyolysis and seizure.”    Sound familiar?    The quinolone pharmacore itself appears to cause all these adverse effects and more, as evidenced by the parent compound nalidixic acid.   Now, some of the quinolones have piperazine derivatives attached to them as well.  For those of us who are floxed with these quinolones, it may be like a double whammy.

In addition, from the full paper “Thyroid Adverse Effects of Psychotropic Drugs: A Review”:    “ . . . Piperazine and Piperidine compounds are incriminated in clinical hypothyroidism in predisposed patients receiving them . . . Patients with compromised thyroid function who receive treatment with atypical antipsychotic drugs may develop hypothyroidism probably through a peripheral effect that involves a competition, with thyroid hormones, in the glucuronidation process in the liver. Cyclic tertiary amines such as piperidine and piperazines are most frequently incriminated in this process.”  So this may be yet another avenue which contributed to the demise of my thyroid gland.

I never had any indications of Myasthenia Gravis (MG) or Thyroid related problems before being floxed.  However, I believe I have major problems with both of these conditions, or closely related variants of these conditions, triggered or caused by the Ciprofloxacin I took.  One problem with the classical MG diagnosis is that the antibody tests for it are focused on the nicotinic receptors.  However, my symptoms, which appeared to be classic for FQT in general, very strongly mirrored and appeared to be muscarinic in nature, and only minimally nicotinic – at least, initially (at this point in time, Year 5 post, I strongly feel like I am developing more classic symptoms of MG).  Although there is a lot of active research in this area, to my knowledge, there are no standardized clinically available antibody tests for muscarinic receptors or any other testing for “muscarinic symptoms”.  So there is no standardized, objective, accepted way to be diagnosed for this yet (this has changed; see Update for Testing below).  Additionally, I suspect non-neuronal ACh issues may be contributing to my systemic symptoms even more than neuronal ACh, and there is even less knowledge about this system than the traditional neuronal ACh system.

As an aside, another traditional diagnosis that matches my overall symptoms quite well is Sjogren’s Syndrome, and if I were to get an “umbrella diagnosis” by the traditional medical community, it would probably be this.  I’ve antibody tested every six months for this particular diagnosis and remain seronegative.  This doesn’t mean I don’t have Sjogrens, or that I won’t develop the antibodies in the future.  But in my mind, I question whether Sjogren’s is truly a completely separate disease process from AITD/MG, or if it might actually be an unrecognized variant of one of these, AITD in particular.  For this reason, I’ve resisted the diagnosis of “Sjogren’s Syndrome” even though my symptoms certainly fit.  Many of the Sjogren’s symptoms are also very muscarinic in nature, and there is active research going on in this area for this disease.

As of this writing, the traditional classical medical diagnoses that match my overall symptoms most closely include Autoimmune Thyroid Disease (AITD), in the form of Hashimoto’s Thyroiditis, and Myasthenia Gravis, in the form of Ocular progressing to Generalized and/or MuSK MG/LEMS.  I also believe Hashi’s Encephalopathy, as a part of the Hashi’s syndrome, is a very high probability.  I am positive for the TPO, Tg, TSI, and TrAB antibodies in AITD, and am borderline positive for the AChR modulating antibodies in MG.   As a matter of interest and curiosity, there are a whole host of antibodies I would like to test, but am unable to order these tests on my own and have been unsuccessful in my attempts so far.  In particular, I really wanted to test for the MuSK/LEMS/Anti-Ganglionic, but unfortunately, haven’t been able to yet.  (Update:  I tested negative for MuSK and LEMS).  It’s unknown whether FQT reactions are autoimmune in nature at all, but the only way to find out is to start looking.  For this reason, I recommend testing for as many autoantibodies as possible for flox victims.  Another test I haven’t been able to do yet but shouldn’t be too hard to get is an RBC Cholinesterase test.  According to the 23andMe test, I don’t have the genetic mutations for this enzyme, and prior to being floxed I handled anesthesia well, but I would be interested in testing the enzyme level itself, which if reduced, might indicate non-genomic damage has occurred.  (Update:  I tested within normal limits for this).

