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Neurobiology of Disease Jan 2020Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need... (Review)
Review
Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.
Topics: Animals; Behavior, Animal; Brain; Disease Models, Animal; Inflammation; Isoflurophate; Male; Neurotoxicity Syndromes; Organophosphate Poisoning; Oxidative Stress; Rats; Rats, Sprague-Dawley; Status Epilepticus
PubMed: 30905768
DOI: 10.1016/j.nbd.2019.03.019 -
Arquivos de Neuro-psiquiatria Mar 2020Currently, pyridostigmine bromide is an indispensable anticholinesterase agent used worldwide to treat patients with Myasthenia Gravis (MG). However, pyridostigmine... (Review)
Review
Currently, pyridostigmine bromide is an indispensable anticholinesterase agent used worldwide to treat patients with Myasthenia Gravis (MG). However, pyridostigmine bromide was unsuccessful in its "pioneering trials" to treat a series of MG patients. There are important historical landmarks before pyridostigmine bromide becomes useful, safe and indispensable for MG therapy. After 70 years of these "pioneering trials", this article reviews some historical aspects related to them, as well as other preliminary trials using pyridostigmine bromide as therapy for MG patients.
Topics: Cholinesterase Inhibitors; Humans; Myasthenia Gravis; Pyridostigmine Bromide
PubMed: 32215460
DOI: 10.1590/0004-282X20190189 -
PloS One 2023Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial... (Observational Study)
Observational Study
Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.
Topics: Humans; Adenosine Triphosphate; Biological Warfare Agents; DNA, Mitochondrial; Energy Metabolism; Gulf War; Leukocytes, Mononuclear; Persian Gulf Syndrome; Pesticides; Pyridostigmine Bromide; Veterans; Case-Control Studies
PubMed: 37910447
DOI: 10.1371/journal.pone.0287412 -
Neuropharmacology Nov 2020Gulf War Illness (GWI) is a chronic multisymptom illness that includes gastrointestinal disorders. Although the exact etiology of GWI is unknown, exposure to the drug...
Pyridostigmine bromide exposure creates chronic, underlying neuroimmune disruption in the gastrointestinal tract and brain that alters responses to palmitoylethanolamide in a mouse model of Gulf War Illness.
Gulf War Illness (GWI) is a chronic multisymptom illness that includes gastrointestinal disorders. Although the exact etiology of GWI is unknown, exposure to the drug pyridostigmine bromide (PB) is considered a major factor. Exposure to PB drives enteric neuroinflammation, promotes immunosuppression, and alters physiological functions of the colon in the short term but whether exposure to PB is sufficient to promote long term dysfunction is not known. Here, we tested whether exposure to PB is sufficient to drive long term changes that reflect GWI, and whether the endogenous anti-inflammatory mediator palmitoylethanolamide (PEA) is sufficient to reduce the detrimental effects of PB in the gut and brain of mice. Exposure to PB alone was not sufficient to cause major changes in neuromuscular transmission but did drive major changes by altering the effects of PEA. Calcium imaging data show that the mechanisms responsible include a shift in receptor signaling mediated by TRPV1, endocannabinoids, and peroxisome proliferator-activated receptors alpha (PPARα). Additional mechanisms include the development of glial reactivity and changes in enteric neurochemical coding and survival. PB and PEA caused major shifts in pro-inflammatory cytokines/chemokines in the brain and colon that persisted up to 5 months following exposure. Many of the effects of PB and PEA exhibit significant sex differences. Together, these results highlight novel mechanisms whereby PB promotes long-lasting changes in nervous system and immune function by inducing occult neuroplasticity that is revealed by subsequent exposure to unrelated drugs in a sex dependent manner.
Topics: Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Cholinesterase Inhibitors; Chronic Disease; Disease Models, Animal; Ethanolamines; Female; Gastrointestinal Tract; Male; Mice; Mice, Inbred C57BL; Neuroimmunomodulation; Palmitic Acids; Persian Gulf Syndrome; Pyridostigmine Bromide
PubMed: 32758565
DOI: 10.1016/j.neuropharm.2020.108264 -
Molecules (Basel, Switzerland) Mar 2020Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme...
AIMS
Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome.
METHODS
Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure.
RESULTS
Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens.
CONCLUSIONS
Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.
