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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 -
Neurobiology of Stress May 2020Pyridostigmine bromide (PB) was administered to soldiers during the first Gulf War as a prophylactic treatment to protect against toxicity in the event of exposure to...
Pyridostigmine bromide (PB) was administered to soldiers during the first Gulf War as a prophylactic treatment to protect against toxicity in the event of exposure to nerve agents. Although originally thought to pose minimal risk to soldiers, epidemiological studies have since correlated PB administration with the development of a variety of symptoms, including cognitive dysfunction, termed Gulf War Illness (GWI). We previously demonstrated in a rodent model of GWI that central cholinergic responses were altered to various stimuli. In the current study we used microdialysis to examine how combinations of PB and repeated restraint stress (RRS) altered extracellular glutamate levels in response to an innate immune challenge (lipopolysaccharide; LPS) and an immobilization stress challenge in the prefrontal cortex (PFC) and hippocampus. There were four groups in this study: vehicle non-stressed control (Veh-NSC), vehicle-stressed (Veh-RRS), PB-NSC, and PB-RRS. While LPS decreased glutamate levels in PB-treated rats relative to vehicle-treated rats in the PFC, PB and stress interacted to attenuate LPS-induced decreases in hippocampal glutamate levels. Although immobilization stress increased glutamate in the PFC, glutamate levels in PB-NSC rats failed to recover in the post-stress period relative to vehicle-treated rats. In the hippocampus, PB-stressed rats failed to exhibit habituation of the glutamate response to immobilization stress relative to vehicle-stressed rats. Collectively, these results indicate that PB and stress interacted to produce brain-region specific effects on glutamate neurochemistry, providing insight into the potential mechanisms underlying interactions between the immune system and persistent cognitive dysfunction in veterans with GWI.
PubMed: 32258255
DOI: 10.1016/j.ynstr.2019.100210 -
Journal of Biochemical and Molecular... Mar 2024Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous... (Review)
Review
Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous studies have shown that an imbalance in the autonomic nervous system is closely related to the pathogenesis of NAFLD. In this study, we investigated the effects of pyridostigmine (PYR), a cholinesterase (AChE) inhibitor, on HFD-induced liver injury and explored the potential mechanisms involving mitochondrial damage and oxidative stress. A murine model of HFD-induced obesity was established using the C57BL/6 mice, and PYR (3 mg/kg/d) or placebo was administered for 20 weeks. PYR reduced the body weight and liver weight of the HFD-fed mice. Additionally, the serum levels of IL-6, TNF-α, cholesterol, and triglyceride were significantly lower in the PYR-treated versus the untreated mice, corresponding to a decrease in hepatic fibrosis, lipid accumulation, and apoptosis in the former. Furthermore, the mitochondrial morphology improved significantly in the PYR-treated group. Consistently, PYR upregulated ATP production and the mRNA level of the mitochondrial dynamic factors OPA1, Drp1 and Fis1, and the mitochondrial unfolded protein response (UPRmt) factors LONP1 and HSP60. Moreover, PYR treatment activated the Keap1/Nrf2 pathway and upregulated HO-1 and NQO-1, which mitigated oxidative injury as indicated by decreased 8-OHDG, MDA and H O levels, and increased SOD activity. Finally, PYR elevated acetylcholine (ACh) levels by inhibiting AChE, and upregulated the α7nAChR and M3AChR proteins in the HFD-fed mice. PYR alleviated obesity-induced hepatic injury in mice by mitigating mitochondrial damage and oxidative stress via α7nAChR and M3AChR.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Pyridostigmine Bromide; alpha7 Nicotinic Acetylcholine Receptor; Kelch-Like ECH-Associated Protein 1; Chemical and Drug Induced Liver Injury, Chronic; Mice, Inbred C57BL; NF-E2-Related Factor 2; Liver; Oxidative Stress; Liver Cirrhosis; Obesity; Diet; Diet, High-Fat
PubMed: 38454809
DOI: 10.1002/jbt.23671 -
Journal of Binocular Vision and Ocular... 2021: To assess the value of measuring diplopia before and after pyridostigmine intake to differentiate myasthenia gravis from sagging eye syndrome.To establish a threshold...