I could control and objectively measure response to a large extent when it came to the TH/Iodine related problems.  But I had no such ability when it came to the ACh related problems, other than clinically available diagnostic testing for currently known antibody markers, or testing a few ACh-related supplements on myself.  I think the ACh related issues are substantial in me.  But there was little to nothing I could do to effect change in that area, other than try some supplements and hope for the best.  As such, as I’ve stated earlier, this is why I placed my focus, and much of my hope for resolution or recovery, on “thyroid related” issues as being a major player in my problems.

Still, there were many reasons I felt that many of my problems could be ACh related, and here are some of them.  As I’ve already stated, I felt that many of my symptoms and acute flox reaction could be described as “cholinergic/anti-cholinergic” in nature, and/or MG-related.   Drug label warnings specifically state the Fluoroquinolones have neuromuscular blocking activity, so pharma is giving us a big clue here.  ACh modulates a host of physiological processes in the central and peripheral nervous systems.  Centrally, ACh regulates motor function, sensory perception, cognitive processing, arousal, sleep/wake cycles, and nociception, while in the periphery it controls heart rate, gastrointestinal tract motility, and smooth muscle activity.   Non-neuronal ACh and AChE are distributed throughout the body, making ACh transmission and metabolism important for all cells in the body, not simply neurogenic cells.  Additionally, Non-neuronal ACh and AChE are found in tendons, and increased expression of both occurs in pathological tendinosis, and is thought to contribute to tendon pathology. (Forsgren/Danielson lab studying role of non-neuronal ACh in chronic tendinosis and tendon pathology  – search “non-neuronal ACh Tendons”).  In relationship to the thyroid, cholinergic interaction with the thyoid gland is extensive, and common epitopes may exist relating thyroid autoimmunity and ACh/muscarinic receptor autoimmunity.  ACh appears to be necessary for iodine organification (so this might be one underlying mechanism of action to explore for Hashi’s).  MuSK form of MG (myasthenia gravis) may be a separate condition from MG and there is a known association between “MuSK MG” and Graves disease.  Magnesium prevents or controls convulsions by blocking neuromuscular transmission and decreasing the release of acetylcholine at the nicotinic ACh motor nerve terminals (the analgesic properties of Mg are due to NMDA receptor blocking action).    In Year 5 post, as my symptoms progressed, it became apparent that Magnesium was actually exacerbating my muscle weakness, presumably by blocking neuromuscular transmission, and magnesium is something that is known to exacerbate MG symptoms (so for any flox victims for whom magnesium makes your symptoms worse, especially muscle weakness, this is something to consider).   ACh is an underlying common denominator anytime we eat; distention in the stomach or innervation by the vagus nerve activates the Enteric Nervous System, in turn leading to the release of ACh.  Once present, ACh activates G cells (produces gastrin) and parietal cells necessary for digestion.   From an FQ-Induced collagen/connective tissue damage point of view, appropriate collagen formation is also very necessary for AChE function and ACh transmission, and lack of it can result in Myasthenia Gravis like symptoms, as these COL Q studies confirm: 1, 2, 3, 4,  (and suppression of collagen prolylhydroxylation as in this FQ study here can affect COL Q; also scroll to “collagenous domains as substrates”, AChE, in this “Prolyl 4-hydroxylase” paper here).    Because of the necessary symbiotic relationship of mitochondria with their host cells (as I described here), anything that affects the host cell will often affect mitochondria as well, and this most certainly will include ACh-related problems.   However, never to be left out of an opportunity for direct damage, it turns out mitochondria also express a number of nicotinic acetylcholine receptors too (1,2).  I won’t be surprised if muscarinic receptors will also be found in mitochondria some day as well.