Topics: Animals; Cholinesterase Inhibitors; Cholinesterase Reactivators; Male; Organophosphates; Oximes; Paraoxon; Physostigmine; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Proportional Hazards Models; Pyridostigmine Bromide; Ranitidine; Rats; Rats, Wistar; Survival Analysis; Tacrine
PubMed: 32230733
DOI: 10.3390/molecules25071521 -
Journal of Biochemical and Molecular... Dec 2021Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three...
Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three factors, which include: fatigue, mood-cognition problems, and musculoskeletal disorders. The cluster of long-term symptoms is unique to military personnel from coalition countries including United States, Australia, and the United Kingdom that served in Operation Desert Storm from 1990 to 1991. Reporting of these symptoms is much lower among soldiers deployed in other parts of the world like Bosnia during the same time period. The exact cause of GWI is unknown, but combined exposure to N,N-diethyl-m-toluamide (DEET), organophosphates like chlorpyrifos (CPF), and pyridostigmine bromide (PB), has been hypothesized as a potential mechanism. Mitochondrial dysfunction is known to occur in most neurodegenerative diseases that share symptoms with GWI and has therefore been implicated in GWI. Although exposure to these and other toxicants continues to be investigated as potential causes of GWI, their combined impact on mitochondrial physiology remains unknown. In this study, the effects of combined GWI toxicant exposure on mitochondrial function were determined in a commonly used and readily available immortalized cell line (N2a), whose higher rate of oxygen consumption resembles that of highly metabolic neurons in vivo. We report that combined exposure containing pesticide CPF 71 μM, insect repellants DEET 78 μM, and antitoxins PB 19 μM, causes profound mitochondrial dysfunction after a 4-h incubation resulting in decreased mitochondrial respiratory states in the absence of proapoptotic signaling, proton leak, or significant increase in reactive oxygen species production.
Topics: Adenosine Triphosphate; Animals; Apoptosis; Cell Line, Tumor; Chlorpyrifos; DEET; Humans; Mice; Mitochondria; Neuroblastoma; Oxygen Consumption; Persian Gulf Syndrome; Protein Kinases; Pyridostigmine Bromide; Signal Transduction; War Exposure
PubMed: 34528356
DOI: 10.1002/jbt.22913 -
BMJ Case Reports Mar 2021A 67-year-old man presented with progressive diplopia. On evaluation, he was noted to have bilateral palsies of cranial nerves III, IV and VI as well as a unilateral...
A 67-year-old man presented with progressive diplopia. On evaluation, he was noted to have bilateral palsies of cranial nerves III, IV and VI as well as a unilateral right true vocal fold paralysis. CT and MRI studies demonstrated a T2-bright left ethmoid mass with no evidence of bony erosion. Direct visualisation demonstrated a polypoid appearing mass of the left sphenoethmoid recess. Operative biopsy was pursued with final pathology demonstrating benign seromucinous hamartoma. Subsequent blood work demonstrated high titres of anti-acetylcholine receptor antibodies consistent with myasthenia gravis. The patient was started on pyridostigmine with improvement in his ocular cranial neuropathies.
Topics: Aged; Cranial Nerve Diseases; Diplopia; Hamartoma; Humans; Male; Myasthenia Gravis; Pyridostigmine Bromide
PubMed: 33722916
DOI: 10.1136/bcr-2020-240460 -
Current Journal of Neurology Apr 2022Swallowing is one of the most complex functions of the central nervous system (CNS), which is controlled by different parts of the brain. Oropharyngeal dysphagia (OD)...
Swallowing is one of the most complex functions of the central nervous system (CNS), which is controlled by different parts of the brain. Oropharyngeal dysphagia (OD) is one of the most common complications after stroke. Despite a variety of behavioral, compensatory, and rehabilitative methods, many stroke patients still suffer from swallowing disorders that adversely affect their quality of life (QOL). The aim of this study was to evaluate the effect of pyridostigmine on patients with post-stroke dysphagia. A randomized, double-blind, placebo-controlled clinical trial was carried out on 40 patients suffering from post-stroke dysphagia. Patients were assigned randomly into two groups: intervention and control groups (20 in each group). The intervention group was treated with pyridostigmine (60 mg, three times a day, 30 minutes before each meal for three weeks), and the control group received placebo treatment in the same way. All patients (intervention and control) were evaluated according to National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Functional Communication Measures (FCM)American Speech-Language-Hearing Association (ASHA) criteria at baseline and after three weeks of intervention. Values of P < 0.05 were considered statistically significant. In the intervention group, the mean values of NIHSS, mRS, and ASHA/FCM were significantly reduced following three weeks of treatment with pyridostigmine (P = 0.002, P = 0.003, and P < 0.001, respectively), but no significant differences were found in the mean NIHSS, mRS, and ASHA/FCM in the placebo group. Although pyridogestamine is somewhat effective in post-stroke dysphagia, it has not been shown to be more important in preventing aspiration pneumonia and length of hospital stay.