: To assess the value of measuring diplopia before and after pyridostigmine intake to differentiate myasthenia gravis from sagging eye syndrome.To establish a threshold for a positive response to pyridostigmine in the diagnosis of myasthenia gravis.: 15 patients with myasthenia gravis and 15 with sagging eye syndrome diplopia were evaluated. Diplopia was measured in five positions (upgaze, downgaze, right gaze, left gaze, and primary position). After baseline measurements, the patient received a single dose (60 mg) of pyridostigmine. After 60 minutes the prism measure was performed again in five positions. Horizontal deviation, vertical deviation at distance was compared before and after a single dose of pyridostigmine in each gaze. Ocular deviations were compared between the two groups to identify the threshold with the highest sensitivity and specificity.: Differences between pretest deviations and posttest deviations in any gaze were found to be statistically significant only in the MG group. The optimum threshold for a positive response to pyridostigmine was a reduction of 2 prism diopters in any component in any gaze. Sensitivity for the detection of myasthenia diplopia was 80.00% and specificity was 86.67%.: Our results suggest that measuring diplopia with prisms before and after pyridostigmine administration can help to detect patients with suspected myasthenia.
Topics: Diplopia; Eye; Humans; Myasthenia Gravis; Pyridostigmine Bromide; Sensitivity and Specificity
PubMed: 33877951
DOI: 10.1080/2576117X.2021.1904097 -
International Journal of Environmental... Nov 2020Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and...
Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts.
Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and 1991. No current single-exposure scenario accounts for all the symptoms observed in GWI, and instead may be due to a multi-exposure scenario. As a larger effort to understand how one category of multi-exposure scenarios of organic compounds such as nerve gas prophylactic pyridostigmine bromide, or insecticides/pesticides such as N,N-diethyl--toluamide (DEET) and permethrin, plus heavy metals found in inhaled dust particles (Al, Fe, Ni, Sr, DU, Co, Cu, Mn, and Zn) might play a role in neural aspects of GWI, we begin this initial study to examine the toxicity and oxidative damage markers of human brain endothelial cell and human astrocyte cell cultures in response to these compounds. A battery of cytotoxicity assessments, including the MTT assay, Neutral Red uptake, and direct microscopic observation, was used to determine a non-toxic dose of the test compounds. After testing a wide range of doses of each compound, we chose a sub-toxic dose of 10 µM for the three organic compounds and 1 µM for the nine metals of interest for co-exposure experiments on cell cultures and examined an array of oxidative stress-response markers including nitric oxide production, formation of protein carbonyls, production of thiobarbituric acid-reactive substances, and expression of proteins involved in oxidative stress and cell damage. Many markers were not significantly altered, but we report a significant increase in nitric oxide after exposure to any of the three compounds in conjunction with depleted uranium.
Topics: Astrocytes; Brain; Cells, Cultured; DEET; Endothelial Cells; Humans; Metals, Heavy; Permethrin; Persian Gulf Syndrome; Pyridostigmine Bromide; Salts
PubMed: 33187257
DOI: 10.3390/ijerph17228336 -
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 -
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 -
Medicina (Kaunas, Lithuania) Apr 2022: As the use of sugammadex for reversing neuromuscular blockade during general anesthesia increases, additional effects of sugammadex have been reported compared to...
: As the use of sugammadex for reversing neuromuscular blockade during general anesthesia increases, additional effects of sugammadex have been reported compared to cholinesterase inhibitors. Here, we compare the incidence of postoperative catheter-related bladder discomfort (CRBD) between sugammadex and pyridostigmine/glycopyrrolate treatments for reversing neuromuscular blockade. : We retrospectively analyzed patients aged ≥ 18 years who underwent surgery under general anesthesia, received sugammadex or pyridostigmine with glycopyrrolate to reverse neuromuscular blockade, and had a urinary catheter in the post-anesthesia care unit between March 2019 and February 2021. After applying the exclusion criteria, 1179 patients were included in the final analysis. The incidence and severity of CRBD were collected from post-anesthesia recovery records. : The incidence was 13.7% in the sugammadex group ( = 211) and 24.7% in the pyridostigmine group ( = 968). Following propensity score matching, 211 patients each were included in the pyridostigmine and sugammadex matched group (absolute standardized difference (ASD), 0.01-0.05). Compared to the pyridostigmine group, the odds ratio for CRBD occurring in the sugammadex group was 0.568 (95% confidential interval, 0.316-1.021, = 0.059). : Sugammadex has a similar effect on the occurrence of postoperative CRBD compared with pyridostigmine.
Topics: Glycopyrrolate; Humans; Pyridostigmine Bromide; Retrospective Studies; Sugammadex; Urinary Bladder; Urinary Catheters
PubMed: 35630007
DOI: 10.3390/medicina58050590