Lastly, I questioned whether quinolones were inhibiting or binding to a common denominator within ACh receptors and/or AChE.  One of these common denominators included tyrosyl residues and/or phosphotyrosyl bonds.   I had started this thought process questioning whether FQ’s were acting as structural analogs of thyroid hormone (tyrosine residues), thyroglobulin, or other TH-related substances, because I felt that some kind of “tyrosine metabolism problem” had developed post floxing in me.   This also included questioning if antibodies or autoimmunity was developing against substances with tyrosine or tyrosyl residues.  The FQ antibiotics bind to bacterial gyrase (topoisomerase) enzyme located close to a catalytic tyrosine in a binding pocket utilizing Mg++, and the topoisomerase enzyme binds to DNA with a phosphotyrosyl bond.   Both nicotinic (nAChR) and all five muscarinic (mAChR) receptors exhibit a highly conserved orthosteric binding site in which tyrosine residues appear to be necessary for functionality, AChE exhibits an aromatic “gorge” highly conserved across different species in which tyrosine is necessary for functionality, and BQCA, an experimental quinolone, is a potent highly selective M1 (muscarinic receptor M1)  which binds to an allosteric site via Tyrosine and Tryptophan residues in vitro (this is an example of another quinolone requiring tyrosine, but binding to a receptor instead of an enzyme, and that receptor is  a  muscarinic one with neuropsych ramifications).   Although I focused more on tyrosyl residues, I also would question Tryptophan residues as being an important common denominator.  FQ’s resemble Tryptophan residues structurally, and I question whether tryptophan metabolism pathways are also affected as a result.  Tryptophan residues appear to be as important, or possibly more so, than tyrosine when it comes to the functionality of the aromatic binding site pockets of nicotinic, muscarinic, and AChE receptors.

Only non-biased studies will be able to determine if and how damage to nicotinic and muscarinic receptors, or any other structural or enzymatic activities associated with the normal production, storage, transmission, and metabolism of ACh, either directly or via autoimmunity, may be occurring with FQ’s.  I strongly suspect there is a connection though.  Whether such studies will ever be done – or published – remains to be seen.

 

References NMDA GABA ACh    References for FQ-Induced Neurological Symptoms, implicating NMDA/GABA receptors and MG/ACh mechanisms.

Update: June 2015:   I discuss ACh in this section as well.

Update:  September 2015:  Scroll to:  Acetylcholine-Related Updates:    Hup A (AChEi), Potatoes, Chocolate, Caffeine (AChEi), and Nicotine (ACh agonist)

Butyrylcholinesterase:   I did not discuss BChE, but I would put this cholinesterase enzyme on the list as well.

Muscle autoantibodies in myasthenia gravis- beyond diagnosis?     A good paper describing current clinical testing which exists for typical as well as less well known subsets of Myasthenia Gravis.   Given the FDA February 2011 FDA Black Box Warning labeling change which actually states that “Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis”, I think every FQ victim with severe muscle weakness should be tested for these, in particular, the lesser known  subsets.

Ganglionic Acetylcholine Receptor Antibodies:    Increasingly found in Acute Autonomic Neuropathies, if only physicians would test for them.   Note the similarities in symptoms of “Pandysautonomia” and “Autoimmune Autonomic Neuropathy Associated with Ganglionic AChR Antibodies” to FQT/FQAD.

Higher dementia risk linked to more use of common drugs and Common over-the-counter drugs can hurt your brain:    More and more, common drugs with anticholinergic effects are proving to be potentially damaging:    “The study used more rigorous methods, longer follow-up (more than seven years), and better assessment of medication use via pharmacy records (including substantial nonprescription use) to confirm this previously reported link.   It is the first study to show a dose response:   linking more risk for developing dementia to higher use of anticholinergic medications.   And it is also the first to suggest that dementia risk linked to anticholinergic medications may persist—and may not be reversible even years after people stop taking these drugs.”    And “A 2013 study found that drugs with a strong anticholinergic effect cause cognitive problems when taken continuously for as few as 60 days.   Drugs with a weaker effect could cause impairment within 90 days.”   Should FQ’s be on the list?

Antibodies as ‘messengers’ in the nervous system.   “Antibodies are able to activate human nerve cells within milliseconds and hence modify their function — that is the surprising conclusion of a study carried out at Human Biology at the Technical University of Munich (TUM).   Antibody mimics neurotransmitters acetylcholine and adenosine triphosphate:   What was striking about this finding was the fact that the antibody does not achieve this effect binding to its genuine target protein. “Interestingly, the nerve-activating effect is transmitted via receptors for neurotransmitters,” said Professor Schemann. “These receptors are usually activated by acetylcholine and adenosine triphosphate.”  In a nutshell, the antibody more or less mimics the effects of the neurotransmitters acetylcholine and adenosine triphosphate.”

Update on Testing:  Tests for four alpha/beta adrenergic and all five muscarinic receptor antibodies are now available.  For a discussion on how to get tested, see here.  Included in the discussion is the lab that will run the tests, here, and the research supporting these tests, here.

 

 

 

 

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