PubMed: 38011458
DOI: 10.18502/cjn.v21i2.10493 -
Scientific Reports Feb 2019Inflammatory processes and cardiovascular autonomic imbalance are very relevant characteristic of the enormous dynamic process that is a myocardial infarction (MI). In...
UNLABELLED
Inflammatory processes and cardiovascular autonomic imbalance are very relevant characteristic of the enormous dynamic process that is a myocardial infarction (MI). In this sense, some studies are investigating pharmacological therapies using acetylcholinesterase inhibitors, such as pyridostigmine bromide (PYR), aiming to increase parasympathetic tone after MI. Here we hypothesized that the use of PYR before the MI might bring an additional positive effect to the autonomic function, and consequently, in the inflammatory response and cardiac function. The present study aimed to evaluate left ventricular function, baroreflex sensitivity, autonomic modulation, and inflammatory profile in PYR-treated rats previously to MI.
METHODS
Male Wistar rats (250-300 g) were treated for 60 days with PYR. After treatment, they were submitted to the MI. After the MI, the autonomic and ventricular function were evaluated, as well as the systemic, left ventricle, and adipose tissue inflammatory profile.
RESULTS
PYR, performed before MI, prevented HR increase, systolic function impairment, baroreflex sensitivity drop, as well as pulse interval variance, RMSSD, blood pressure and parasympathetic modulation reduction in treated rats compared to untreated rats. Also, this positive functional changes may have been a result of the reduced inflammatory parameters in the left ventricle (IFN-γ, IL-6, and IL-1β), as well as increased IL-10 expression and IL-10/TNF-α ratio in treated animals before MI.
CONCLUSION
Prior treatment with PYR prevents impairment of the autonomic nervous system after MI, which may be associated with the attenuated expression of inflammatory factors and heart dysfunction.
Topics: Animals; Autonomic Nervous System; Blood Pressure; Cholinesterase Inhibitors; Disease Models, Animal; Gene Expression Regulation; Interferon-gamma; Interleukin-10; Interleukin-1beta; Interleukin-6; Male; Myocardial Infarction; Pyridostigmine Bromide; Rats; Rats, Wistar; Ventricular Function, Left
PubMed: 30792425
DOI: 10.1038/s41598-019-38841-y -
Journal of Environment and Health... 2017Several studies have implicated immune system disruption in the pathophysiology of GWI. In addition, alterations in brain structure and functioning have been associated...
Several studies have implicated immune system disruption in the pathophysiology of GWI. In addition, alterations in brain structure and functioning have been associated with specific exposures in theater, including pyridostigmine bromide and nerve gas agents. Recent studies conducted up to 25 years after the 1991 conflict have examined factors associated with the continuation or worsening of GWI. Drawing upon published studies of neural and immune system abnormalities in veterans with GWI, this paper proposes a model of GWI that takes into account neurologic and immunologic pathways, neuroimmune mechanisms of disease pathophysiology, individual predisposition due to sex and genetic background, and comorbid factors including neurological conditions such as neuritis/neuralgia and epilepsy that may occur along a continuum with GWI. The proposed neuroimmune model of GWI is likely to be useful for designing new research studies, clarifying factors involved in the continuation or worsening of GWI, and identifying biomarker screening algorithms for the illness. The proposed model goes beyond previously proposed frameworks for GWI by taking into account potential differences in risk based upon female male sex, time elapsed since exposure to neurotoxicants, duration and severity of illness, comorbid conditions, and genotype.
PubMed: 29862319
DOI: 10.15436/2378-6841.17.1665